In February 2013, Glaxosmithkline (GSK) Announced a Commitment To

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure:  Information will be excluded in order to protect the privacy of patients and all named persons associated with the study  Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.  Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040

The GlaxoSmithKline group of companies

A twenty-four week, randomised, double-dummy, double-blind, parallel group study to compare the occurrence of exacerbations between SERETIDE DISKUS 50/250µg 1 inhalation bd and formoterol/budesonide Breath-Actuated Dry Powder Inhaler 4.5/160µg 2 inhalations bd in subjects with moderate to severe asthma.

Clinical Study Report for Study SAM40040 (Development Phase IV)

Document Number: GM2004/00056/00

Compound Number: CCI18781/ GR33343

Investigational Product: SERETIDE

Generic Drug Name: salmeterol/fluticasone propionate combination

Indication Studied: Asthma

Initiation Date: 26 Nov 2001

Completion Date: 13 Jan 2003

Early Termination Date: N/A

Date of Report: August 2004

Sponsor Signatory: (and Medical Officer) Vice President European Clinical Respiratory Medicines Development Centre

This study was performed in compliance with Good Clinical Practices including the archiving of essential documents.

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Synopsis

Document Number: GM2004/00056/00 Study Number: SAM40040

Investigator(s): Multicentre study. Principal Investigator: Professor

Study center(s): Subjects were recruited in 178 centres in 18 countries (193 centres received study drug)

Publication(s): None at the time of this report

Study period: 26 Nov 2001 – 13 Jan 2003 Phase of Development: IV

Objectives: The primary objective of this study was to compare the efficacy of SERETIDE™ DISKUS™ (SFC) and formoterol/budesonide combination BADPI (FBC) in preventing the occurrence of asthma exacerbations in moderate to severe asthma. Secondary objectives compared the two treatments with respect to: severity and number of exacerbations, time to first exacerbation, lung function, asthma symptoms, need for relief medication and level of asthma control.

Methodology: This was a multi-national, multi-centre, double-blind, double-dummy, parallel group, randomised, 24 week study. Following a two week run-in period, subjects were randomised to either SFC 50/250µg 1 inhalation bd or FBC BADPI 4.5/160µg 2 inhalations bd for 24 weeks. Randomisation was 1:1 for the two treatment groups. Subjects attended study visits at Weeks 4, 8, 16 and 24 of the treatment period. A post-study safety assessment was performed by telephone, approximately 7 days after the end of treatment.

Number of subjects: A total of 1769 subjects were screened for entry to the study. Of these, 1397 were randomised to treatment, 697 to SFC and 700 to FBC. The data from one centre (6 subjects) was excluded from the Intent-to-Treat (ITT) Population, due to a lack of adherence to good clinical practice (GCP), and the final ITT Population consisted of 1391 subjects. One hundred and thirty three subjects withdrew from the study after randomisation: 71 (10%) subjects from the SFC group and 62 (9%) subjects from the FBC group. The main reasons for withdrawal in both treatment groups were: lost to follow-up (SFC: 16 (2%), FBC: 13 (2%)), consent withdrawn (SFC: 11 (2%), FBC: 15 (2%)), protocol violation (SFC: 13 (2%), FBC: 12 (2%)) and adverse event (SFC: 13 (2%), FBC: 10 (1%)).

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Diagnosis and main criteria for inclusion: Male or female out patients aged 18 years or over with a documented clinical history of asthma for at least 6 months prior to screening and who were currently receiving 1000-2000µg /day BDP or equivalent, for at least 4 weeks prior to Visit 1. For entry to the treatment period, subjects were required to demonstrate a reversible increase in FEV1 of at least 12% (and ≥200mls), 15 minutes after inhaling 200-400µg of VENTOLIN™, and an asthma symptom score (day and night combined) of at least 2 (two or more episodes of symptoms during the day/night) on at least 4 of the last 7 evaluable days of the run-in period.

Treatment administration: At the end of the run-in period, subjects were randomised to receive either: SERETIDE DISKUS 50/250µg 1 inhalation bd (batch numbers: and formoterol/budesonide BADPI placebo, 2 inhalations bd (batch numbers: or SERETIDE DISKUS placebo 1 inhalation bd (batch numbers: and formoterol/budesonide BADPI 4.5/160µg, 2 inhalations bd (batch numbers:

Subjects were asked to take one inhalation from the DISKUS inhaler and two inhalations from the BADPI every morning and every evening for 24 weeks. Inhaled relief medication (VENTOLIN) and oral prednisolone, for the treatment of moderate or severe asthma exacerbations, were provided locally by the GSK operating company.

Criteria for evaluation: Primary efficacy was evaluated by number of exacerbations, expressed as a rate over the 24 week treatment period. Exacerbations were defined as mild, moderate or severe based on the following criteria: Mild: morning PEF >20% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or; more than 3 additional reliever occasions/24-hour period with respect to baseline for ≥ 2 consecutive days, or; awakening at night due to asthma for ≥ 2 consecutive nights Moderate A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7 to 10 days. This may be either a) morning PEF >30% below baseline for ≥ 2 days, b) a clinical deterioration assessed by the investigating physician as requiring oral corticosteroid treatment. Severe deterioration in asthma which required hospital admission

Secondary efficacy assessments included: severity and number of exacerbations, time to first exacerbation, lung functions assessments (PEF and FEV1), asthma symptoms, need for relief medication and level of ‘well-controlled’ asthma. Safety was assessed by the incidence of adverse events.

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Statistical methods: The total sample size was determined on the basis of anticipated differences between treatments in average asthma exacerbation rate over a twenty-four week treatment period. Based on data from the EDICT study [Ringdal, 2002] and the FACET paper [Pauwels, 1997], the average exacerbation rate for FBC BADPI is estimated to be 1 per subject per six months. In order to detect a reduction of 20% in the relative risk of exacerbations with SFC, at a two-sided α=0.05 significance level with 90% power using Poisson regression techniques, 525 subjects per group were required. The primary efficacy endpoint, rate of exacerbations over the 24 week treatment period, was analysed using a maximum likelihood based analysis, assuming the Poisson distribution, with time on treatment as an offset variable. The model included adjustments for effects of sex, country grouping and age. When the standardised deviance residuals from the Poisson model were examined they indicated that the model was a poor fit for the data and the analysis was repeated using the Negative Binomial model. Of the secondary endpoints, the number and severity of exacerbations were analysed using logistic (proportional odds) regression, and time to first exacerbation was analysed using a survival analysis (Cox’s proportional hazard model). Lung function endpoints (FEV1 and PEF), symptom scores and scores for the Asthma Control Questionnaire were analysed using analysis of covariance adjusting for baseline, country, gender, age and treatment. The proportion of subjects achieving ‘well-controlled’ asthma was assessed using a 2-sided Fisher’s Exact Test. In the protocol-defined analyses, lung function and symptom score endpoints were analysed in three intervals, weeks 1-8, weeks 9-16 and weeks 17-24. Trends were observed in the individual components (percent predicted morning PEF, short-acting beta-agonist use and night-time awakenings) that contributed to the definitions of asthma exacerbations and it was postulated that this may have had an effect on the exacerbation rate. Therefore, the primary endpoint analysis was repeated, adjusting for interval and using the Last Observation Carried Forward (LOCF) approach, to account for missing data due to subject withdrawals. In addition, moderate/severe exacerbation rates were analysed separately due to a numerical imbalance observed when exacerbation severity was first investigated. Finally, as a result of discrepancies in the number of exacerbations reported by the investigator versus protocol-defined exacerbations, further analyses were performed using only exacerbation data as strictly defined by the protocol. The purpose of this was to present a more sensitive and objective analysis of the data.

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Summary: Primary Efficacy: The mean rate of exacerbations over the 24 week treatment period as recorded by the investigators was similar in both treatment groups: 2.69 per 24 weeks in the SFC group and 2.79 per 24 weeks in the FBC group. This comparison was not statistically significantly different between treatment groups (SFC/FBC ratio 0.96, 95% CL 0.84, 1.10, p- value 0.571). Post-Hoc Analyses: Analysis of all exacerbations, adjusting for interval, gave mean annual rates of 5.87 for SFC and 6.07 for FBC; SFC/FBC ratio 0.97, 95% CL 0.84, 1.11, p=0.645. Analysis of all exacerbation rates, adjusting for interval (mean rate/year: SFC: 5.87, FBC: 6.07; SFC/FBC ratio 0.97, 95% CL 0.84, 1.11, p=0.645) showed a reduction in both treatment groups over time: 30% reduction in Weeks 9-16 (95% CI: 24% - 36%; p < 0.001) and a 36% reduction in Weeks 17-24 (95% CI: 30% - 42%; p < 0.001) compared with Weeks 1-8. There was no significant difference between the two treatment groups. Similar results were seen when the analysis was repeated using only protocol-defined exacerbations. There was no statistically significant difference between the two treatment groups in terms of the moderate/severe exacerbation rate over 24 weeks. However, when the analysis was repeated for the moderate/severe exacerbations as recorded by the investigators, adjusting for interval, SFC showed a 29% reduction in moderate/severe exacerbation rate compared with FBC and this difference approached statistical significance (95% CI: 0% – 49% reduction; p= 0.052). In the analysis of protocol-defined moderate/severe exacerbations a statistically significant treatment-by-interval interaction was found (p=0.05), indicating that the treatment difference varied between intervals. Over 24 weeks, the SFC group showed a 30% reduction in the rate of such exacerbations compared with the FBC group and this difference approached statistical significance (95% CI: 52% reduction – 1% increase; p=0.059). A by-interval analysis of protocol defined moderate/severe exacerbations showed the largest difference between treatments during Weeks 17-24 where the SFC group showed a 57% reduction in the protocol-defined moderate/severe exacerbation rate compared with FBC and this difference was statistically significant (95% CI 21%-77% reduction, p=0.006). Secondary Efficacy: The number of exacerbations per subject during the treatment period was similar in both treatment groups, the majority of these exacerbations were mild and most subjects had their first exacerbation during Weeks 1-4. There were no statistically significant differences between treatment groups for the number of exacerbations per subject, severity of exacerbations or time to first exacerbation. Over the treatment period, both groups showed a steady increase in mean morning PEF (mean±SD increase of 39±46.99 L/min and 38.6±46.68 L/min in the SFC and FBC groups respectively) and FEV1 (adjusted mean±SE change of 0.29±0.02L and 0.27±0.02L in the SFC and FBC groups respectively). There was no statistically significant difference between the two groups. Similarly, subjects in both treatment groups showed improvements in asthma symptoms, amount of relief medication use and asthma control, with no statistically significant difference between the groups.

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Title: A twenty-four week, randomised, double-dummy, double-blind, parallel group study to compare the occurrence of exacerbations between SERETIDE DISKUS 50/250µg 1 inhalation bd and formoterol/budesonide Breath-Actuated Dry Powder Inhaler 4.5/160µg 2 inhalations bd in subjects with moderate to severe asthma.. Safety: The proportion of subjects with at least one AE that started during treatment was similar in both treatment groups: 384 (55%) in the SFC group and 377 (54%) in the FBC group. The most common AEs in each group were headache and upper respiratory tract infection. The incidence of drug-related AEs was <10% in both groups, the most commonly reported drug- related events were: hoarseness/dysphonia (SFC: 13/697 (2%), FBC: 13/700 (2%)), candidiasis of mouth/throat (SFC: 12/697 (2%), FBC: 7/700 (1%)) and headaches (SFC: 9/697 (1%), FBC: 12/700 (2%)). No deaths occurred in the study and a small proportion of subjects reported SAEs: 20 (3%) subjects in the SFC group and 12 (2%) subjects in the FBC group. Only one SAE was considered related to study drug: a severe hoarseness/dysphonia in a subject in the FBC group. A small proportion of subjects had an AE that resulted in their withdrawal from the study: 14(2%) subjects in the SFC group and 10 (1%) subjects in the FBC group. The incidence of oral candidiasis was low in each treatment group and none of the events reported were serious. Conclusions: The primary endpoint, mean rate of all exacerbations over 24 weeks was similar in both treatment groups. Post hoc analyses investigating the benefits of sustained treatment have been conducted on exacerbation data for this study. These analyses have shown treatment differences in favour of SFC with a significant time interval effect in relation to severe and moderate exacerbations over weeks 1 -24 (p=0.059) and particularly in weeks 17 - 24 of the treatment period (p = 0.006) Regular treatment with SFC and FBC resulted in improvement in lung function and exacerbation rates. Both treatments were well tolerated and the overall incidence of AEs and proportion of subjects with SAEs was similar across both groups. Date of Report: August 2004

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TABLE OF CONTENTS

Page SYNOPSIS ...... 2 ABBREVIATIONS ...... 13 1. ETHICS ...... 15 1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ...... 15 1.2. Ethical Conduct of the Study ...... 15 1.3. Subject Information and Consent...... 15 2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...... 15 3. INTRODUCTION ...... 16 3.1. Background ...... 16 3.2. Study Rationale ...... 16 4. STUDY OBJECTIVES ...... 17 4.1. Primary objective ...... 17 4.2. Secondary objectives ...... 17 4.3. Other Objectives ...... 17 4.4. Safety ...... 17 5. INVESTIGATIONAL PLAN ...... 18 5.1. Study Design ...... 18 5.2. Protocol Amendments ...... 19 5.3. Selection of Study Population ...... 20 5.3.1. Inclusion Criteria ...... 20 5.3.2. Exclusion Criteria ...... 20 5.3.3. Predetermined Criteria for Subject Withdrawal ...... 22 5.4. Investigational Products ...... 22 5.4.1. Description of Investigational Products ...... 22 5.4.2. Dosages and Administration ...... 23 5.4.3. Dose Rationale...... 24 5.4.4. Blinding...... 24 5.4.5. Treatment Assignment ...... 24 5.4.6. Assessment of Compliance ...... 25 5.4.7. Treatment of Investigational Product Overdose...... 25 5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . 25 5.5.1. Permitted Medications ...... 25

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5.5.2. Prohibited Medications ...... 26 5.5.3. Medical Device ...... 27 5.5.4. Non-drug Therapies ...... 27 5.6. Study Assessments and Procedures ...... 27 5.6.1. Demographic and Baseline Assessments ...... 27 5.6.2. Efficacy Assessment ...... 27 5.6.3. Safety Assessments...... 32 5.6.4. Health Outcomes Assessments ...... 35 5.7. Data Quality Assurance ...... 35 5.8. Data Analysis Methods ...... 37 5.8.1. Timings of Planned Analyses ...... 37 5.8.2. Sample Size Considerations ...... 39 5.8.3. Analysis Populations ...... 39 5.8.4. Treatment Comparisons...... 40 5.8.5. General Considerations for Data Analyses ...... 40 5.8.6. Data Handling Conventions ...... 41 5.8.7. Study Population ...... 44 5.8.8. Efficacy Analyses ...... 48 5.8.9. Safety Analyses ...... 51 5.8.10. Health Outcomes Analyses ...... 52 6. STUDY POPULATION RESULTS...... 54 6.1. Disposition of Subjects ...... 54 6.2. Protocol Deviations ...... 54 6.3. Populations Analysed...... 55 6.4. Demographics and Other Baseline Characteristics ...... 55 6.4.1. Demographic Characteristics ...... 55 6.4.2. Baseline Characteristics...... 57 6.4.3. Other Current Medical Conditions ...... 57 6.4.4. Previous Medications ...... 58 6.5. Concomitant Medications ...... 59 6.5.1. Asthma medications ...... 59 6.5.2. Non-asthma medications ...... 59 6.6. Treatment Compliance ...... 59 7. EFFICACY RESULTS ...... 60 7.1. Primary Efficacy Results ...... 60 7.1.1. Results of Covariate Analysis ...... 60 7.1.2. Negative Binomial Model ...... 60

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7.1.3. Post Hoc Analyses ...... 61 7.2. Secondary Efficacy Results ...... 69 7.2.1. Number of Exacerbations...... 69 7.2.2. Severity of Exacerbations ...... 69 7.2.3. Time to First Exacerbation ...... 69 7.3. Other Efficacy Results ...... 69 7.3.1. PEF ...... 69 7.3.2. Clinic FEV1...... 71 7.3.3. Asthma Symptoms ...... 71 7.3.4. Use of Relief Medication ...... 72 7.3.5. Withdrawals Due to Lack of Efficacy ...... 74 7.3.6. ‘Well-Controlled’ Asthma ...... 74 7.3.7. Asthma Control Questionnaire (ACQ) ...... 74 7.4. Efficacy Conclusions ...... 74 8. HEALTH OUTCOMES RESULTS ...... 75 8.1. Resource Utilisation ...... 75 8.1.1. Unscheduled Asthma-related Healthcare Contacts ...... 75 8.1.2. Time Missed from Work or Usual Activities ...... 75 8.2. Health Outcomes Conclusions ...... 76 9. SAFETY RESULTS ...... 77 9.1. Extent of Exposure ...... 77 9.2. Adverse Events (AEs) ...... 77 9.2.1. Pre-treatment Adverse Events ...... 77 9.2.2. Treatment emergent Adverse Events ...... 77 9.2.3. Post-treatment Adverse Events ...... 78 9.2.4. Drug-related Adverse Events ...... 78 9.3. Serious Adverse Events ...... 79 9.3.1. Fatal Events ...... 79 9.3.2. Non-Fatal Events ...... 79 9.4. Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study ...... 80 9.5. Pregnancies ...... 81 9.6. Other Safety Evaluations ...... 81 9.6.1. Oropharyngeal candidiasis...... 81 9.7. Medical Device Incidents, Near-Incidents, Malfunctions and Remedial Action ...... 81 9.8. Safety Conclusions ...... 82

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10. DISCUSSION AND CONCLUSIONS ...... 83 11. REFERENCES ...... 85 12. CASE NARRATIVES...... 86 STUDY POPULATION DATA SOURCE TABLES ...... 115 EFFICACY DATA SOURCE FIGURES AND TABLES ...... 223 HEALTH ECONOMIC TABLES...... 312 SAFETY DATA SOURCE TABLES...... 316 ATTACHMENT Attachment 1 ...... 353

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LIST OF FIGURES

Page Figure 1 Adjusted Moderate/Severe Exacerbation Rates by Study Interval . . 65 Figure 2 Cumulative Plot by Study Day of All Protocol-Defined Exacerbations ...... 66 Figure 3 Cumulative Plot by-Study Day of Moderate/Severe Protocol-Defined Exacerbations ...... 67 Figure 4 Adjusted Moderate/Severe Protocol-Defined Exacerbation Rates by Study Interval ...... 68

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LIST OF TABLES

Page Table 1 Time and Events Schedule...... 19 Table 2 Demographic Characteristics of the ITT Population ...... 56 Table 3 Summary of baseline Lung Function Characteristics ...... 58 Table 4 Summary of Rate of Exacerbations Over 24 Weeks ...... 60 Table 5 Statistical Analysis of the Rate of Exacerbations Over 24 Weeks using the Negative Binomial Model ...... 61 Table 6 Rate of All Exacerbations Adjusting for Interval ...... 62 Table 7 Summary of Severity of Exacerbations ...... 63 Table 8 Rate of Moderate/Severe Exacerbations Over 24 Weeks...... 63 Table 9 Rate of Moderate/Severe Exacerbations Adjusting for Interval. . . . . 64 Table 10 Summary of Rate of Protocol-Defined Moderate/Severe Exacerbations Adjusting for Interval ...... 67 Table 11 Estimated rate Ratio for Protocol Defined Moderate/Severe Exacerbations for Each Time Interval ...... 68 Table 12 Mean change in morning PEF (L/min) over Weeks 1-24 ...... 70 Table 13 Summary of Results of Asthma Symptoms and Relief Medication Use ...... 73 Table 14 Summary of Unscheduled Asthma-related Healthcare Contacts . . . 75 Table 15 Summary of Most Common Adverse Events* that Started During Treatment (Safety Population) ...... 78

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Abbreviations

ACQ Asthma Control Questionnaire AE Adverse Event BADPI Breath-actuated Dry Powder Inhaler BD Twice daily CFC Chlorofluorocarbon Cm Centimetre CRF Case Report Form DRC Daily Record Card ECCS European Community Coal and Steel FBC Formoterol/budesonide combination FEV1 Forced Expiratory Volume in one second GCP Good Clinical Practice GCSP Global Clinical Safety and Pharmacovigilance GEE General Estimating Equations GSK GlaxoSmithKline GWOPS GlaxoWellcome Operations (Committee) ICS Inhaled Corticosteroid IEC Independent Ethics Committee IRB Institutional Review Board ITT Intent-To-Treat IVRS Interactive Voice Response System Kg Kilograms LABA Long-acting β2-agonist LOCF Last Observation Carried Forward MDI/pMDI Metered Dose Inhaler/Pressurised Metered Dose Inhaler MEDRA Medical Dictionary for Regulatory Activities MIDAS Medical Conditions, Indications, Diagnoses, Adverse Events and Symptoms PEF Peak Expiratory Flow PP Per Protocol RAP Reporting and Analysis Plan SAE Serious Adverse Event SCAD System for Central Allocation of Medication SD Standard Deviation SE Standard Error SFC Salmeterol/fluticasone propionate combination THERAPY GSK Data Coding System for Medication UK United Kingdom

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Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies BECONASE Symbicort DISKUS FLIXONASE SERETIDE VENTOLIN

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1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational centre ethics committee or institutional review board. Study medication was not shipped to the investigator site until copies of the IEC or IRB approval had been received at GSK.

1.2. Ethical Conduct of the Study

This study was conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, including, where applicable, the 1996 version of the Declaration of Helsinki.

1.3. Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures, and in accordance with all applicable regulatory requirements. Case report forms were provided for each subject’s data to be recorded.

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

• This was a multi-centre, pan-European study conducted in 178 centres in 18 countries. Subjects were selected from a primary or secondary care environment and treated on an out-patient basis. • GSK was responsible for the administration of this study including the supply of double-dummy, double-blind study medication. VENTOLIN™ relief medication and prednisolone were sourced locally in each country. • CSR authors: Respiratory GCS, BDS Statistics and Programming, Respiratory and BDS Statistics and Programming, Respiratory.

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3. INTRODUCTION

3.1. Background

Greening et al. in 1994 [Greening, 1994] showed that adding a long acting beta agonist (LABA) to an inhaled corticosteroid (ICS) is superior to doubling the dose of ICS in treating patients with asthma. Further studies on poorly controlled patients treated with ICS show that the addition of a LABA improves lung function and reduces symptoms in moderate to severe asthma [Woolcock, 1996; van Noord, 1999; Pearlman, 1999; Condemi, 1999]. The evidence supporting these findings has now made the co- prescribing of these two categories of medication the treatment of choice in persistent asthma [GINA, 2002], further supported by incorporation into international asthma treatment guidelines [BTS, 2003]

Until recently, delivery of the single component medications to the lungs involved the use of multiple inhalers, affecting patient acceptability and compliance to treatment, particularly to the anti-inflammatory steroid component as the patient may feel no immediate benefit.

Combination products, SERETIDE™ and formoterol/budesonide have been developed containing an ICS and a LABA in the same inhaler device. SERETIDE has been marketed since 1999, and contains the LABA salmeterol xinafoate 50µg and the ICS fluticasone propionate at one of 3 doses, 100, 250 or 500µg in a single DISKUS™ inhaler. Symbicort, containing the LABA formoterol 4.5µg (delivered dose), and the ICS, budesonide at one of 2 doses, 80 and 160µg (delivered dose) in a single breath-actuated dry powder inhaler (BADPI) device, received regulatory approval in Europe in 2001. The current study compared SERETIDE DISKUS 50/250µg 1 inhalation bd (SFC) with formoterol/budesonide BADPI 4.5/160µg 2 inhalations bd (FBC) in subjects with moderate to severe asthma.

3.2. Study Rationale

A recent comparison study of SFC 50/250µg bd with formoterol 12µg bd and budesonide 800µg bd showed that SFC is significantly better at preventing exacerbations, increasing nights without awakenings and decreasing nocturnal symptoms. However, there is little information on the efficacy of FBC compared to its component products, and a small amount of published data comparing FBC with SFC. FBC has been shown to have a faster onset of bronchodilation than SFC during the first 30 minutes after the first dose of medication.

The primary objective of this study was to compare the occurrence of exacerbations between the two combination products. Further to this, the study assessed the efficacy of SFC and FBC in treating subjects with moderate to severe asthma by comparing the severity of asthma exacerbations, lung function parameters, symptoms, the need for relief medication and asthma control.

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4. STUDY OBJECTIVES

4.1. Primary objective

To compare the efficacy of the two treatment groups in preventing the occurrence of asthma exacerbations in moderate to severe asthma

4.2. Secondary objectives

To compare the efficacy of two treatment groups in treating moderate to severe asthma with respect to the following parameters:

• severity of exacerbations

4.3. Other Objectives

• lung function (Peak Expiratory Flow (PEF), Forced Expiratory Volume in one second (FEV1)) • symptoms • need for relief medication • ‘well-controlled’ asthma

4.4. Safety

To compare the two treatment groups with respect to the incidence of adverse events

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5. INVESTIGATIONAL PLAN

5.1. Study Design

This was a multi-national, multi-centre, double-blind, double-dummy, randomised, parallel group, twenty-four week study to compare the occurrence of exacerbations between SFC and FBC in subjects with moderate to severe asthma. Randomisation was 1:1 for the two treatment groups.

Subjects meeting the Visit 1 (Week -2) inclusion criteria were entered into a 2-week run- in period. During the run-in period, subjects continued to take their pre-study inhaled corticosteroid (ICS) at the pre-study dose; 1000-2000µg /day beclomethasone dipropionate (BDP) or equivalent. At the end of this 2-week period, subjects complying with inclusion/exclusion criteria were randomised to either SFC or FBC for twenty-four weeks. Subjects who failed the entry criteria at the end of the run-in (Visit 2) were allowed to repeat the run-in once and attend for randomisation at Visit 2a. Subsequent scheduled visits occurred at Weeks 4, 8, 16 and 24. Throughout the study, subjects completed a paper daily record card (DRC) recording their morning PEF, evening PEF, daytime and night-time asthma symptoms, use of relief medication, any other concomitant medications, and details of asthma exacerbations and other adverse events (AEs). A post-study safety assessment was performed by telephone approximately 7 days after the end of treatment. The total duration of the study was 27 weeks, but could have been extended to 29 weeks if the run-in was repeated. The protocol Time and Events Schedule is shown in in-text (Table 1). Further details of the study assessments and procedures conducted for each study period can be found in Section 5 of the study protocol.

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Table 1 Time and Events Schedule

Timeline: Visit 1 Visit 2/2a Visit 3 Visit 4 Visit 5 Visit 6 Optional -2w ± 4d (Day 0) 4w ± 1w 8w ± 1w 16w ± 1w 24 ± 1w follow-up Period Run-in Treatment Follow-up Treatments Usual SFC DISKUS (50µg salmeterol xinafoate + 250µg Appropriate inhaled fluticasone propionate, actuated dose) 1 inhalation bd asthma steroids OR medication FBC BADPI (formoterol 4.5µg + budesonide 160µg, delivered dose) 2 inhalations bd Relief VENTOLIN Relief VENTOLIN Visit 1 2/2A 3 4 5 6 7 Informed Consent X Demography X Reversibility X X Inclusion/Exclusion X X Criteria Medical History X Oropharyngeal X X X X X X X exam Lung Function X X X X X X X (FEV1) Issue Daily Record X X X X X Cards Issue Study X X X Medication ACQ X X X X X Collect Daily X X X X X Record Cards Collect Study X X X X Medication Adverse Event X1 X X X X X Concurrent X X X X X X X Medication 1. only SAEs collected at Visit 1

5.2. Protocol Amendments

There was one protocol amendment to this study that applied to all participating study sites. It was dated 1 October 2002. The amendment was implemented approximately one year after study initiation and three months prior to completion. The reasons for the amendment were as follows:

• In order to comply with trademark laws it was necessary to change the name of the comparator product to formoterol/budesonide throughout the protocol • Clarification of inclusion criterion number 4 such that ‘no change in regular medication’ was amended to ‘no change in regular asthma medication dose’ • Corrections of minor inconsistencies, errors and omissions The amendment had little impact on the conduct or interpretation of the study.

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5.3. Selection of Study Population

5.3.1. Inclusion Criteria

5.3.1.1. Inclusion criteria for entry to the run-in period

1. Male or female outpatients 2. At least 18 years of age at the time of Visit 1 (Screening Visit). 3. Documented clinical history of asthma for at least 6 months prior to Visit 1 4. No change in regular asthma medication dose or use of oral/parenteral steroids in the 4 weeks before Visit 1a 5. Subjects who were receiving 1000-2000µg /day BDP or equivalent, such as 800- 1600µg /day budesonide, 500-1000µg /day fluticasone propionate or QVAR, for at least 4 weeks prior to Visit 1 6. Signed and dated written informed consent was obtained from the subject prior to study participation 7. Able to comply with therapy and to complete daily record cards and subject- completed questionnaires correctly.

5.3.1.2. Inclusion criteria at Visit2/2a

In addition to the criteria in Section 5.3.1.1, subjects had to comply with the following criteria at the end of the run-in period (Visit2/2a):

1. At Visit 1 or 2/2a, a demonstrable reversible increase in FEV1 of at least 12% (and ≥200mls), 15 minutes after inhaling 200-400µg of VENTOLIN or; at any time in the 2 years prior to screening, documentary evidence of a reversible increase in FEV1, of at least 12% (and ≥200mls), 15 mins after inhaling a short- acting bronchodilator 2. During the 2-week run-in period (10 to 18 days), subjects must have had an asthma symptom score (day and night combined) of a least 2 (see Section 5.6.2.3) recorded in their daily record card (DRC) on at least 4 of the last 7 evaluable days 3. During the 2-week run-in period, subjects must have completed DRCs on at least 10 days (run-in window was 10-18 days). Subjects who failed to meet this criterion were permitted to repeat the run-in once, at the investigators’ discretion.

5.3.2. Exclusion Criteria

1. History of upper or lower respiratory tract infection, middle ear or sinus infection within 4 weeks prior to Visit 1

a subjects who were receiving combination therapy containing ICS and LABA had this stopped at Visit 1 and an equivalent dose of fluticasone propionate was prescribed for the run-in period

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2. An acute asthma exacerbation requiring emergency hospital/clinic treatment and/or hospitalisation within 4 weeks prior to Visit 1 3. A smoking history of ≥10 pack years, or likely to change smoking habits during the study, or having given up smoking within 4 weeks of Visit 1 4. Previous participation in a clinical study in which the subject was exposed to an investigational or non-investigational medication or device within 30 days prior to Visit 1 5. Concurrent participation in another clinical study in which the subject was or would have been exposed to an investigational or a non-investigational medication or device 6. Any evidence of or treatment of malignancy (other than localised basal cell, squamous cell skin cancer or localised cancer in situ that has been resected) within the previous five years 7. A pregnant woman or any woman intending to become pregnant 8. A woman breastfeeding an infant(s) 9. Inability or unwillingness to take study medication (non-compliance), follow directions or unable to complete a written paper daily record card and self-rating questionnaires 10. Previous allergic reaction to study medications or any excipients of the formulations

11. Subjects receiving any of the following medications: long-acting inhaled β2-agonists, oral β2-agonists or slow-release bronchodilators, combination therapy (containing β2- agonist and/or inhaled corticosteroids for asthma), sodium cromoglycate or nedocromil sodium, ketotifen, leukotriene-receptor antagonists, anticholinergics, short-acting inhaled β2-agonists (other than VENTOLIN provided at Visit 1), theophyllines. These medications had to be stopped at Visit 1. (During the run-in, subjects continued on their pre-study dose of inhaled corticosteroids, which were stopped at Visit 2/2a)a. 12. Use of oral/parenteral corticosteroids during the 4 weeks prior to Visit 1 13. Use of depot corticosteroids during the 12 weeks prior to Visit 1 14. History of alcohol or medication abuse

15. Pre-bronchodilator FEV1 of <50% of predictive normal values using European Community for Coal and Steel (ECCS) standard ranges [ECCS, 1983] (bronchodilators must have been withheld for 6 hours previously) 16. Use of any concurrent prohibited medications (subjects must not have taken prohibited medications during the run-in and must have remained off these medications for the duration of the study as listed in Section 5.5.2)

a subjects who were receiving combination therapy containing ICS and LABA had this stopped at Visit 1 and an equivalent dose of fluticasone propionate was prescribed for the run-in period

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5.3.3. Predetermined Criteria for Subject Withdrawal

A subject was considered to have completed the study if they had participated fully in the study for 27 weeks. A subject could voluntarily discontinue participation in the study at any time. The investigator could also, at his or her discretion, discontinue a subject from participating in the study at any time.

5.3.3.1. Subject withdrawal from the investigational product

The following pre-determined criteria were considered in assessing a subject’s early withdrawal from study medication:

• insufficient data to assess asthma control during the period between two visits as it would not have been possible to evaluate the subject’s treatment (see Section 5.8.1.2) • if a subject discontinued their study medication at any time, it was up to the discretion of the investigator whether the subject should continue or be withdrawn from the study

5.3.3.2. Subject withdrawal from the study

• Subjects who failed the entry criteria or failed to maintain their DRC and had incomplete data during the run-in (4 days of complete data required within the last 7 days of the run-in and 10 days of run-in data overall) were discontinued from the study. • Subjects withdrawn due to an adverse event (AE) were followed up, where possible, to determine the outcome of the AE. • Any subject who became pregnant during the study was withdrawn from the study and followed to determine the outcome of the pregnancy. If a subject was prematurely discontinued for any reason, the investigator made every effort to perform the following evaluations: collect used/unused study medication; check for adverse events, changes in concurrent medication, exacerbations, administer ACQ, record FEV1, unscheduled asthma-related healthcare contacts, record date and reason for discontinuation, and collect subject DRC.

5.4. Investigational Products

5.4.1. Description of Investigational Products

The Clinical Trials Supplies Department at GlaxoSmithKline Research and Development supplied the following study medications and devices.

• SERETIDE 50/250µg strength DISKUS inhaler containing 50µg salmeterol xinafoate /250µg fluticasone propionate per inhalation (batch numbers: manufactured at Ware, GWOPS)

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• Placebo DISKUS inhaler to match the active study medication (batch numbers: manufactured at Ware, GWOPS) • Formoterol/budesonide 4.5/160µg strength Breath-Actuated Dry Powder Inhaler (BADPI) containing 4.5µg formoterol and 160µg budesonide, delivered dose (batch numbers: manufactured at CTS, Galen) • Placebo BADPI to match the active formoterol/budesonide study medication (batch numbers: manufactured at CTS, Galen) Each DISKUS contained 60 doses of study medication or placebo, each BADPI contained 120 doses of study medication or placebo.

Inhaled relief medication, (VENTOLIN via the DISKUS inhaler or pressurised CFC or non-CFC MDI), was provided by the GSK operating company. These were provided locally as bulk supplies to each centre, to be dispensed as required both during the run-in and the treatment periods.

Oral prednisolone for the treatment of moderate or severe asthma exacerbation was provided locally by the GSK operating company.

All study medications were required by the investigator to be stored separately from any other medication and in accordance with the manufacturer’s instructions. All investigational products were required to be stored safely and properly at 2 to 25°C.

The local GSK operating company provided each centre with supplies of standard Mini- Wright peak flow meters, and dipstick urine pregnancy tests.

5.4.2. Dosages and Administration

During the run-in period, subjects continued on their current inhaled corticosteroid plus allowed short-acting bronchodilators.

At Visit 2/2a (start of study treatment) subjects were randomised in equal numbers to one of the following treatment groups:

SERETIDE DISKUS 50/250µg 1 inhalation bd and formoterol/budesonide BADPI placebo, 2 inhalations bd

SERETIDE DISKUS placebo 1 inhalation bd and formoterol/budesonide BADPI 4.5/160µg, 2 inhalations bd

Subjects were issued with eight weeks worth of treatment at Visits 2/2a, 4 and 5. Each treatment pack contained either 3 active DISKUS and 3 placebo BADPI or 3 placebo DISKUS and 3 active BADPI. Subjects were asked to take one inhalation from the

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DISKUS inhaler and two inhalations from the BADPI every morning and every evening for 24 weeks (Visit 2/2a to Visit 6).

5.4.3. Dose Rationale

Several studies have shown that adding an inhaled long-acting β2-agonist to inhaled steroid treatment is more effective than doubling the steroid dose. Delivery of inhaled medications to the desired site of action allows use of smaller doses than the oral or parenteral routes.

SFC 50/250µg 1 inhalation bd or FBC 4.5/160µg 2 inhalations bd are the recommended doses in a population of moderate to severe asthmatics.

5.4.4. Blinding

Blinded study medication was packed and supplied by GSK. All treatment packs contained both DISKUS and BADPI devices (either active DISKUS/placebo BADPI or active BADPI/placebo DISKUS) and looked identical. The double-dummy design ensured that both subjects and investigators remained blind to the active medication being received.

Only in the case of an emergency, when knowledge of the study medication was essential for the clinical management or welfare of the subject, could the investigator unblind a subject’s treatment assignment. In these circumstances a subjects treatment could be identified following a series of questions on the automated 24-hour Interactive Voice Recognition System (IVRS). If the blind was broken for any reason, the investigator notified GSK immediately of the unblinding incident without revealing the subject’s study treatment assignment. In addition, the investigator recorded the date and reason for revealing the blinded treatment assignment for that subject in the Case Report Form (CRF).

If a serious adverse event (SAE) as defined in Section 5.6.3.2 was reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff unblinded the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies was required, the report would identify the subject’s treatment assignment. When applicable, a copy of the regulatory report was sent to investigators in accordance with relevant regulations, GSK policy, or both.

5.4.5. Treatment Assignment

Subjects were assigned to study treatment in accordance with the randomisation schedule from the IVRS which is part of the System for the Central Allocation of Medication (SCAD). The treatment block size was four. The randomisation schedule was given to the automated system administrator prior the start of the study. The treatment number assigned was recorded on the CRF.

Each subject was assigned a Treatment Pack at Visit 2/2a (randomisation visit), Visit 4 and Visit 5 of the study treatment phase. The principal investigator or designee contacted

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the IVRS system at each of these scheduled visits to obtain the pack number. Each treatment pack number was recorded on the medication accountability record.

5.4.6. Assessment of Compliance

The investigator was responsible for study medication accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designated study site personnel maintained study medication accountability records throughout the course of the study. The amount of study medication received from GSK, the amount supplied and/or administered to and returned by subjects was documented.

A medication dispensing and accountability log was provided and the investigator or designee recorded the number of inhalers dispensed to and returned by each subject. The subject was requested to return all used and unused study inhalers and the investigator or designee reconciled or resolved any discrepancies.

Start and stop dates of study treatment and any reason for premature discontinuation of study medication and/or non-compliance were entered in the ‘Trial Medication’ and ‘End of Study Record’ pages in the CRF. Number of remaining doses from each study treatment inhaler prescribed was entered in the Compliance section of the CRF.

5.4.7. Treatment of Investigational Product Overdose

As there were no data available from clinical trials on overdose with SFC or FBC, data on overdose with salmeterol, fluticasone propionate, formoterol and budesonide, as contained in the appropriate datasheets, were given to the investigator. The investigator used their clinical judgement to determine if an overdose had occurred.

5.5. Prior and Concomitant Medications and Non-Drug Therapies

5.5.1. Permitted Medications

5.5.1.1. Permitted asthma medications

During the run-in period, subjects continued to take their pre-study ICS medication. This treatment was stopped at Visit 2/2a. Where indicated, individual courses of oral corticosteroids (40-60mg prednisolone daily, or equivalent, for 10 days) were permitted during the study for the treatment of asthma exacerbations.

The sponsor provided the following reliever medication from local commercial stock: salbutamol sulphate DISKUS or pMDI designed to deliver 100µg salbutamol actuated dose.

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5.5.1.2. Medication permitted for other disorders

All medications for other disorders could be continued providing the dose remained constant and their use was not expected to affect lung function. However, no systemic corticosteroids for other conditions were permitted. Intranasal steroids (e.g. BECONASE™ or FLIXONASE™) could be used for rhinitis. Subjects were encouraged to keep the dose constant throughout the study but any changes in dose were permitted providing it was within the recommended dose range. Short courses of intranasal steroids could also be taken for seasonal rhinitis.

If the subject developed oropharyngeal candidiasis, antifungal lozenges could be taken. An adverse event form was completed and the medication recorded in the concurrent medication page of the CRF.

5.5.2. Prohibited Medications

5.5.2.1. Non-permitted asthma medication

The following asthma medications were not permitted during the study:

• Oral, parenteral or depot corticosteroids other than a short course required to treat an exacerbation of asthma during the treatment period. • Long-acting inhaled β2-agonists (e.g. salmeterol) • Oral β2-agonists (e.g. bambuterol) • Slow release bronchodilators • Combination medication (containing any β2-agonist or corticosteroid) for asthma other than the study medication provided during the treatment period • Anticholinergics • Theophyllines • Sodium Cromoglycate • Nedocromil Sodium • Ketotifen • Short-acting inhaled β2-agonists other than the salbutamol (VENTOLIN) provided • Anti-Leukotrienes including suppressers of leukotriene production and antagonists The following asthma medication was not permitted during the treatment period and was discontinued at Visit 2/2A:

• Inhaled steroids other than the study medication Full details of all concurrent asthma medication and concurrent medication for other disorders were recorded in the CRF.

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5.5.3. Medical Device

No GSK medical devices were used in this study. All subjects were provided with Mini- Wright Peak Flow meters.

5.5.4. Non-drug Therapies

Not applicable to this study.

5.6. Study Assessments and Procedures

A schedule of the measurements and evaluations performed at each clinic visit is summarised in in-text Table 1, Section 5.1.

5.6.1. Demographic and Baseline Assessments

The following were recorded at Visit 1:

• Demographic information including gender, ethnic origin, date of birth, height, weight • History of asthma including duration of asthma • History of asthma exacerbations in the 12 months prior to Visit 1 • Concurrent medical conditions and concurrent medication (both asthma and non- asthma). All concurrent medications were entered in the Concurrent Medications Section of the CRF throughout the study, beginning at Visit 1. • Use of corticosteroids for asthma in the 12 months prior to Visit 1, and duration of inhaled corticosteroid treatment. The following were recorded at Visit 1, 2 or 2a:

• Calculated percent of predicted FEV1.

• FEV1 airway reversibility assessment of at least ≥12% (and ≥200mls) at Visits 1, 2/2a or during the run-in period, if documentary evidence of reversibility in the previous 2 years is not available. The following was recorded at Visit 2 or 2a:

• Confirmation that an asthma symptom score of 2 (day and night combined) on at least 4 of the last 7 evaluable days of the run-in period had been achieved.

5.6.2. Efficacy Assessment

5.6.2.1. Primary efficacy endpoint

The primary endpoint was the number of asthma exacerbations experienced by the subject as expressed as a rate over the 24-week treatment period.

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Exacerbations were assessed by the physician at each scheduled visit by reviewing the DRC entries, as well as specific questioning on adverse events. Subjects who experienced worsening of their symptoms between visits were advised to:

• increase relief medication usage for relief of symptoms • contact the investigator or primary physician immediately and report to the clinic as soon as possible (ideally within 24-hours) • record their symptoms, PEF and relief medication usage in their DRC as previously instructed • if intervention therapy was required during the treatment period, subjects could receive oral corticosteroids (40-60mg prednisolone daily, or equivalent, for 10 days), over and above their study medication. Asthma Exacerbation Definitions

Exacerbations were defined based on one or more of the following characteristics taking the worst to determine the applicable severity:

Mild

• morning PEF >20% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or; • more than 3 additional reliever occasions/24-hour period with respect to baseline for ≥ 2 consecutive days, or; • awakening at night due to asthma for ≥ 2 consecutive nights Moderate

A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either: • morning PEF >30% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or; • a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment Individual courses of oral corticosteroids were classified as separate exacerbations only if they were administered >1 week apart. Any course started within one week of finishing the previous course was considered part of the previous exacerbation.

Severe

• Deterioration in asthma which required hospital admission. Time/date of resolution

• Time/date at which the exacerbation had resolved, in the opinion of the investigator and/or subject

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Details of exacerbations were collected in the “Asthma Exacerbations” page of the CRF and DRC as follows:

Date of onset and resolution, daily morning PEF during the exacerbation; details of management of the exacerbation (e.g. clinic or emergency room visit, self-managed, hospital admission etc.); duration of in-subject care (if applicable) and total time off from school, work, or usual activities; restriction/prevention from continuing usual activities.

An exacerbation resulting in hospitalisation, or meeting any of the other definitions of serious (see Section 5.6.3.2), was recorded as a serious adverse event (SAE) in the “Serious Adverse Event” pages of the CRF.

5.6.2.2. Secondary efficacy endpoints

The secondary endpoints were severity and number of exacerbations, and time to first exacerbation. The information for these endpoints was collected as described in Section 5.6.2.1.

5.6.2.3. Other efficacy endpoints

Peak expiratory flow (PEF)

Morning and evening PEF were recorded daily on the DRC, prior to use of relief or study medication.

At Visit 1, the subject was given a Peak Flow Meter and taught how to measure their PEF. At each visit the subject’s ability to measure their PEF was checked and, if the investigator had any concerns, the subject was retrained. The instructions for use were provided with each Peak Flow Meter. Subjects were instructed to measure PEF whilst in the sitting position.

Forced expiratory volume in one second (FEV1)

FEV1 was measured at each clinic visit. Subjects were requested not to use short-acting bronchodilators for at least 6 hours prior to the measurement.

A subject’s predicted FEV1 was calculated at each visit, based on the ECCS standard ranges [ECCS, 1983] for 18 years and older. At Visit 1 or 2/2a, subjects were required to have a FEV1 of ≥ 50% of their predicted value. Failure to demonstrate this resulted in exclusion from the study.

Assessment of airway reversibility by FEV1 was performed at either Visit 1 or 2/2a, if documented evidence was not available from the previous two years. The highest of three technically acceptable measurements of FEV1 was taken before and 15 minutes after inhalation of 200-400µg short-acting bronchodilator. Percent reversibility was calculated as follows:

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Post-bronchodilator FEV –pre-bronchodilator FEV 1 1 X 100 pre-bronchodilator FEV1

The time of short-acting bronchodilator administration and the time and result of the FEV1 measurement was recorded on the “Pulmonary Function Testing” page in the CRF.

Asthma symptoms (DRC)

Subjects recorded their level of symptoms on the DRC each morning and evening, prior to use of relief or study medication. The following symptom scores were used:

Daytime Symptom Score:

0 = No symptoms during the day

1 = Symptoms for one short period during the day

2 = Symptoms for two or more short periods during the day

3 = Symptoms for most of the day which did not affect my normal daily activities

4 = Symptoms for most of the day which did affect my normal daily activities

5 = Symptoms so severe that I could not go to work or perform normal daily activities.

Night-time Symptom Score:

0 = No symptoms during the night

1 = Symptoms causing me to wake once or wake early

2 = Symptoms causing me to wake twice or more (including waking early)

3 = Symptoms causing me to be awake for most of the night

4 = Symptoms so severe that I did not sleep at all

Use of relief medication

Subjects recorded each use of relief medication on the DRC (use for relief of symptoms, not prophylactic use). Information for the previous 12 hours (overnight) was recorded each morning and a record of daytime use was made each evening (see Section 5.8.1.2 Change to planned conduct).

‘Well-controlled’ asthma

A subject’s weekly asthma control was derived based on symptoms, use of relief medication, peak flow measurements, exacerbations, emergency visits and adverse events.

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A week of ‘well-controlled’ asthma was defined as meeting the following criteria assessed over 7 consecutive days:

1. two or more of the following 3 criteria:

• a symptom score of greater than 1 on no more than two days • no more than 2 days of rescue salbutamol/albuterol use, up to a maximum of 4 occasions per week • ≥80% predicted AM PEF every day AND

2. all of the following criteria:

• no night-time awakenings due to asthma • no exacerbations • no emergency visits • no treatment related adverse effects enforcing a change in asthma therapy

Asthma Control Questionnaire

The Asthma Control Questionnaire (ACQ) was completed at each clinic visit following randomisation (Visits 2 to 6). The ACQ is a seven item questionnaire which has been developed as a measure of subjects’ asthma control that can be quickly and easily completed in clinical practice (Attachment 1).

The first six questions are designed to be self-completed by the subject, with the seventh requiring completion by clinic staff. The six subject-completed questions enquire about the frequency and/or severity of symptoms (nocturnal awakening, asthma symptoms on waking in the morning, activity limitation, shortness of breath, wheeze) and use of short- acting bronchodilator, over the previous week. The response options for all these questions consist of a score between zero (no impairment/limitation) and six (total impairment/limitation). The final item on the questionnaire is completed by a member of clinic staff, who record the subject’s FEV1 % predicted, again using a seven point response option anchored between zero (>95% predicted) and six (<50% predicted).

At each clinic visit the investigator provided each subject with the ACQ. The subject was given a quiet area in which to complete the questionnaire and was instructed to answer the first six questions only. Upon completion of these questions, the subject returned the ACQ to the investigator. Questions 1 to 6 were completed prior to the physician consultation or any discussion over clinical test results.

Any deviation from the questionnaire schedule was clearly noted. The investigator asked the subject to complete the questionnaire as accurately as possible. If the subject requested help or clarification with any of the questions, he or she was asked to reread the instructions and give the answer that best reflected how he/she had felt over the previous week. The subject was reassured that there were no right or wrong answers. The

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It was recommended that the ACQ was administered at the same time during each visit. To avoid biasing responses, the subjects were not told the results of diagnostic tests prior to completing the questionnaire.

Adequate time was allowed to complete all items on the ACQ. No stated or implied time for completing the ACQ was given, though the survey typically takes under 5 minutes to complete. Upon completion, the questionnaire was returned to the subject’s CRF.

Resource Utilisation

See Section 5.6.4.

5.6.3. Safety Assessments

5.6.3.1. Adverse events (AEs)

Monitoring of AEs was conducted throughout the study, from entry to final completion or discontinuation. The investigator was responsible for the detection and documentation of events meeting the definition of an AE or serious adverse event (SAE) as provided in the protocol. During the treatment period, when there was a safety evaluation, the investigator or study site personnel were responsible for detecting AEs and SAEs. In order to fulfill international safety reporting obligations, the investigator included in his or her assessment any SAEs resulting from study participation.

An AE was defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which did not necessarily have a causal relationship with the treatment.

An AE was therefore any unfavourable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

An AE included:

• exacerbation of a pre-existing illness (excluding asthma or exacerbations of asthma unless they met a definition of SAE) • increase in frequency or intensity of a pre-existing episodic event or condition • condition detected or diagnosed after study medication administration even though it may have been present prior to the start of the study • continuous persistent disease or symptoms present at baseline that worsened following the start of the study

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An AE did not include:

• medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); the condition that led to the procedure was an AE • pre-existing disease or conditions present or detected at the start of the study that did not worsen • situations where an untoward medical occurrence had not occurred (e.g., hospitalizations for cosmetic elective surgery, social and/or convenience admissions) • the disease or disorder being studied or sign or symptom associated with the disease or disorder unless more severe than expected for the subject’s condition • overdose of either study medication or concurrent medication without any signs or symptoms For GSK clinical trials, AEs may include pre- or post-treatment events that occurred as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen).

5.6.3.2. Serious adverse events

An SAE was defined as any adverse event occurring at any dose that resulted in any of the following outcomes:

a. Death b. A life-threatening adverse event c. Inpatient hospitalization or prolongation of existing hospitalization d. A disability/incapacity e. A congenital anomaly in the offspring of a subject who received medication f. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of medication dependency or medication abuse. Clarifications:

• “Occurring at any dose” did not imply that the subject was receiving study medication. • Life-threatening meant that the subject was, in the view of the investigator, at immediate risk of death from the event as it occurred. This definition did not include an event that, had it occurred in a more severe form, might have caused death.

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• Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study was not considered an AE. • Complications that occurred during hospitalization were AEs. If a complication prolonged hospitalization, the event was an SAE. • “Inpatient” hospitalization meant the subject had been formally admitted to a hospital for medical reasons. This may or may not have been overnight. It did not include presentation at a casualty or emergency room. • With regard to criteria “f” above, medical and scientific judgment was used in deciding whether prompt reporting was appropriate in this situation. Lack of Efficacy as an AE or SAE

“Lack of efficacy” per se was not reported as an AE. The signs and symptoms or clinical sequelae resulting from lack of efficacy were reported if they fulfilled the AE or SAE definition (including clarifications).

5.6.3.3. Pregnancies

Female subjects already known to be pregnant were not eligible for entry into the study. Local legal restrictions on use of these medications in female subjects of childbearing potential were observed. If a subject became pregnant during the study, the subject was withdrawn.

A urine dipstick pregnancy test was performed at Visit 1 and at Visit 6.

Any female subject who became pregnant while participating in the study was followed to determine the outcome of the pregnancy. Generally, follow-up was no longer than 6 to 8 weeks following the estimated delivery date. The investigator or his or her designee collected pregnancy information on the appropriate GSK form and submitted it to GSK within 2 weeks of learning of the subject’s pregnancy.

While pregnancy itself was not considered to be an adverse event (AE) or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons was recorded as an AE or a SAE. Furthermore, any SAE occurring as a result of a post-study pregnancy and which was reasonably related to the study medication was reported to GSK, if the investigator learnt of this SAE through spontaneous reporting.

5.6.3.4. Clinical laboratory evaluations

There were no laboratory evaluations conducted in this study.

5.6.3.5. Oropharyngeal Examinations

An oropharyngeal examination was performed at each visit to assess the presence of candidiasis. An oral swab was taken if there were visible signs of infection. Oral swabs for testing were sent to a local laboratory for analysis.

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5.6.3.6. Medical devices

No GSK medical devices were used in this study. Mini Wright Peak Flow meters were provided to all subjects.

5.6.4. Health Outcomes Assessments

5.6.4.1. Resource Utilisation

Information on unscheduled, asthma-related healthcare resource utilisation associated with the subject’s condition was collected during the study. Scheduled, protocol-driven utilisation such as physician visits and study medication were not included.

Following the collection and review of DRC and AEs at each scheduled visit, the investigator asked the subject if they had had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit. If the answer was yes, the following information was recorded on the Unscheduled Asthma Related Healthcare Contacts form in the CRF: date of contact; number of visits/calls (in the case of primary care contacts); number of visits to outpatient clinics; number of visits to hospital Accident and Emergency departments; number of days hospitalised; and whether it was related to an asthma exacerbation.

The investigator prompted the subject to give answers that were as complete as possible. If the subject could not recall an exact figure, an estimate was acceptable. The investigator could refer to his/her records to verify or supplement information given by the subject, if necessary.

5.7. Data Quality Assurance

Subject data was collected on CRFs provided to the investigator by GSK. In addition, subject-generated data was collected on daily record cards and subject-completed questionnaires (ACQ). The investigator or designee recorded all required subject data and an explanation was documented for any missing data. The investigator signed and dated a declaration on the CRF attesting to his/her responsibility for the quality of all data recorded and that the data represented a complete and accurate record of each subject’s participation in the study.

In accordance with applicable regulations, GCP, and GSK procedures, monitors periodically contacted the site, including conducting on-site visits. The extent, nature and frequency of on-site visits were based on such considerations as the study objective and/or endpoints, the purpose of the study, study design complexity, and enrollment rate.

During these contacts, the monitor:

• checked and assessed the progress of the study • reviewed study data collected • conducted Source Document Verification

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• identified any issues and addressed their resolution This was done in order to verify that the:

• data were authentic, accurate, and complete • safety and rights of subjects were being protected • study was conducted in accordance with the currently approved protocol, GCP and all applicable regulatory requirements The investigator agreed to allow the monitor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the monitor to discuss findings and any relevant issues.

In addition to contacts during the study, the monitor also contacted the site prior to the start of the study to discuss the protocol and data collection procedures with site personnel.

At study closure, monitors conducted the following activities in conjunction with the investigator:

• Returned all study data to GSK • Data clarifications and/or resolutions • Accountability, reconciliation, and arrangements for unused study medications • Review of site study records for completeness • Return of treatment codes to GSK At its discretion, GSK conducted some quality assurance audits of this study. If such an audit occurred, the investigator agreed to allow the auditor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor to discuss findings and any relevant issues.

Data management was performed in accordance with ICH GCP and Standard Operating Procedures. The data were entered into a database by the GSK data management designee who also validated it according to predefined validation checks, either at the point of entry and/or at a later stage in processing. Any inconsistencies or anomalies were queried with the investigator or their designees, and the database updated accordingly, until all data were deemed “clean” or authorised. Quality control procedures were applied to ensure that the quality of the data in the final database met the expected standards.

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5.8. Data Analysis Methods

5.8.1. Timings of Planned Analyses

5.8.1.1. Interim analyses and data monitoring

No formal unblinded interim statistical analyses were planned or conducted for this study.

5.8.1.2. Changes in the conduct of the study or planned analyses

5.8.1.2.1. Definition of ‘Well Controlled’ Asthma

To be consistent with definitions used in other studies, emergency visits were considered to be all contacts recorded on the “Unscheduled Asthma Related Healthcare Contacts” page of the CRF rather than just ‘Emergency Room / A & E Dept’ visits or ‘Inpatient Hospitalisation’ visits as stated in the Reporting and Analysis Plan (RAP).

5.8.1.2.2. Subject withdrawal from the investigational product

In the protocol it was stated that subjects would be withdrawn from the study if there was ‘insufficient data to assess their asthma control during the period between two visits as it would not have been possible to evaluate the subject’s treatment’. However, asthma control was not assessed at each visit but was derived at the end of the study when all the data had been collected. An Asthma Control score was not required at each visit as no treatment decisions were based on this score.

5.8.1.2.3. Use of relief medication

In the protocol it was stated that information on use of relief medication would be recorded on the DRC each morning for the previous 24 hours. However, for practical reasons, information was recorded each morning and evening for the previous 12 hours.

5.8.1.2.4. Number of exacerbations

In the protocol it was stated that the number of exacerbations per subject would be assigned to one of the following four categories: 0, 1, 2, >2. However when the analysis was carried out it was thought better to provide more information on the distribution of the exacerbations and they were actually assigned to one of the following five categories: - 0, 1, 2, 3, >3. Other than the categories the analysis remained unchanged from that stated in the RAP.

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5.8.1.2.5. Post hoc analyses

All Exacerbations Adjusting for Interval

In the protocol-defined analyses, lung function and symptom score endpoints were analysed in 3 intervals, weeks 1-8, weeks 9-16 and weeks 17-24. Trends were observed in the individual components (percent predicted morning PEF, short-acting beta-agonist use and night-time awakenings) that contributed to the definitions of asthma exacerbations and it was postulated that this may have had an effect on the exacerbation rate.

For each subject the number of all exacerbations that started in each of the 3 intervals was counted. However this approach led to missing data due to withdrawals. The method used to account for the subjects who withdrew was the Last Observation Carried Forward (LOCF) approach. This was considered to be an appropriate option as assuming ‘no exacerbations’ in missing intervals and thus performing no imputation may have led to an underestimation of the exacerbation rates in later time periods. The methods described below, also used to deal with missing data, were explored to support and verify the robustness of the LOCF method.

Generalised Estimating Equations (GEE) were used to fit the models. This methodology takes into account the correlation between the intervals within each subject.

As the Negative Binomial was considered to be a better distribution with which to fit the data than the Poisson distribution (as discussed in Section 5.8.8.1), a GEE model assuming the negative binomial distribution was fitted. This model also took into account the time interval. The time in each interval was used as the offset. (The use of an offset in a model is a method of accounting for the fact time spent in the study varies between subjects). Another GEE model was fitted with the subset of moderate/severe exacerbations adjusting for time interval. However as the Poisson distribution was found to adequately fit this subset this was the distribution used to fit this model.

Confidence intervals and p-values presented were based on empirical (rather than model- based) estimates of the standard errors of the estimates.

All models were adjusted for effects of gender, country grouping and age.

Moderate/Severe Exacerbations

When the severity of exacerbations was investigated it was noted that there was a numerical imbalance between number of moderate and severe exacerbations between the SFC (67) and FBC (80) groups, a difference that was not apparent when all exacerbations were analysed together. Therefore the moderate and severe exacerbations were investigated separately and the primary analysis, as stated in the RAP, was run on this subset.

Protocol Defined Exacerbations

All the results of the planned analyses were based on exacerbations as recorded by the investigator in the CRF. On analysing the exacerbation data it became apparent that there

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were a considerable number of exacerbations that were not reported by the investigator but that met the definition of exacerbation as per the protocol. This mainly occurred when the investigator reported several distinct exacerbations as one long exacerbation (mainly due to the frequency of the subject visits) and this resulted in an under-reporting of the number of mild exacerbations. In addition, the number of moderate exacerbations was slightly over-reported by the investigator as not all the investigator-reported moderate exacerbations had required a course of oral corticosteroids, a pre-defined criterion in the protocol.

As a result of these discrepancies, further analyses were performed using only exacerbation data as strictly defined by the protocol. The purpose of this was to present a more sensitive and objective analysis of the data.

5.8.2. Sample Size Considerations

The total sample size for this study was determined on the basis of anticipated differences between treatments in average asthma exacerbation rate over a twenty-four week treatment period. Based on data from the EDICT study [Ringdal, 2002] and the FACET study [Pauwels, 1997], the average exacerbation rate for the formoterol/budesonide combination group was estimated to be 1 per subject per six months. Therefore, in order to detect a reduction of 20% in the relative risk of exacerbations with salmeterol xinafoate/fluticasone propionate combination, at a two-sided α=0.05 significance level with 90% power using Poisson regression techniques, 525 subjects per group were required.

Incorporating a 20% overage to account for invalidity and withdrawals, it was anticipated that 656 subjects per group should be randomised, 1312 in total.

5.8.3. Analysis Populations

Four populations were considered for analysis:

Total Population

The Total Population consisted of all subjects who entered the study. This population was used for tabulating and listing reasons for withdrawal before randomisation and listing adverse events for these subjects.

Intent-to-Treat Population

The Intent-To-Treat (ITT) Population represented all subjects randomised to treatment that had taken at least one dose of study medication and had at least one post- randomisation diary assessment. Randomised subjects were only excluded if there was clear evidence of failure to take any study medication or if there was no on-treatment DRC data. Subjects in the ITT Population were analysed for efficacy according to the treatment group to which they were randomised. The ITT Population was used for all tables and analyses (except those specified for the Total, Safety or Per Protocol

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Populations) and was the primary population for all efficacy endpoints and for all safety endpoints (provided all subjects received the treatment to which they were randomised).

Following a site audit, six subjects in one centre were excluded from the ITT Population due to issues of non-compliance with GCP. The issues related to the reliability of the drug storage temperature log and changes made to subject diary cards, following discussions with the investigator, which may have affected subject eligibility for the trial. All data for these subjects were included in the Safety Population.

Safety Population

The Safety Population represented all subjects who had been randomised to treatment and had taken at least one dose of study medication. If any subjects did not receive study treatment as randomised, they were analysed for safety according to the treatment they actually received. If the Safety Population differed from the ITT Population, the patient population for the tables and listings of safety data were labeled as the Safety Population.

Per Protocol Population

This population consisted of all subjects in the ITT Population who did not have any protocol violations which could impact treatment effect. These violations were defined explicitly in the RAP and the decision to exclude a subject from the Per Protocol Population was made prior to breaking the study blind. For the Per Protocol Population, subjects were analysed according to the treatment received, providing the same treatment was taken for the duration of the study. If study medication was changed then the subject was considered a partial protocol violator (i.e. from the point of change onwards). This population was only used for confirmatory analysis of the primary endpoint if one or more of these full violations were observed in >20% of subjects.

5.8.4. Treatment Comparisons

The comparison of interest was the treatment comparison of salmeterol xinafoate/fluticasone propionate combination with formoterol/budesonide combination.

5.8.5. General Considerations for Data Analyses

5.8.5.1. Multicentre studies

It was anticipated that subjects would be enrolled in approximately 315 centres with a maximum of 20 countries. Since it was likely that a high proportion of centres would recruit a small number of subjects, it was planned to amalgamate centres within country with the aim of obtaining a minimum of 60 subjects within each country. It was also planned that countries with fewer than 60 randomised subjects could be combined with the country of nearest geographical location or ethnic origin. Details of country amalgamations were decided prior to unblinding.

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In fact, subjects were enrolled in 178 centres in 18 countries. Of these, Austria, Belgium, Czech Republic, Denmark, Ireland, Italy, Norway and Switzerland recruited less than 60 subjects and these countries were amalgamated as follows:

Austria + Czech Republic (47 + 41 = 88 subjects)

Belgium + France (38 + 120 = 158 subjects)

Denmark + Norway (55 + 22 =77 subjects)

Italy + Switzerland (54 + 55 = 109 subjects)

Ireland + UK (29 + 110 = 139 subjects)

All other countries recruited more than 60 subjects and were not amalgamated.

5.8.5.2. Other strata and covariates

Covariates expected to have an influence on efficacy were baseline value, country cluster, sex and age. All of these variables were included in all efficacy analyses, where appropriate, as explanatory covariates.

5.8.5.3. Examination of subgroups

Interactions of treatment with sex, country and age were tested in separate analysis models for statistical significance at the 10% level. If an interaction was considered meaningful, it was planned that the effects of treatment would also be presented separately for each subgroup factor level.

Tests for interactions were not performed for any of the secondary endpoint analyses or for the analysis of the Per-Protocol population.

5.8.5.4. Multiple comparison/multiplicity

As there was a single primary endpoint with a single primary analysis, supported by several secondary analyses, the nominal levels of significance were not impacted by multiple comparisons and no adjustments were made.

5.8.6. Data Handling Conventions

5.8.6.1. Premature discontinuation and missing data

Length of time (days) on the study was defined as:

(treatment stop date – treatment start date) + 1

For any subject who withdrew from the study prematurely, all available data up to the time of discontinuation were included in the analysis. In addition, missing data were

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imputed for the purposes of efficacy analyses if subjects withdrew from the study due to lack of efficacy or adverse event due to lack of efficacy. For lung function measurements and symptom scores, values were calculated using a last observation carried forward approach, taking the last on treatment observation together with whether or not it had been affected by rescue medication use (for use in the per protocol analysis). For clinic lung function measurements the value from the last scheduled visit on treatment was carried forward.

The actual number of days with non-missing values was used as the denominator in the derivation of ‘percentage’ endpoints, e.g. % symptom-free days/nights, rather than the total number of days in the assessment period.

For exacerbations, if a subject withdrew from the study before 24 weeks of treatment, the number of exacerbations was imputed in order to give the number of exacerbations in 24 weeks, as follows:

No. of exacerbations per 24 weeks = 6 x no. of exacerbations / no. of 4 week periods, where number of 4 week periods equals the number of weeks on treatment divided by 4, rounded up. This imputation was only for the purposes of summarising the rate of and the analysis of the number of exacerbations. These summaries and analysis were also repeated without imputation as a sensitivity analysis.

5.8.6.2. Derived and transformed data

Asthma exacerbations

Definitions of asthma exacerbations can be found in Section 5.6.2.1.

Mean percent predicted morning/evening PEF

Predicted PEF was calculated using the following equations [ECCS, 1983], according to the sex, height and age of the subject, where height was measured to the nearest cm and age was in whole years attained:

For males:

Predicted PEF = [(6.14 x Height (cm) / 100) – (0.043 x Age (yrs)) + 0.15] x 60

For females:

Predicted PEF = [(5.50 x Height (cm) / 100) – (0.030 x Age (yrs)) – 1.11] x 60

For subjects between 18 and 25 years of age, an age of 25 years was used in the above equations.

Percent predicted morning (or evening) PEF was calculated using the following formula:

AM (or PM) PEF x 100 Predicted PEF

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FEV1 and percentage reversibility

Predicted FEV1 was calculated using the ECCS (ref) formula:

Predicted FEV1 = (4.301 x Height (cm) / 100) – (0.029 x Age (yrs)) – 2.492 (for males)

Predicted FEV1 = (3.952 x Height (cm) / 100) – (0.025 x Age (yrs)) – 2.604 (for females)

For subjects between 18 and 25 years of age, an age of 25 years will be used in the above equations. Percent reversibility was calculated as follows:

Post-bronchodilator FEV –pre-bronchodilator FEV 1 1 X 100 pre-bronchodilator FEV1

Mean circadian variation in PEF

Circadian variation was calculated according to the following formula:

(|PEFpm-PEFam| ÷ mean(PEFam,PEFpm)) x 100 where the PEFpm was the evening PEF from the DRC and PEFam was the PEF from the following morning.

Assessment of ‘well-controlled’ asthma

Subjects had their asthma control assessed weekly (7 consecutive days starting from Day 1 on the DRC) for the duration of the study based on symptoms, use of relief medication, peak flow measurements, night-time awakenings, exacerbations, emergency visits and adverse events. The definition of ‘well-controlled’ asthma is given in Section 5.6.2.3.

For DRC measures data were required on at least 5 of the 7 days, otherwise that criterion was classified as unevaluable. However, if a subject had failed the criteria with less than 5 days of data then the week was classified as not ‘well-controlled’. For example, if a subject only had 3 days of data in a week but had a night-time awakening in those 3 days then the week was not ‘well-controlled’.

As the subject population for this study were moderate and severe asthmatics, only moderate and severe exacerbations were considered in the assessment of asthma control status as these were considered to be most clinically relevant.

Emergency visits were taken from the ‘Unscheduled Asthma Related Healthcare Contacts’ page of the CRF. Emergency visits were considered to be any contact recorded on this page of the CRF (see Section 5.8.1.2.1). The date of contact was used to determine the point at which control failed. Only the week of the visit was classed as uncontrolled.

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Adverse events leading to a change in asthma therapy were defined to be any adverse event that led to withdrawal and was related to treatment.

Each week was classified as either ‘controlled’, ‘not controlled’ or ‘unevaluable’.

Definition of baseline for efficacy analyses

For the purposes of all DRC efficacy analyses, baseline was defined as the mean of the daily values over the last seven days (prior to treatment start date) of the two-week run- in. For clinic visit efficacy endpoints, baseline was defined as the pre-VENTOLIN Visit 2/2a assessment.

5.8.6.3. Assessment windows

Study visits were performed at the required intervals relative to the Randomisation Visit, Visit 2/2a. The following windows were acceptable:

Visit 1 (Screening visit) Week –2 (or Week –4 ±4 days if run-in repeated ±8 days

Visit 2/2a (Randomisation visit) Day 0

Visit 3 Week 4 Day 28 ±7 days

Visit 4 Week 8 Day 56 ±7 days

Visit 5 Week 16 Day 112 ±7 days

Visit 6 Week 24 Day 168 ±7 days

A follow-up telephone contact occurred 7 days after Visit 6/withdrawal ± 2 days.

5.8.6.4. Values of clinical concern

No laboratory data were collected in this study.

5.8.7. Study Population

Tabulations of the study populations were produced using the ITT Population and the Per Protocol Population, when specified.

5.8.7.1. Disposition of subjects

A data display using the Total Population was produced to account for all subjects involved in the study, including the number of subjects randomised.

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Individual subject listings were also prepared showing treatment allocation, country of recruitment and investigator. Information regarding the number of patients screened by investigator and country allocation was tabulated. Summaries of the number of patients randomised for both the ITT and PP Populations were also tabulated.

Overall percentages of withdrawal from the study were tabulated by treatment group, as were the reasons for withdrawal. Tables and listings of withdrawals were split into those that occurred prior to randomisation, using the Total Population and those that occurred post-randomisation, using the Intent-To-Treat Population. Withdrawals after randomisation by time in study were also tabulated.

A listing of subjects who did not satisfy the entry criteria was given and the number in each treatment group tabulated.

For all patients in the ITT Population, a tabulation of the number of patients attending each scheduled clinic visit was prepared.

5.8.7.2. Protocol deviations

Subject data was examined for evidence of protocol violations in order to assess how well the protocol was followed. Where possible, inclusion and exclusion criteria were assessed. If any of the data were not available, a written confirmation from the investigator was given on the compliance of his/her subjects.

Violators of these criteria were shown in a listing. They were not excluded from any ITT Population analyses. However, major protocol violators were excluded from the Per Protocol Population. Minor protocol violators were not excluded from the Per Protocol Population. Subjects could be either full or partial protocol violators. A full protocol violator was completely excluded from the Per Protocol Population. A partial protocol violator was excluded from the Per Protocol Population from the point that they violated the protocol. For subjects who violated the protocol during the treatment period due to non-permitted changes in medication or non-permitted concurrent medication, the analysis only used data recorded prior to the violation. Where lung function measurements have been affected by the use of rescue medication, data was excluded at the particular assessment it occurred.

Major protocol violations

A subject was a major protocol violator if they were reported in the CRF or subsequently found to have failed to meet one or more of the inclusion criteria shown in Section 5.3.1 and/or met one or more of the exclusion criteria shown in Section 5.3.2.

DRC data violations

Violators of the following criterion were partial violators and data were only excluded at the particular assessment it occurred:

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• Subjects who had lung functions measurements affected by the use of rescue medication, i.e. subjects had taken relief medication within 6 hours of measuring PEF in the DRC. Other violations

• Subjects who, having completed the study with all devices returned, failed to take a total of at least 80% or who had taken over 125% study drug, as reported in the drug accountability records for the DISKUS and BADPI. • Subjects who, having completed the study with some devices not returned, failed to take a total of at least 80% study drug, as reported in the drug accountability records for the DISKUS and BADPI. • Unblinding of the treatment allocation for subjects (except for emergency treatment or care of the subject) resulted in partial violators and subjects’ data was excluded from the analysis from the time at which the unblinding occurred. Minor protocol violations

The following violations were not used to exclude subjects, nor exclude subject data, from the Per Protocol analysis but were identified in a data listing:

• Subjects whose visits fell outside of the windows defined in Section 5.8.6.3 Assessment Windows (except Visit 6 when this occurred as an Early Withdrawal Visit). • For subjects with less than 8 weeks of diary data: those who failed to record a total of at least 70% of the required PEF diary data during the treatment period. For those with greater than 8 weeks of diary data, at least 30% of the PEF data for the number of days in the treatment period before withdrawal needed to be recorded.

5.8.7.3. Demographic and baseline characteristics

Data collected at Visit 1 pertaining to demography i.e. age, sex, ethnic origin, height, and weight were tabulated by treatment group using both Intent-To-Treat and Per Protocol Populations, and listed for the ITT Population. Summaries for the childbearing status and pregnancy test results of female subjects and smoking status were provided.

Baseline data, i.e. current medical conditions and medications taken were reported using the ITT Population. A unique terms report showing the relationship between medications’ verbatim, preferred and grouped terms was given.

Summaries of asthma medications was split between any medication that started prior to treatment start, i.e. randomisation (regardless of when it ceased) and any medication that was present during the treatment period (regardless of when it commenced). Non-asthma medications that were present during the treatment period only, were reported. Asthma and non-asthma medications were listed separately. The following ‘all medication’ verbatim text was coded using the THERAPY dictionary to obtain the appropriate therapy group and preferred term.

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Disease history was summarised by treatment group, including:-

• Duration of asthma symptoms • Duration of inhaled corticosteroid use The number of asthma exacerbations in the previous 12 months that required oral corticosteroids and/or antibiotics treatment or in-patient hospitalisation was summarised by treatment group. The initial assessment and diagnosis of asthma were listed.

No formal statistical comparisons between treatments were performed for baseline and demographic characteristics.

Baseline clinic lung function data recorded at Visits 1 and 2/2A (both pre-VENTOLIN and post-VENTOLIN assessments) were summarised by treatment group using both Intent-to-Treat and Per Protocol Populations, including:-

• Clinic Pre-VENTOLIN FEV1

• Clinic Post-VENTOLIN FEV1

• Predicted Normal FEV1 and % Predicted Normal FEV1 • % Reversibility In addition, the mean values of the DRC data recorded over the last seven days of the run-in period were summarised by treatment group using both Intent-to-Treat and Per- Protocol Populations, including:-

• Mean morning PEF • Mean evening PEF • Mean circadian variation in PEF • Mean % predicted morning PEF • Mean % predicted evening PEF • Mean daytime symptom scores • Mean night-time symptom scores • % symptom-free days • % symptom-free nights • % VENTOLIN–free days • % VENTOLIN-free nights

5.8.7.4. Treatment compliance

Subjects who returned all their devices and failed to take a total of at least 80% or took over 125% study drug were classified as protocol violators. Subjects who did not return all their devices and failed to take at least 80% study drug were also classified as protocol violators. Compliance was tabulated and listed by treatment group and was defined as:

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Compliance = number of doses used /number of doses expected to be used x 100%

Assuming that treatment was started on the date of the randomisation visit, and that only one dose was taken that day, whilst 2 were taken every other day, the number of doses expected to be used was:

Expected no. of doses used = [ 2 x (treatment stop date – treatment start date)] + 1

The actual number of doses used was calculated from the number of doses prescribed (e.g. for the DISKUS this would have been 60 x number of inhalers given) minus the number of doses remaining when the inhalers were returned.

If the data were missing (e.g. the DISKUS was not returned), worst case was assumed, i.e. that zero doses were taken.

5.8.8. Efficacy Analyses

All confidence intervals calculated in the study analyses were symmetric and of size 95% and all hypothesis tests were 2-sided and conducted using a 5% significance level unless otherwise stated.

No formal statistical comparisons between treatments were performed for baseline and demographic characteristics – these data were summarised by treatment group and assessed informally for evidence of imbalance.

5.8.8.1. Primary efficacy measure

The primary efficacy endpoint was the number of asthma exacerbations experienced by the subject, expressed as a rate over the 24 week treatment period, based on the ITT Population.

The rate of exacerbations over the 24 week treatment period was analysed using maximum likelihood based analysis, assuming the Poisson distribution, with time on treatment as an offset variable. No imputation was performed. The model included adjustment for effects of sex, country (grouping) and age. The adjusted mean rates per 24-week treatment period, treatment ratio and associated p-values and confidence intervals were presented.

Interactions of treatment with sex, country (grouping) and age were tested in separate analysis models for statistical significance at the 10% level. If an interaction was considered meaningful, the effects of treatment were presented separately for each subgroup factor level.

Any potential over-dispersion was accounted for by using the deviance estimate of the scale parameter in the model. A sensitivity analysis was conducted without adjusting for any overdispersion.

The analysis was repeated for the Per-Protocol Population.

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For the purposes of all primary and secondary analyses, any exacerbations, regardless of severity, which began pre-treatment were not included. Only exacerbations that were treatment emergent (up to day 175) were included in the analyses.

All exacerbation data for each subject in the ITT Population were listed.

When the standardised deviance residuals from the Poisson model were examined they indicated that the model was a poor fit for the data. This indicated that the Poisson distribution may not have been a suitable model for this data. An alternative distribution was used to fit the model to assess the robustness of the result. The Negative Binomial was used as it improved the fit of the model.

5.8.8.2. Secondary efficacy measures

Tests for interactions were not performed for any of the secondary endpoints, nor were analyses of the Per-Protocol Population.

Number of exacerbations

The number of exacerbations per subject was assigned to one of the five following categories: 0, 1, 2, 3, >3. Only exacerbations occurring within the planned treatment period were included in the analysis. The percentage of subjects in each category were presented by treatment group, and treatment groups compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country (grouping) and treatment. This model was used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

For subjects withdrawing early from the study the number of exacerbations was imputed as described in Section 5.8.6.1. The analysis was repeated without imputation as a sensitivity analysis.

The number of subjects with at least one exacerbation was analysed using the Cochran- Mantel-Haenszel test, stratified by country (grouping). Percentages, differences in percentages between treatments, 95% confidence intervals and p-values were presented. No imputation was necessary for this endpoint.

Severity of exacerbations

The number and percentage of subjects with mild, moderate and severe exacerbations were presented by treatment.

Each subject was assigned to a ‘severity’ category based on the maximum severity of any of their exacerbations. The percentage of subjects in each category was presented by treatment group, and treatment groups were compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country (grouping) and treatment. This model was used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

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Time to first exacerbation

Time to first exacerbation was summarised using survival analysis. Subjects who withdrew from the study early and did not experience any exacerbations were censored at their last day of treatment. Subjects completing the study without experiencing any exacerbations were censored at their last day of treatment or day 175 ((168 days + the allowable 7 day visit window as specified in Section 5.8.6.3), whichever is earlier. For subjects experiencing an exacerbation, the treatment period was truncated to175 days, so that any subject experiencing their first exacerbation outside of the planned treatment period will be censored at day 175. A Cox’s proportional hazard model was used to compare treatment groups. Age and sex were covariates in the model, which was also stratified by country grouping.

A Kaplan Meier estimate of the survival curve was produced for this endpoint.

5.8.8.3. Other efficacy measures

PEF

Mean daily morning and evening PEF were derived from the DRC over the 24-week treatment period. Individual subject means were compared between treatment groups using analysis of covariance, allowing for effects due to baseline, country, sex, age and treatment. This model was used to estimate the treatment group difference and p-value, and calculate the 95% confidence interval for this difference.

Summary statistics for the raw and adjusted values of the mean and mean change from baseline were also presented. Similarly, mean values were derived and analysed for Weeks 1-8, 9-16 and 17-24.

Mean values for percent predicted morning and evening PEF (Weeks 1-24) were analysed using analysis of covariance and summarised by treatment group. Mean circadian variation in PEF (Weeks 1-24) was summarised by treatment group, no formal analysis was performed.

Clinic FEV1

Summary statistics were tabulated by treatment group at all clinic visits. Values recorded at Visit 6 (week 24), were analysed using analysis of covariance in the same way as diary card PEF values. The visit 2/2a (day 0) value was used as baseline. Clinic FEV1 data for each patient were listed.

Asthma symptoms (DRC)

For daytime and night-time symptom scores (Weeks 1-24) mean symptom scores on the DRC were calculated for each subject and analysed using analysis of covariance in the same way as for the lung function endpoints. A tabulation of summary statistics by treatment group was also produced.

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For percentage of symptom free days/nights (Weeks 1-24), the percentage of days/nights with a symptom score of zero was calculated for each subject and assigned to one of the following four categories:- 0% to 25%, >25% to 50%, >50% to 75%, >75%. The numbers of subjects in each of the treatment groups were compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country (grouping) and treatment. This model was used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

Missing data were not imputed for this endpoint.

Use of relief medication

The percentage of days/nights on which no relief VENTOLIN (Weeks 1-24) was taken was calculated for each subject and analysed in the same way as percentage symptom free days and nights. Missing data were not imputed for this endpoint.

Mean daily VENTOLIN use (Baseline, Weeks 1-24, 1-8, 9-16 and17-24) was derived from the DRC data and was summarised and (except at baseline) analysed using the Wilcoxon Rank Sum Test with treatment as a single covariate.

Withdrawals due to lack of efficacy

The number and percentage of subjects withdrawing during the treatment period due to lack of efficacy were tabulated by treatment group. A 95% confidence interval for the difference in the proportion of these withdrawals was also presented.

‘Well-controlled’ asthma

The difference between treatments in the proportion of patients who achieved ‘well- controlled’ asthma at anytime during the treatment period was assessed using a 2-sided Fisher's Exact test, and presented with the associated 95% confidence interval.

The number of weeks with ‘well-controlled’ asthma was analysed non-parametrically using the Wilcoxon Rank Sum test with treatment as a single covariate.

Asthma Control Questionnaire

The ACQ total score was calculated for each subject at each visit from the 7 questions of the ACQ (as detailed in Attachment 1) and analysed using analysis of covariance as described for mean daily PEF for each time point (Weeks, 4, 8, 16 and 24). Scores at baseline, each visit and change from baseline were presented. Individual scores for each subject were listed.

5.8.9. Safety Analyses

5.8.9.1. Extent of exposure

The extent of exposure, calculated as the number of days between start of treatment and end of treatment was summarised by treatment group and listed.

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5.8.9.2. Adverse events

Adverse events (AEs) were coded using the GSK MIDAS dictionary, and grouped by body system. Within each treatment group, adverse events were summarised by frequency and proportion of total subjects, by event type and by category of body system. Separate summaries were given for all AEs, most common AEs occurring on treatment, for drug-related AEs, for SAEs, and for AEs leading to withdrawal. Where appropriate, each phase of the study (pre-treatment, treatment and follow-up) was tabulated separately.

The proportion of subjects reporting at least one AE, at least one drug-related AE, at least one SAE, and at least one AE leading to withdrawal was calculated for each treatment group.

The relationship between verbatim and dictionary terms (body system and group term) were listed.

Deaths and serious adverse events

Deaths were listed only. SAEs were tabulated and listed separately. Case narratives were also provided by GSK GCSP personnel.

Pregnancies

Pregnancy data were listed as adverse events.

Clinical laboratory data

There were no laboratory evaluations conducted in this study.

Oropharyngeal candidiasis

The number and percentage of patients with clinical evidence of candidiasis were tabulated by treatment group. Individual subject data were listed.

5.8.10. Health Outcomes Analyses

5.8.10.1. Resource utilisation

Unscheduled Asthma-related Healthcare Contacts

Direct healthcare resource use data collected on the Unscheduled Asthma-related Healthcare Contacts form were summarised. Estimates of healthcare resource use were made based on resources used by subjects during the treatment phase of the study. The total number of units consumed for each type of healthcare contact were summarised independently. For healthcare contacts involving hospitalisation, the total number of hospitalisations was summarised as well as the total number of inpatient days. Hospitalisations involving both ICU and general ward visits were counted as single visits.

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Primary care (general practice) contacts (surgery visits and house calls) were summarised separately. Data for each subject were listed.

Time Missed From Work or Usual Activities

Time off work, as collected in the DRC, was summarised by treatment group in the following way: The number of days missed from work and the percentage of days with no time off work were summarised using descriptive statistics. In addition, the following categories were summarised: Number of days with no time off work, Number of half days lost, Number of complete days lost, the Total number of days lost and Number of days unknown due to missing data. These summaries also showed the number of subjects who fell within each category.

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6. STUDY POPULATION RESULTS

6.1. Disposition of Subjects

A total of 1769 subjects were screened for this study of which 1397 were randomised to treatment, 697 to the SFC group and 700 to the FBC group (Table 12.1). This comprised the Safety Population. Six of these subjects were excluded from the ITT Population (see Section 6.2) and the ITT Population comprised 1391 subjects, 694 in the SFC group and 697 in the FBC group. The Per Protocol Population consisted of 978 subjects, following the removal of 413 full protocol violators. The reasons for exclusion from the Per- Protocol Population are summarised in Table 12.8 (see Section 6.2).

Table 12.2 shows a summary of randomised subjects by investigator. Subjects were recruited in 178 centres in 18 countries, with the majority of individual centres contributing <1% of the total randomised.

A total of 372 (21%) subjects were withdrawn prior to randomisation (Table 12.3). The main reason for withdrawal was due to subjects not fulfilling the entry criteria (282 subjects (16%)). A summary of entry criteria failure is given in Table 12.7. The majority of subjects failed an entry criteria at Visit 2/2A, the most common reasons being inability to demonstrate either the required level of reversibility in FEV1 or the required asthma symptom score.

After randomisation, 133 (10%) subjects were withdrawn, 71/694 (10%) in the SFC group and 62/697 (9%) in the FBC group (Table 12.4). Table 12.5 summarises subject withdrawals after randomisation by time. Least subjects were withdrawn in the first 2 weeks of the study. The largest number of subjects withdrawn at any one Visit was at Week 8 in both treatment groups (SFC: 24 (3%), FBC: 18 (3%)). At least 89% of subjects in the SFC group, and 90% in the FBC group, in the ITT Population attended each clinic visit (Table 12.6).

6.2. Protocol Deviations

A total of 202/694 (29%) subjects in the SFC group and 211/697 (30%) subjects in the FBC group were totally excluded from the PP Population due to major protocol deviations (Table 12.8). A further 30 subjects (4%) in each treatment group were partially excluded from the PP Population due to protocol deviations (Table 12.8). Subjects could have had more than one reason for exclusion from the PP Population.

In both treatment groups, the most common deviation resulting in total exclusion from the PP Population was due to poor compliance in taking study medication. Where all

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devices had been returned, compliance of <80% or >125% occurred in 67 subjects (10%) in the SFC group and 55 subjects (8%) in the FBC group. Where not all devices had been returned, compliance of <80% occurred in 64 subjects (9%) in the SFC group and 65 subjects (9%) in the FBC group.

The most common reasons for partial exclusion from the PP Population were ‘subject took corticosteroid after Visit 1’ (SFC: 11 (2%), FBC: 12 (2%)) and moderate exacerbation not treated with oral corticosteroids (SFC: 11 (2%), FBC:6 (<1%)).

6.3. Populations Analysed

A summary of the study populations is shown in Table 12.1. The total population (1769 subjects) consisted of all subjects who entered the study. The Safety Population represented all subjects who had been randomised to treatment and had taken at least one dose of study medication. This consisted of 697 subjects in the SFC group and 700 subjects in the FBC group.

The ITT Population consisted of all subjects randomised to treatment that had taken at least one dose of study medication and had at least one post-randomisation diary assessment (excluding the six subjects from one centre as stated in Section 6.2). This consisted of 694 subjects in the SFC group and 697 subjects in the FBC group and this was the primary population for all efficacy and safety endpoints. The PP Population (492 subjects in the SFC group and 486 subjects in the FBC group) was a subset of the ITT Population with major protocol violators excluded; an analysis on the PP Population was performed on the primary endpoint only. Reasons for exclusion from the PP Population are summarised in Section 6.2.

6.4. Demographics and Other Baseline Characteristics

6.4.1. Demographic Characteristics

Demographic characteristics of the ITT Population are summarised in in-text Table 2 with further details presented in Table 12.9 and Table 12.14.

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Table 2 Demographic Characteristics of the ITT Population

Parameter SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391)

Age (years), mean (range) 45.6 (18-91) 47.1 (18-82) 46.3 (18-91)

Sex, n(%) Female 387 (56%) 409 (59%) 796 (57%) Male 307(44%) 288 (41%) 595 (43%)

Ethnic origin White 686 (99%) 691 (>99%) 1377 (99%) Black 1 (<1%) 2 (<1%) 3 (<1%) Asian 5 (<1%) 4 (<1%) 9 (<1%) Other 2 (<1%) 0 2 (<1%)

Height (cm), mean (range) 167.8 (142-198) 167.3 (140-204) 167.5 (140-204)

Weight (kg), mean (range) 76.22 (35 – 150) 76.42 (40-153.8) 76.32 (35-153.8)

Smoking History, n (%) Never smoked 446 (64%) 440 (63%) 886 (64%) Current smoker 65 (9%) 73 (10%) 138 (10%) Former smoker 183 (26%) 184 (26%) 367 (26%) Source: Table 12.9 and Table 12.14 N=number of subjects in each treatment group n= number of subjects with demographic characteristic

Demographic characteristics of the ITT Population were well matched between treatment groups. Slightly over half of the subjects in each group were female and almost all the patients in both groups were white. The demographic characteristics of the PP Population were similar to those of the ITT Population (Table 12.10).

Table 12.11 summarises the childbearing potential of the ITT Population. In both treatment groups, slightly over half of the female subjects were of non-childbearing potential (either sterile or post-menopausal). Of the remainder, the most common method of birth control was oral contraceptive, followed by abstinence and intrauterine contraceptive device.

Approximately two thirds of subjects had never smoked (Table 12.14). Of the remainder 10% of subjects were current smokers and approximately one quarter were former smokers.

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6.4.2. Baseline Characteristics

6.4.2.1. Asthma history

The asthma history of subjects in the ITT Population is shown in Table 12.12. The disease history was similar in each treatment group. Most subjects had had asthma for either >25 years (SFC: 145 (21%), FBC: 144 (21%)), ≥1 year to < 5 years (SFC: 147 (21%), FBC: 128 (18%)) or ≥ 5 years to < 10 years (SFC: 125 (18%), FBC: 146 (21%)). The majority of subjects had been using an inhaled corticosteroid for ≥ 1 year to <15 years.

The number of subjects experiencing an exacerbation that required treatment with antibiotics and/or corticosteroids, in the previous year, is shown in Table 12.13. A total of 454 (65%) of subjects in the SFC group and 452 (65%) subjects in the FBC group had had no exacerbations. Approximately one fifth of subjects in each group (SFC: 145 (21%), FBC: 452 (20%)) had had one exacerbation requiring treatment and nine percent of subjects in each group had two such exacerbations. A small number of subjects had had three or more exacerbations (SFC: 36 (5%), FBC: 44 (6%)).

The majority of subjects in each group had not had any exacerbations in the previous year that required hospitalisation (SFC: 650 (94%), FBC: 650 (93%)). A total of 39 (6%) subjects in the SFC group and 41 (6%) subjects in the FBC group had had one such exacerbation (Table 12.13).

6.4.2.2. Baseline lung function

In-text Table 3 summarises the baseline lung function characteristics of the ITT Population, with full details given in Table 12.15 and Table 12.21. Lung function data were well balanced between subjects randomised to SFC and FBC, at both Visit 1 and Visit 2/2a. Similar results were shown for the Per Protocol Population (Table 12.16 and Table 12.22).

The baseline results for the ACQ are shown in Table 12.23. The mean (range) score for the two treatment groups was comparable (SFC: 2.07 (0-4.9), FBC: 2.05 (0-4.9).

6.4.3. Other Current Medical Conditions

Table 12.17 summarises the current medical conditions by treatment group for the ITT Population. The proportion of subjects with at least one condition was similar between treatments: 561/694 (81%) subjects in the SFC group and 555/697 (80%) subjects in the FBC group. Overall, the types of conditions observed in each treatment group were also similar. In both treatment groups, allergy disorders were most common: 331/694 (48%) subjects in the SFC group and 311/696 (45%) subjects in the FBC group. Ear nose and throat disorders were present in 186 (27%) subjects in the SFC group and 172 (25%) subjects in the FBC group, whilst cardiovascular conditions were present in 155 (22%) and 149 (21%) subjects respectively. Other body systems for which conditions were reported in >10% of subjects in either treatment group were eyes, gastrointestinal, endocrine and metabolic and musculoskeletal.

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Table 3 Summary of baseline Lung Function Characteristics

Parameter SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391)

Documented Reversibility* (n) 693 696 1389 Yes 377 (54%) 355 (51%) 732 (53%) No 316 (46%) 341 (49%) 657 (47%)

Pre-BD FEV1 (L) at Visit 1 (n) 689 690 1379 Mean (range) 2.5 (0.7–5.7) 2.4 (0.9-5.5) 2.4 (0.7-5.7)

Post-BD FEV1 (L) at Visit 1 (n) 358 372 730 Mean (range) 2.8 (1.1-6.1) 2.7 (1.0-5.5) 2.8 (1.0-6.1)

% predicted FEV1 at Visit 1 (n) 689 690 1379 Mean (range) 78.8 (32.5-137.2) 78.3 (41.4-146.3) 78.5 (32.5-146.3)

Reversibility at Visit 1 (n) 358 372 730 Mean (range) 21.4 (-5.0-90.2) 22.3 (-6.2-151.9) 21.8 (-6.2-151.9)

Pre-BD FEV1 (L) at Visit 2/2a (n) 693 696 1389 Mean (range) 2.5 (0.6-5.4) 2.4 (0.8-5.6) 2.4 (0.6-5.6)

Post-BD FEV1 (L) at Visit 2/2a (n) 90 104 194 Mean (range) 2.7 (1.2-5.6) 2.6 (0.9-4.8) 2.7 (0.9-5.6)

% predicted FEV1 at Visit 2/2a (n) 693 696 1389 Mean (range) 78.7 (25.7-133.2) 78.5 (30.8-142.5) 78.6 (25.7-142.5)

Reversibility at Visit 2/2a (n) 90 104 194 Mean (range) 19.6 (3.1-69.8) 24.0 (7.7-104.2) 21.9 (3.1-104.2)

Mean am PEF** (L/min), n 694 696 1390 Mean (range) 357.6 (64-771) 348.4 (99-741) 353 (64-741) Source: Table 12.15 and Table 12.21 N=number of subjects in each treatment group n= number of subjects with baseline value *Documented evidence of reversibility within last 2 years **mean over last 7 days of the Run-in period; BD = bronchodilator

6.4.4. Previous Medications

Table 12.18 summarises the asthma medication started prior to study treatment. Most subjects had been taking an inhaled corticosteroid prior to the study (SFC: 689 (>99%), FBC: 696 (>99%) and the majority had been using a short-acting beta-agonist (SFC:546 (79%), FBC: 524 (75%)). Approximately a third of subjects had been taking a LABA (SFC: 240 (35%), FBC: 265 (38%)) and a similar proportion of subjects had been taking

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a corticosteroid and bronchodilator combination (SFC: 223 (32%), FBC: 236 (34%)). All other categories of asthma medication started prior to randomisation were used by less than 10% of subjects in either treatment group.

6.5. Concomitant Medications

6.5.1. Asthma medications

A total of 97 (14%) subjects in the SFC group and 115 (16%) subjects in the FBC group took an asthma medication in addition to the study medication during the treatment period (Table 12.19). The most common medication taken in both groups was corticosteroids, including prednisolone (SFC: 67 (10%), FBC: 80 (11%)). All other categories of asthma medication including short acting beta-2 agonists not provided as study medication were taken by ≤3% of subjects in either treatment group.

6.5.2. Non-asthma medications

Table 12.20 shows the non-asthma medications taken during treatment by subjects in the ITT Population. The proportion of subjects taking at least one non-asthma medication was similar in both treatment groups (SFC: 491 (71%), FBC: 486 (70%). The types of concomitant medications taken were also similar between treatments: In both groups, anti-histamines (H1 antagonists) were the most common concomitant medication (SFC: 142/491, (20%); FBC:105/486, (15%)). Other concomitant medications taken by more than 10% of subjects in either treatment group were miscellaneous analgesics, corticosteroids, non-steroidal anti-inflammatories and estrogens/progestogens combined.

6.6. Treatment Compliance

Subjects who returned all their devices and failed to take a total of at least 80% or took over 125% study drug were classified as protocol violators. Subjects who did not return all their devices and failed to take at least 80% study drug were also classified as protocol violators (see Section 5.8.7.4). The mean percentage compliance was 89% in both groups (Table 12.24). A total of 150 (22%) subjects in the SFC group and 145 (21%) subjects in the FBC group took <80% of their prescribed study medication.

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7. EFFICACY RESULTS

7.1. Primary Efficacy Results

The primary efficacy endpoint in this study was number of asthma exacerbations expressed as a rate over the 24-week treatment period. A summary of the results and the statistical analysis comparing the treatment groups (ITT Population) is shown in in-text Table 4, and in full detail in Table 13.1 and Table 13.3.

Table 4 Summary of Rate of Exacerbations Over 24 Weeks

ITT Population SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Mean ±SD Exacerbation Rate*, 3.06 ±4.44 3.07±4.27

Mean Rate from Poisson Model 2.69 2.79

Treatment Comparison (SFC/FBC) Ratio 0.96 95% CL 0.84, 1.10 p-value 0.571 Source Table 13.1 and Table 13.3 * Exacerbation data imputed for subjects withdrawing prematurely

There was no statistically significant difference between the two treatment groups in the rate of exacerbations. Similar results were shown for the Per Protocol Population (Table 13.2 and Table 13.4). No statistically significant evidence of interactions between treatment and age/sex or country grouping was found.

No further analyses were performed for the Per Protocol Population as the results of the primary analysis were the same for the ITT and Per Protocol Populations.

7.1.1. Results of Covariate Analysis

There were no statistically significant interactions of treatment with sex, country (grouping) or age.

7.1.2. Negative Binomial Model

The Negative Binomial model adjusted for gender, country grouping and age was fitted as an alternative to the Poisson as it gave a better fit to the data. The standardised residuals were checked and they indicated that the Poisson distribution was inadequately fitting the data therefore the Poisson model was not a suitable model for this data. The Negative Binomial was fitted and the results obtained were very similar to those from the

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Poisson model. However, examination of the standardised deviance residuals indicated that there was a dramatic improvement in fit of the model, suggesting the negative binomial distribution was much better to deal with this data.

The results of the analysis from the Negative Binomial model, shown in Table 13.5 and in-text Table 5, are very similar to those obtained from the Poisson model, the point estimates of the rates for the treatments were very slightly increased, and the 95% confidence interval for the rate ratio were slightly wider.

Table 5 Statistical Analysis of the Rate of Exacerbations Over 24 Weeks using the Negative Binomial Model

ITT Population SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Mean Rate Per 24 Weeks from 2.72 2.82 Negative Binomial Model

Treatment Comparison (SFC/FBC) Ratio 0.96 95% CL 0.83, 1.12 p-value 0.628 Source Table 13.5

7.1.3. Post Hoc Analyses

7.1.3.1. All exacerbations adjusting for interval

For each subject the number of all exacerbations that started in each of the 3 intervals was counted. However this approach led to missing data due to withdrawals. Therefore, a GEE model was fitted using the negative binomial distribution adjusting for gender, country grouping, age and time interval. The results presented in Table 13.7 and in-text Table 6 used the LOCF approach for dealing with withdrawn subjects and shows the exacerbation rate, adjusting for interval, as an annualised rate.

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Table 6 Rate of All Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Mean Rate Per Year from GEE Model 5.87 6.07

Treatment Comparison (SFC/FBC) Ratio 0.97 95% CL 0.84, 1.11 p-value 0.645 Source Table 13.7

There was no statistically significant difference in overall exacerbation rates between the two treatment groups, after adjusting for gender, country grouping, age and interval. However, for both treatment groups, there was a highly statistically significant effect of time demonstrating a consistent reduction in exacerbation rates as time progressed. Overall, in weeks 9-16 there was an estimated 30% reduction (95% CI: 24% - 36%; p < 0.001) in the rate of exacerbations compared with weeks 1-8. In week 17-24 there was an estimated 36% reduction (95% CI: 30% - 42%; p < 0.001) in the rate of exacerbations compared with weeks 1-8.

A treatment-by-interval interaction was tested in a separate model, but was found not to be statistically significant (p = 0.82). This indicated that there was no statistically significant evidence that the estimated exacerbation rate ratio between the treatments varied between intervals.

The results obtained from other approaches for missing data were very similar, indicating that the analysis was robust to the method of dealing with missing data.

7.1.3.2. Moderate/severe exacerbations over 24 weeks

When the severity of exacerbations was investigated it was noted that there was a numerical imbalance between the SFC and FBC groups in the number of moderate/severe exacerbations (67 for SFC vs 80 for FBC, see in-text Table 7 and Table 13.12). Therefore the moderate and severe exacerbations were investigated separately and the primary analysis, as stated in the RAP, was run on this subset.

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Table 7 Summary of Severity of Exacerbations

Number (%) Subjects

Severity1 SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Severe 4 (<1%) 1 (<1%)

Moderate 63 (9%) 79 (11%)

Mild 369 (53%) 371 (53%)

No exacerbation 258 (37%) 246 (35%) Source Table 13.12 1. Maximum severity of exacerbation experienced by subjects.

A Poisson Model adjusted for gender, country grouping and age was fitted on the subset of moderate and severe exacerbations. The results of the analysis are shown in Table 13.6 and in-text Table 8.

Table 8 Rate of Moderate/Severe Exacerbations Over 24 Weeks

SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Mean Rate Per 24 Weeks from 0.08 0.11 Poisson Model

Treatment Comparison (SFC/FBC) Ratio 0.75 95% CL 0.54, 1.05 p-value 0.095 Source Table 13.6

There was no statistically significant difference between the two treatment groups in terms of the moderate/severe exacerbation rate over 24 weeks.

The Poisson model appeared to fit the data better than when used for all exacerbations as the counts for moderate/severe exacerbations were very low with greater consistency across patients.

7.1.3.3. Moderate/severe exacerbations adjusting for interval

A GEE model was fitted using the Poisson distribution adjusting for gender, country grouping, age and interval (time). The results in Table 13.8 and in-text Table 9 used the

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LOCF approach for dealing with withdrawn subjects and show the rate of moderate/severe exacerbations, adjusting for interval, as an annualised rate.

Table 9 Rate of Moderate/Severe Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Mean Rate Per Year from GEE Model 0.18 0.25

Treatment Comparison (SFC/FBC) Ratio 0.71 95% CL 0.51, 1.00 p-value 0.052 Source Table 13.8

The SFC group showed a 29% reduction in investigator defined moderate/severe exacerbation rate compared with the FBC group and this difference approached statistical significance (95% CI: 0% – 49% reduction; p= 0.052).

For both treatment groups, there was a statistically significant effect of interval (time). Overall, in weeks 9-16 there was an estimated 33% reduction (95% CI: 6% - 53%; p = 0.02) in the rate of moderate/severe exacerbations compared with weeks 1-8. In week 17-24 there was an estimated 28% reduction (95% CI: 1% - 48%; p = 0.0457) in the rate of these exacerbations compared with weeks 1-8.

A treatment-by-interval interaction was tested in a separate model (GEE model assuming negative binomial distribution adjusting for age, country group, gender and time interval), but was found not to be statistically significant (p = 0.28). This indicated that there was no statistically significant evidence that the estimated exacerbation rate ratio between the treatments varied between intervals.

Figure 1 shows the adjusted moderate/severe exacerbations for each interval from this model. This is presented as a summary only. The results obtained from other approaches were almost identical, indicating that the analysis was performed using a robust method for dealing with missing data.

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Figure 1 Adjusted Moderate/Severe Exacerbation Rates by Study Interval

0.291 0.3

0.258 0.252 0.250 0.25

0.213

0.2

0.169

0.147 0.15 0.130

0.1

0.05 Adjusted Annual Moderate/Severe Annual Moderate/Severe RateExacerbation Adjusted

0 Weeks 1-24 Weeks 1-8 Weeks 9-16 Weeks 17-24 Study Interval

SFC FBC

7.1.3.4. Protocol defined exacerbations

Although the investigators were given instructions about how to record the number and severity of exacerbations, the final decision about their duration and severity was left to investigator discretion. As a result there were some discrepancies between numbers of investigator-recorded and protocol-defined exacerbations (see Section 5.8.1.2.3), so further analyses were performed using exacerbation data as strictly defined in the protocol. The purpose of this was to present a more sensitive and objective analysis of the data.

Figure 2 shows the cumulative number of exacerbations by study day in each treatment group. From approximately eight weeks of treatment, the cumulative number of exacerbations is slightly higher in the FBC group compared with the SFC group and this difference increased as time progressed. However, as for investigator-recorded exacerbations, there was no statistically significant difference between the groups (See Section 7.1.3.1).

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Figure 2 Cumulative Plot by Study Day of All Protocol-Defined Exacerbations

7.1.3.4.1. Protocol-defined moderate/severe exacerbations

In the analysis of protocol-defined moderate/severe exacerbations (using the LOCF for withdrawn subjects) a statistically significant treatment-by-interval interaction (tested at the 10% significance level) was found (p=0.05). This indicated that the treatment difference varied between intervals, in contrast to the investigator-recorded exacerbations where there was no statistically significant treatment-by-interval interaction (Section 7.1.3.3). The results presented in this section included the interaction term in the GEE model which allowed the treatment difference (exacerbation ratio) and corresponding confidence intervals and p-values in each interval to be estimated from the model using all the data (i.e. without the subsetting of the data into individual intervals).

A summary of the rate of protocol-defined moderate/severe exacerbations, adjusting for interval, is shown in in-text Table 10 and Table 13.9. The SFC group showed a 30% reduction in the rate of such exacerbations compared with the FBC group and this difference approached statistical significance (95% CI: 52% reduction – 1% increase; p=0.059). A cumulative plot of the number of moderate/severe exacerbations by study day in each treatment group is shown in Figure 3. The treatment lines start to diverge after about three months of treatment and the difference between the groups increased with time such that the largest difference in cumulative number of moderate/severe exacerbations was observed in the last 8 weeks of treatment.

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Table 10 Summary of Rate of Protocol-Defined Moderate/Severe Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Adjusted Mean Rate per Year 0.155 0.223

Treatment Comparison (SFC/FBC) Ratio 0.70 95% CL 0.48, 1.01 p-value 0.059 Source Table 13.9

Figure 3 Cumulative Plot by-Study Day of Moderate/Severe Protocol-Defined Exacerbations

Figure 4 shows the adjusted annual protocol-defined moderate/severe exacerbation rates in each interval of the study and in-text Table 11 shows the estimated exacerbation rate ratio for each of the intervals. The largest difference between treatments was shown in the Weeks 17-24 where the SFC group showed a 57% reduction in the protocol-defined moderate/severe exacerbation rate compared with FBC and this difference was statistically significant (95% CI 21%-77% reduction, p=0.006).

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Table 11 Estimated rate Ratio for Protocol Defined Moderate/Severe Exacerbations for Each Time Interval

Interval Estimated Rate Ratio 95% CI p-value (SFC / FBC)

Weeks 1-24 (overall) 0.70 0.48, 1.01 0.059

Weeks 1-8 1.01 0.61, 1.67 0.960

Weeks 9-16 0.78 0.45, 1.35 0.371

Weeks 17-24 0.43 0.23, 0.79 0.006 Source Table 13.9

Figure 4 Adjusted Moderate/Severe Protocol-Defined Exacerbation Rates by Study Interval

0.3 † * 0.25 0.244 0.223 0.227 0.224

0.202 0.2

0.155 0.157 0.15

0.105 0.1

0.05 Adjusted Annual Moderate/Severe Exacerbation Rate

0 Weeks 1-24 Weeks 1-8 Weeks 9-16 Weeks 17-24 Study Interval † Overall treatment difference: p=0.059 * Treatment difference in Interval 3: p=0.006 SFC FBC

The results obtained from other approaches were almost identical, indicating that the analysis was robust to the method of dealing with missing data.

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7.2. Secondary Efficacy Results

7.2.1. Number of Exacerbations

A summary of the number of exacerbations per subject during the 24 week treatment period is shown in Table 13.10. A total of 258 (37%) subjects in the SFC group and 246 (35%) subjects in the FBC group had no exacerbations during the treatment period. Similarly, approximately a third of subjects in each treatment group had >3 exacerbations (SFC: 210 (30%), FBC: 202 (29%)). The remainder of subjects had between 1 and 3 exacerbations. There was no statistically significant difference in these results between treatment groups. There was also no difference in the proportion of subjects with at least one exacerbation during the treatment period (SFC:436 (63%), FBC: 451 (65%), p=0.454) (Table 13.11).

7.2.2. Severity of Exacerbations

The number of subjects with exacerbations classed as mild, moderate or severe is summarised in Table 13.12. Of those subjects having exacerbations, the majority had mild exacerbations, the numbers being similar in both treatment groups (SFC: 369 (53%), FBC: 371 (53%)). Overall, there was no statistically significant difference between treatments in the severity of exacerbations (SFC/FBC odds ratio 1.11; 95% CL 0.90, 1.36; p=0.317).

7.2.3. Time to First Exacerbation

Table 13.13 shows a summary of the time to first exacerbation in each treatment group. In both treatment groups a large number of subjects had their first exacerbation in Weeks 1-4 (SFC: 310/694, FBC 301/697). As the study progressed smaller numbers of subjects had their first exacerbation at a particular time interval. The survival estimate column shows the Kaplan-Meier estimates of the probability of surviving to the end of the interval without experiencing a first exacerbation. This data is also shown in Figure 13.3. The survival times were similar for both treatment groups.

The survival analysis of time to first exacerbation based on Cox’s Proportional Hazards model is summarised in Table 13.14. The Kaplan-Meier estimate of the median time to first exacerbation was 40 days in the SFC group and 47 days in the FBC group. There was no statistically significant difference between treatment groups (SFC/FBC hazard ratio 1.03; 95% CL 0.91, 1.18; p=0.617).

7.3. Other Efficacy Results

7.3.1. PEF

7.3.1.1. Mean morning and evening PEF

In both treatment groups, there was a steady increase in mean morning PEF during the treatment period (Table 13.15). The baseline PEF was slightly higher in the SFC group

6269 CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040 compared with the FBC group (SFC: 357.6 L/min, FBC: 348.4 L/min) but the extent of the increase from baseline in mean morning PEF was comparable between treatment groups. Over Weeks 1-24 the increase in raw mean±SD in the SFC group was 39±46.88 L/min compared with 38.6±46.68L/min in the FBC group.

Statistical analysis showed there was no significant difference between treatments with regards to change from baseline in mean morning PEF over the whole treatment period (Table 13.16 and in-text Table 12).

Table 12 Mean change in morning PEF (L/min) over Weeks 1-24

SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Subjects, n 686 691 Baseline raw mean (SD) 357.5 (112.75) 348.3 (111.64) Raw mean Weeks 1-24 (SD) 396.5 (110.90) 386.8 (112.66) Adjusted mean Weeks 1-24 (se) 394.6 (1.74) 394.3 (1.75) Adjusted mean change (se) 41.8 (1.74) 41.4 (1.75)

Statistical analysis (SFC-FBC) Difference (SE) 0.34 (2.37) 95% CL –4.30, 4.99 p-value 0.885 Source Table 13.16 N=number of subjects in each treatment group n=number of subjects included in assessment

Similar results were shown for mean evening PEF (Table 13.17). Over Weeks 1-24, the raw mean±SD increase in the SFC group was 32.7±46.13 L/min compared with 32.9±45.72L/min in the FBC group. The results of the statistical analysis showed a non- significant difference between treatments of –0.33L/min (95% CI: –4.90, 4.24; p=0.887) (Table 13.18).

7.3.1.2. Percent predicted morning and evening PEF

The mean percent predicted morning PEF at baseline, and change over treatment is shown in Table 13.19. Baseline values were very similar for the two treatment groups (SFC: 78.9%, FBC: 78.2%) and there was a steady increase in values over the treatment period. Over Weeks 1-24 the raw mean±SD increase in the SFC group was 9.0±10.9% compared with 8.9±10.74% in the FBC group. The results of the statistical analysis showed a non-significant difference between treatments of 0.22% (95% CI: –0.84, 1.28; p=0.683) (Table 13.20).

Similar results were shown for percent predicted evening PEF (Table 13.21). Over Weeks 1-24 the raw mean±SD increase in the SFC group was 7.6±10.7% compared with

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7.6±10.46% in the FBC group. The results of the statistical showed a non-significant difference between treatments of 0.07% (95% CI: –0.97, 1.10; p=0.902) (Table 13.22).

7.3.1.3. Circadian variation in PEF

The mean circadian variation in PEF over weeks 1-24 is summarised in Table 13.23. Baseline mean±SD values were similar in the two treatment groups (SFC: 8.8±6.74 L/min, FBC: 9.2±6.65 L/min) and there was a steady decrease in mean circadian variation during both treatments. Over Weeks 1-24 the raw mean±SD decrease in the SFC group was –3.1±5.56L/min compared with –2.9±5.44L/min in the FBC group. No statistical analysis was performed on this endpoint.

7.3.2. Clinic FEV1

There was a steady increase in clinic FEV1 over the treatment period in both treatment groups (Table 13.24). A summary of raw values and change from baseline to Week 24 is shown in Table 13.25. At baseline, the mean±SD values were 2.45±0.85L in the SFC group and 2.40±0.85L in the FBC group. By Week 24 these values had increased to 2.71±0.91L and 2.64±0.89L in the two groups respectively. The results of the statistical analysis showed a non-significant difference between treatments of 0.03L (95% CI: – 0.02, 0.07; p=0.221) (Table 13.26)

7.3.3. Asthma Symptoms

A summary of daytime symptom scores is presented in Table 13.27. At baseline the mean±SD symptom scores were comparable in both treatment groups (SFC: 1.8±0.75, FBC: 1.8±0.73). Over Weeks 1-24 mean daytime symptom score decreased to 0.8 in both groups. The statistical analysis showed a non-significant difference between treatments of 0.03 (95% CL –0.04, 0.10; p=0.425) (Table 13.28).

Baseline night-time symptom scores were also similar for the two treatment groups (SFC: 1.0±0.68 FBC: 0.9±0.69) and the mean symptom score decreased to 0.4 in both treatment groups over Weeks 1-24 (Table 13.29). The results of the statistical analysis showed no significant difference between treatments (Table 13.30).

Both treatment groups showed a large increase in the mean±SD percentage of symptom- free days between baseline (SFC: 8.2±16.98% FBC: 7.3±16.32%) and treatment over Weeks 1-24 (SFC: 52.4±38.99% FBC: 52.0±38.53%) (Table 13.31). In both treatment groups the largest number of subjects had either >75% symptom-free days (SFC:273 (40%) FBC: 280 (40%)) or ≤25% symptom free days (SFC: 236 (34%) FBC: 235 (34%) (Table 13.32). There was no significant difference between treatments in the analysis of the frequency distribution of symptom-free days (odds ratio 1.03, 95% CL 0.84, 1.25, p=0.80).

The mean±SD percentage of symptom-free nights was similar in both groups at baseline (SFC: 31.5±35.77% FBC: 35±37.64%). Over Weeks 1-24 this increased to 68±35.91% and 67.2±36.71% respectively (Table 13.33). In both treatment groups the majority of

6471 CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040 subjects had >75% symptom-free nights (SFC:401 (58%) FBC: 402 (58%)). There was no significant difference between treatments in the analysis of the frequency distribution of symptom-free nights (odds ratio 0.97, 95% CL 0.78, 1.19, p=0.758) (Table 13.34).

A summary of results of asthma symptoms is shown in in-text Table 13.

7.3.4. Use of Relief Medication

In both treatment groups there was a similar increase in the percentage of days when no relief medication was used (Table 13.35). The baseline mean±SD was 25.7±36.08% in the SFC groups and 24.6±35.34% in the FBC group. Over Weeks 1-24 this increased to 66.4±36.69% and 64.8±36.27% in the two groups respectively. The majority of subjects had >75% days with no relief use (SFC:388 (57%) FBC: 307 (55%)) (Table 13.36). There was no significant difference between treatments in the analysis of the frequency distribution of rescue-free days (odds ratio 0.95, 95% CL 0.77, 1.17, p=0.620) (Table 13.36).

At baseline the mean±SD percentage of nights when no relief medication was used was 50.7±40.86% in the SFC group and 52.3±40.84% in the FBC group (Table 13.37). Over Weeks 1-24 this increased to 80.4±29.5% and 78.7±30.66% in the two groups respectively. There was no significant difference between treatments in the analysis of the frequency distribution of rescue-free nights (odds ratio 0.92, 95% CL 0.73, 1.17, p=0.512) (Table 13.38).

The mean daily VENTOLIN use decreased in both treatment groups between baseline (mean±SD number of occasions; SFC: 2.28±1.8, FBC: 2.34±1.83) and treatment over Weeks 1-24 (SFC: 0.9±1.30, FBC: 0.94±1.34) (Table 13.39). There was no statistically significant difference between treatment groups.

A summary of results is shown in in-text Table 13.

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Table 13 Summary of Results of Asthma Symptoms and Relief Medication Use

Parameter SFC FBC Summary of 50/250 4.5/160 Statistical Analysis (N=694) (N=697)

Daytime Symptom B/L 1.8±0.75 1.8±0.73 Diff (SE): 0.03 (0.04) Score (mean±SD) 95%CL: -0.04, 0.10 WK 1-24 0.8±0.79 0.8±0.78 p-value: 0.425

Night-time Symptom B/L 1.0±0.68 0.9±0.69 Diff (SE): -0.02 (0.03) Score (mean±SD) 95%CL: -0.07, 0.03 WK 1-24 0.4±0.56 0.4±0.56 p-value: 0.383

Percentage Symptom- 0 - ≤25% 236(34%) 235(34%) Odds ratio: 1.03 Free Days (n(%)) >25% - ≤50% 67(10%) 88(13%) 95%CL: 0.84, 1.25 >50% - ≤75% 109(16%) 89(13%) p-value 0.800 >75% - ≤100% 273(40%) 280(40%)

Percentage Symptom- 0 - ≤25% 134(20%) 148(21%) Odds ratio: 0.97 Free Nights (n(%)) >25% - ≤50% 49(7%) 54(8%) 95%CL: 0.78, 1.19 >50% - ≤75% 102(15%) 88(13%) p-value 0.758 >75% - ≤100% 401(58%) 402(58%)

Percentage of Days 0 - ≤25% 149(22%) 149(22%) Odds ratio: 0.95 with no Relief >25% - ≤50% 51(7%) 77(11%) 95%CL: 0.77, 1.17 Medication (n(%)) >50% - ≤75% 98(14%) 87(13%) p-value 0.620 >75% - ≤100% 388(57%) 377(55%)

Percentage of Nights 0 - ≤25% 67(10%) 79(11%) Odds ratio: 0.92 with no Relief >25% - ≤50% 33(5%) 39(6%) 95%CL: 0.73, 1.17 Medication (n(%)) >50% - ≤75% 75(11%) 67(10%) p-value 0.512 >75% - ≤100% 509(74%) 505(73%)

VENTOLIN Use (mean±SD no. WK 1-24 0.9±1.3 0.94±1.34 p-value: 0.321 occasions) Source Table 13.27 - Table 13.30, Table 13.32, Table 13.34, Table 13.35, Table 13.38, Table 13.39 B/L = baseline WK 1-24 = over weeks 1-24 N=number of subjects in each treatment group n=number of subjects included in assessment

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7.3.5. Withdrawals Due to Lack of Efficacy

The percentage of subjects withdrawing from the study due to lack of efficacy was <1% in both treatment groups (SFC: 5/694, FBC: 2/697) and the statistical analysis showed no significant difference between treatments (Table 13.40).

7.3.6. ‘Well-Controlled’ Asthma

The proportion of subjects who achieved a week of ‘well-controlled’ asthma at any point during the treatment period was the same in both treatment groups (SFC: 483 (70%), FBC: 486 (70%)) (Table 13.41). Over Weeks 1-24, the mean number of weeks with ‘well-controlled’ asthma was slightly higher in the SFC group compared with the FBC group (10.2±9.2 vs 9.6±9.1 weeks) but this difference was not statistically significant (p=0.3905) (Table 13.42).

7.3.7. Asthma Control Questionnaire (ACQ)

The mean total scores on the ACQ decreased steadily during treatment in both groups, the scores being comparable between groups (Table 13.43). The mean±SD total scores at baseline were similar in both treatment groups: 2.07±0.84 in the SFC group and 2.05±0.86 in the FBC group (Table 13.44). At Week 4 the mean±SD score was 1.26±0.88 in the SFC group and 1.26±0.84 in the FBC group with the majority of subjects having a score of <2 (Table 13.43). At the end of the treatment period, the respective mean scores were 1.02±0.85 and 1.03±0.86, and there had been a shift in the distribution of scores such that more subjects were scoring in the lower categories i.e. having milder symptoms.

Table 13.44 summarises the raw mean scores and change from baseline at each assessment visit. The maximum mean change from baseline was seen at Week 24 (SFC: - 1.04±0.87, FBC: -1.03±0.92). The statistical analysis of change from baseline at Week 24 showed no significant difference between treatments (difference –0.01, 95% CL – 0.09, 0.07, p=0.829) (Table 13.45).

7.4. Efficacy Conclusions

Regular treatment with SERETIDE and Symbicort significantly reduced asthma exacerbations and resulted in improvement in lung function and symptomatology. Both treatments were found to be similarly efficacious.

The primary endpoint, the mean rate of all exacerbations over 24 weeks was similar in both treatment groups

Post hoc analyses investigating the benefits of sustained treatment have been conducted on exacerbation data for this study. These analyses have shown treatment differences in favour of SERETIDE with a significant time interval effect in relation to severe and moderate exacerbations over weeks 1 -24 (p=0.059) particularly in weeks 17 -24 of the treatment period (p = 0.006)

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8. HEALTH OUTCOMES RESULTS

8.1. Resource Utilisation

8.1.1. Unscheduled Asthma-related Healthcare Contacts

A summary of unscheduled asthma-related healthcare contacts is shown in Table 14.1 and in-text Table 14.

Table 14 Summary of Unscheduled Asthma-related Healthcare Contacts

Rate of Contact per 10000*

Contact method SFC 50/250 FBC 4.5/160 (N=694) (N=697)

Telephone 3.3 4.6

Home/day 0.5 0.4

Home/night 0 0

Office/practice 5.0 4.4

Outpatients Clinic 2.5 2.6

Emergency room/A&E 0.7 0.9

Hospital ICU 0.6 0

Hospital general ward 1.4 0.4

No. of hospitalisations 0.5 0.1 Source Table 14.1 *Rate of contact per 10,000 treatment days=(no. units/length treatment) x 10,000

The majority of unscheduled contacts made during the study were either by telephone or by contact with a primary care unit, and the rate of contact for these was similar for both treatment groups. Very few subjects had unscheduled hospital contacts during the study.

8.1.2. Time Missed from Work or Usual Activities

The median (range) number of days missed from work during the treatment period was similar in both treatment groups (SFC: 0 (0 to 136) days, FBC: 0 (0 to 142)) days (Table 14.2). The median (range) percentage of days with no time missed off work was 95.6 (0 to 100) % in the SFC group and 95.9 (0 to 100) % in the FBC group.

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8.2. Health Outcomes Conclusions

• The rate of unscheduled asthma-related contacts during the study was generally low in both treatment groups and the majority of contacts were by telephone or through a primary care unit. • The number of days lost from work was similarly low in both treatment groups.

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9. SAFETY RESULTS

9.1. Extent of Exposure

The mean duration of exposure to study medication was similar in each treatment group: mean (range) was 15.9 (4 to 216) days in the SFC group and 161.8 (5 to 217) days in the FBC group (Table 15.1). The majority of subjects were exposed to study medication for either 113-168 days (SFC: 242 (35%), FBC: 261 (37%) or >168 days (SFC: 392 (56%), FBC: 389 (56%)).

9.2. Adverse Events (AEs)

9.2.1. Pre-treatment Adverse Events

The proportion of subjects reporting an AE in the pre-treatment period was comparable between treatment groups: 101/697 (14%) in the SFC group and 111/700 (16%) in the FBC group (Table 15.3). The most commonly reported AE in both groups was headache (SFC: 46/697 (7%), FBC: 43/700 (6%), followed by upper respiratory tract infection (SFC: 7/697 (1%), FBC: 18/700 (3%). All other AEs occurred in <1% of subjects in either treatment group.

9.2.2. Treatment emergent Adverse Events

The proportion of subjects with an AE that started during treatment was similar in both treatment groups: 384/697 (55%) in the SFC group and 377/700 (54%) in the FBC group (Table 15.4). The number of subjects reporting events in each body system was also comparable, AEs being most commonly reported in the ear, nose and throat body system: 203/697 (29%) subjects in the SFC group and 181/700 (26%) in the FBC group. Other commonly affected body systems were the neurological (SFC: 114/697 (16%), FBC: 112/700 (16%)), lower respiratory (SFC: 108/697 (15%), FBC: 96/700 (14%)), gastrointestinal (SFC: 102/697 (15%), FBC:76/700 (11%)) and musculoskeletal (SFC: 75/697 (11%), FBC: 72/700 (10%)) systems. AEs in other body systems were reported for less than 10% of subjects in each treatment group.

In-text Table 15 summarises the most common individual AEs (reported for ≥3% subjects in either treatment group) that started during treatment. The frequency of individual AEs was similar in both treatment groups (Table 15.9).

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Table 15 Summary of Most Common Adverse Events* that Started During Treatment (Safety Population)

Number (%) Subjects Event SFC 50/250 FBC 4.5/160 (N=697) (N=700)

Any event 384 (55) 377 (54)

Headaches 101 (14) 95 (14)

Upper respiratory tract infection 101 (14) 94 (13)

Rhinitis 45 (6) 34 (5)

Lower respiratory infections 33 (5) 34 (5)

Musculoskeletal pain 27 (4) 40 (6)

Viral respiratory infections 27 (4) 29 (4)

Throat irritation 32 (5) 23 (3)

Cough 25 (4) 22 (3) Source: Table 15.9 *Occurring in ≥3% subjects in either treatment group

9.2.3. Post-treatment Adverse Events

In the post-treatment period 16/697 (2%) subjects in the SFC group and 14/700 (2%) subjects in the FBC group reported an AE (Table 15.5). No single type of AE was reported by ≥1% of subjects in either treatment group.

9.2.4. Drug-related Adverse Events

Drug-related AEs were reported by the reporting investigators for 58/697 (8%) subjects in the SFC group and 61/700 (9%) subjects in the FBC group (Table 15.6). The most commonly reported drug-related events in both treatment groups were: hoarseness/dysphonia (SFC: 13/697 (2%), FBC: 13/700 (2%)), candidiasis of mouth/throat (SFC: 12/697 (2%), FBC: 7 (1%)) and headaches (SFC: 9/697 (1%), FBC: 12/700 (2%)). No other drug-related event was reported by >1% subjects in either treatment group.

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9.3. Serious Adverse Events

9.3.1. Fatal Events

No subjects died during the study.

9.3.2. Non-Fatal Events

Twenty (3%) subjects in the SFC group and 12 (2%) subjects in the FBC group had a serious adverse event (SAE) during the study (Table 15.7). No individual SAE occurred in ≥1% of subjects in either treatment group. Case narratives for these subjects are presented in Section 12. Further information can be found below, presented by treatment phase.

9.3.2.1. Pre-treatment serious adverse events

Three subjects had a SAE during the run-in period.

Both SAEs resolved during the treatment period and the subjects continued in the study.

The subject did not continue in the study.

9.3.2.2. Treatment emergent serious adverse events

Thirty subjects reported a treatment emergent SAE 19 (3%) in the SFC group and 11 (1%) in the FBC group. Five subjects were withdrawn permanently from the study due to their SAE, four from the SFC group and one from the FBC group:

SFC

Neither SAE was assessed as related to study medication and the events resolved after nine and seven days respectively. After discharge from hospital study medication was permanently discontinued and the subject was withdrawn from the study as he was reported as feeling unable to comply with the study regime.

The event was not assessed as related to study medication and resolved after 10 days.

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These events were not assessed as related to study medication and resolved between 20-27 days after onset.

FBC

The SAE did resolve and was assessed as related to study medication.

9.3.2.3. Post-treatment serious adverse events

One subject had a SAE during the post –treatment period. The event resolved after one week and the investigator did not consider the event to be related to treatment.

9.4. Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study

A very small proportion of subjects had an AE that resulted in their withdrawal from the study: 14 (2%) subjects in the SFC group and 10 (1%) subjects in the FBC group (Table 15.8). Of these, four subjects were withdrawn due to SAEs, one of which was assessed a related to study medication (see Section 9.3.2). The remainder was withdrawn due to non-serious AEs.

In the SFC group the most common AEs leading to withdrawal were gastrointestinal events (5 subjects, <1%) and lower respiratory events (5 subjects, <1%). In the FBC group, the most common events were neurological (5 subjects, <1%).

A case narrative for each subject is presented in Section 12.

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9.5. Pregnancies

Three subjects became pregnant whilst enrolled in this study. All three were receiving SFC at the time and were withdrawn from the study immediately. Case narratives for these subjects are presented in Section 12 (Pregnancies).

A case narrative for this subject can be found in Section 12.

9.6. Other Safety Evaluations

9.6.1. Oropharyngeal candidiasis

Sixteen (2%) subjects in the SFC group and 10 (1%) subjects in the FBC group had an AE reported as candidiasis of mouth/throat (Table 15.4). Of these, 12 in the SFC group and 7 in the FBC group were assessed by the investigator as related to treatment (Table 15.6).

In addition, one subject (<1%) in each group reported a fungal infection of mouth and throat and one subject in the SFC group reported a fungal gastrointestinal infection, all of which were assessed by the investigator as related to study medication (Table 15.4 and Table 15.6).

Six subjects (<1%) in the SFC group and seven subjects (1%) in the FBC group had an AE of candidiasis, site unspecified. Other than for one subject in the FBC group, all these AEs were assessed as related to study medication (Table 15.4 and Table 15.6).

None of the AEs relating to oropharyngeal candidiasis were reported as SAEs.

Both subjects had been receiving SFC and the events were considered by the investigator as related to study treatment. Case narratives for these subjects are presented in Section 12.

Oral swabs were collected from 14 subjects (2%) in each treatment group due to clinical evidence of candidiasis. Of these eight subjects (1%) in the SFC group and seven subjects (1%) in the FBC group had a positive swab result.

9.7. Medical Device Incidents, Near-Incidents, Malfunctions and Remedial Action

No medical devices incidents were reported.

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9.8. Safety Conclusions

• The proportion of subjects with at least one AE that started during treatment was similar in both treatment groups: 384 (55%) in the SFC group and 377 (54%) in the FBC group. The most common AEs in each group were headache and upper respiratory tract infection. • The incidence of drug-related AEs, as reported by the investigators, was <10% in both groups. The most commonly reported drug-related events in both treatment groups were: hoarseness/dysphonia, candidiasis of mouth/throat and headaches. • No deaths occurred in the study and a small proportion of subjects reported SAEs: 20 (3%) subjects in the SFC group and 12 (2%) subjects in the FBC group. Only one SAE was considered related to study drug, this was in the FBC group. • A small proportion of subjects had an AE that resulted in their withdrawal from the study: 14 (2%) subjects in the SFC group and 10 (1%) subjects in the FBC group • The incidence of oral candidiasis was similarly low in each treatment group and none of the events reported were serious. Two subjects (<1%) from the SFC group were withdrawn due to a candidiasis-related AE.

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10. DISCUSSION AND CONCLUSIONS

The primary objective of this multinational, multicentre study was to compare the efficacy of SFC 500/250µg 1 inhalation bd with FBC 4.5/160µg 2 inhalations bd in preventing the occurrence of asthma exacerbations in subjects with moderate to severe asthma.

The two treatment groups were very well matched in terms of demography, baseline lung function and previous medications. Although subjects were recruited from a large number of centres and countries with many centres contributing six or less subjects to the study, country grouping was included, where appropriate, as a variable in all efficacy analyses and tests of treatment interactions with country grouping, were not significant. This would indicate that the results are valid for a wide range of countries.

Both treatments were highly effective in improving lung function and other measures of asthma control.

Over the 24 week treatment period, the rate of exacerbations was similar in both treatment groups and there was no statistically significant difference between them. Similar findings were made for overall number of exacerbations, severity of exacerbations and time to first exacerbation.

The reporting analysis plans for this study were written before data from other studies also looking at exacerbation rates were available. In the reporting analysis plan an assumption was made that the rate of exacerbations in this population of asthmatics would remain constant throughout the 24 week treatment period. When the data was released it was apparent that there was an effect of regular treatment on the lung function, relief medication use and symptom parameters with time. Therefore, it was thought possible that there might also be a similar treatment effect with time for the rate of exacerbations. This is consistent with recent publications [Woolcock, 2001] reviewing data from a number of studies showing that the rate of improvement of different parameters measuring asthma control is variable, with rapid improvement in asthma symptoms but a more steady improvement over time over several months in lung function and airways hyperresponsiveness.

A post hoc analysis was therefore performed on the primary endpoint data for this study to determine if there was any time interval effect using appropriate statistical models.

This analysis over time showed that overall there was a 30% lower annual rate of moderate/severe exacerbations for SFC than with FBC and this effect increased with time, so that in the last 8 weeks of treatment there was a 57% difference in the moderate/severe exacerbation rate in favour of SFC, which was statistically significant.

In this study the definition of mild, moderate and severe exacerbations was provided for the investigators. However, it was difficult to assess the exact number of mild exacerbations because they were frequent and due to the frequency of clinic visits they were counted as one long exacerbation by the investigator. However, when they were captured in the CRF they were recorded as several shorter exacerbations. The definition

7683 CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040 of moderate and severe exacerbations was much clearer to define because these should have been treated with oral steroids in an outpatient or hospital in-patient setting. However, some patients whose diary card lung function and symptom data indicated an exacerbation warranting OCS use were not treated as per protocol and so an additional analysis of protocol defined exacerbations was performed

Both treatment groups showed a similar and clinically relevant improvement in PEF and FEV1 from baseline to the end of treatment. Similar improvements in asthma symptoms and use of relief medication were also shown in both treatment groups.

The data from this study would suggest that treatment effects on exacerbation rates need to be studied in longer term studies of at least six months duration and preferably longer.

Overall, both treatments were shown to be safe and well-tolerated. The incidence and type of AEs were similar in both treatment groups and not unexpected in subjects with moderate to severe asthma. The incidence of drug-related AEs as assessed by investigators was also similar in both treatment groups with no new safety signals identified.

In conclusion, the data from this study showed that regular, twice daily treatment with SFC and FBC over six months significantly reduced the rate of exacerbations in the study population of moderate asthmatic adults. The lung function and symptom markers of asthma control also improved over time with both combination treatments. However, in a post-hoc analysis further examining the effect of sustained, regular therapy over the six month study period, SFC was found to be significantly superior to FBC in reducing the rate of moderate/severe exacerbations over time.

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11. REFERENCES

British Thoracic Society (BTS) Asthma Guidelines. Thorax 2003; 58 (Suppl1): 1-93

Condemi JJ, Goldstein S, Kalberg C, Yancey S, Emmett A, Rickard K. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group. Ann Allergy Asthma Immunol 1999;82:383-389.

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: NHLBI/WHO Workshop Report. National Institutes of Health, National Heart Lung and Blood Institute, 2002

Greening, AP; Ind, PW; Northfield, M and Shaw, G. Added salmeterol versus higher- dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219-24.

Pauwels TA, Lofdahl C-G, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-1411.

Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky P, Woodring A, Prillaman B, Shah T. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. Ann Allergy Asthma Immunol 1999;82(3):257-65.

Ringdal N. Chuchalin A. Chovan L. Tudoric N. Maggi E. Whitehead PJ. EDICT Investigators. Evaluation of different inhaled combination therapies (EDICT): a randomised, double-blind comparison of SERETIDE (50/250 microg bd DISKUS vs. formoterol (12 microg bd) and budesonide (800 microg bd) given concurrently (both via Turbuhaler) in patients with moderate-to-severe asthma. Respiratory Medicine 2002;96(11):851-61.

Standardisation of lung function as contained in the report of the working party of the European Community for Coal and Steel (ECCS). Bull Eur Physiopath Resp 1983;19(Suppl 5). van Noord JA, Schreurs AJ, Mol SJ, Mulder PG. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 1999;54:207-212.

Woolcock, A; Lundback, B; Ringdal, N and Jacques, LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med.1996;153:1481-88.

Woolcock AJ. What are the important questions in the treatment of asthma? Clin Exp All Rev 2001;1:62-64.

7885 This section contained patient narratives which are textual descriptions of medical history, treatment and outcome for individual patients who experienced a clinically important adverse event including serious adverse events during the trial. They have been excluded to protect patient privacy. This data may be made available subject to an approved research proposal and a determination of the ability to provide information from the specific narratives whilst protecting the patient’s privacy. For further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL GM2004/00056/00 SAM40040

Study Population Data Source Tables

Page Table 12.1 Summary of Population Screened...... 117 Table 12.2 Summary of Randomised Subjects by Investigator...... 118 Table 12.3 Summary of Withdrawals Prior to Randomisation ...... 126 Table 12.4 Summary of Withdrawals After Randomisation ...... 127 Table 12.5 Summary of Withdrawals After Randomisation by Time ...... 128 Table 12.6 Summary of Attendance at Each Clinic Visit ...... 129 Table 12.7 Summary of Entry Criteria Failure ...... 130 Table 12.8 Summary of Reason For Exclusion From the Per-Protocol Population ...... 131 Table 12.9 Summary of Demographic and Baseline Characteristics Intent-to-Treat Population ...... 135 Table 12.10 Summary of Demographic and Baseline Characteristics Per-Protocol Population ...... 137 Table 12.11 Summary of Childbearing Potential ...... 139 Table 12.12 Summary of Asthma History ...... 140 Table 12.13 Summary of Asthma Exacerbations During The Last Year. . . . . 141 Table 12.14 Summary of Smoking Status ...... 143 Table 12.15 Summary of Baseline Lung Function Characteristics Intent-to-Treat Population ...... 144 Table 12.16 Summary of Baseline Lung Function Characteristics Per-Protocol Population ...... 147 Table 12.17 Summary of Current Medical Conditions...... 150 Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date ...... 153 Table 12.19 Summary of Asthma Medication Taken During the Treatment Period ...... 160 Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period ...... 165

115 CONFIDENTIAL GM2004/00056/00 SAM40040

Table 12.21 Summary of Baseline Diary Card (Day -7 to -1) Intent-to-Treat Population ...... 211 Table 12.22 Summary of Baseline Diary Card (Day -7 to -1) Per-Protocol Population ...... 216 Table 12.23 Summary of Asthma Control Assessment Using The Asthma Control Questionnaire at Baseline ...... 221 Table 12.24 Summary of Percentage Compliance ...... 222

116 Protocol: SAM40040 Population: Total Table 12.1 Summary of Population Screened

SFC 50/250 FBC 4.5/160 Total ———————————————————————————————————————————————————————————————————————————————

Total Population 1769

Safety Population 697 (39%) 700 (40%) 1397 (79%)

Intent-to-Treat Population 694 (39%) 697 (39%) 1391 (79%)

Per-Protocol Population 492 (28%) 486 (27%) 978 (55%)

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Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

SFC 50/250 FBC 4.5/160 Total Principal Investigator ID/ Country Investigator Name (N=694) (N=697) (N=1391) ———————————————— ——————————————————————————————————————————————————————————————————

Austria Dr 4 (<1%) 3 (<1%) 7 (<1%) Dr. 4 (<1%) 4 (<1%) 8 (<1%) Dr. 2 (<1%) 2 (<1%) 4 (<1%) Dr. 5 (<1%) 4 (<1%) 9 (<1%) Dr. 6 (<1%) 8 (1%) 14 (1%) Dr. 2 (<1%) 3 (<1%) 5 (<1%)

CONFIDENTIAL Belgium Drr 2 (<1%) 1 (<1%) 3 (<1%) Dr 3 (<1%) 3 (<1%) 6 (<1%)

118 Dr 1 (<1%) 2 (<1%) 3 (<1%) Prof 5 (<1%) 5 (<1%) 10 (<1%) Dr 4 (<1%) 3 (<1%) 7 (<1%) Prof 2 (<1%) 2 (<1%) 4 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 1 (<1%) 0 1 (<1%)

Czech Republic Dr 7 (1%) 6 (<1%) 13 (<1%) Dr 6 (<1%) 5 (<1%) 11 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 3 (<1%) 2 (<1%) 5 (<1%) Dr 4 (<1%) 4 (<1%) 8 (<1%)

GM2004/00056/00 Denmark Dr 2 (<1%) 3 (<1%) 5 (<1%) Dr 6 (<1%) 7 (1%) 13 (<1%) Dr 5 (<1%) 6 (<1%) 11 (<1%)

7 (1%) 7 (1%) 14 (1%) SAM40040 6 (<1%) 6 (<1%) 12 (<1%)

Page 1 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

Estonia Dr 8 (1%) 8 (1%) 16 (1%) Dr 6 (<1%) 6 (<1%) 12 (<1%) Dr. 6 (<1%) 6 (<1%) 12 (<1%) Dr. 6 (<1%) 6 (<1%) 12 (<1%) Dr. 8 (1%) 8 (1%) 16 (1%) Dr. 4 (<1%) 4 (<1%) 8 (<1%)

CONFIDENTIAL France Dr 1 (<1%) 1 (<1%) 2 (<1%) Dr 3 (<1%) 4 (<1%) 7 (<1%)

119 Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 3 (<1%) 3 (<1%) 6 (<1%) Dr 5 (<1%) 4 (<1%) 9 (<1%) Dr 3 (<1%) 2 (<1%) 5 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%) Dr 5 (<1%) 5 (<1%) 10 (<1%) Dr 2 (<1%) 1 (<1%) 3 (<1%) 9 (1%) 8 (1%) 17 (1%) Dr 3 (<1%) 2 (<1%) 5 (<1%) 4 (<1%) 4 (<1%) 8 (<1%) 2 (<1%) 2 (<1%) 4 (<1%)

4 (<1%) 5 (<1%) 9 (<1%) GM2004/00056/00 Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 3 (<1%) 3 (<1%) 6 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%)

Dr 1 (<1%) 2 (<1%) 3 (<1%) SAM40040 Dr 2 (<1%) 2 (<1%) 4 (<1%)

Page 2 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

SFC 50/250 FBC 4.5/160 Total Principal Investigator ID/ Country Investigator Name (N=694) (N=697) (N=1391) ———————————————— ———— ———————————————————————————————————————————————

France Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 0 1 (<1%) 1 (<1%)

Germany Dr 10 (1%) 10 (1%) 20 (1%) Dr 4 (<1%) 4 (<1%) 8 (<1%) Dr 6 (<1%) 5 (<1%) 11 (<1%)

Dr 7 (1%) 7 (1%) 14 (1%) CONFIDENTIAL Dr 6 (<1%) 7 (1%) 13 (<1%) Dr 6 (<1%) 8 (1%) 14 (1%)

120 Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 2 (<1%) 1 (<1%) 3 (<1%) Dr 12 (2%) 11 (2%) 23 (2%) 0 1 (<1%) 1 (<1%) Dr. 4 (<1%) 4 (<1%) 8 (<1%) Dr. 12 (2%) 12 (2%) 24 (2%) Dipl.-Med. 10 (1%) 10 (1%) 20 (1%) Dr. 4 (<1%) 4 (<1%) 8 (<1%) Dr. med. 7 (1%) 8 (1%) 15 (1%) 2 (<1%) 1 (<1%) 3 (<1%) 0 1 (<1%) 1 (<1%)

Greece Dr 7 (1%) 7 (1%) 14 (1%) GM2004/00056/00 Prof 8 (1%) 7 (1%) 15 (1%) Dr A. 0 1 (<1%) 1 (<1%) Dr E. 8 (1%) 9 (1%) 17 (1%)

Prof 2 (<1%) 2 (<1%) 4 (<1%) SAM40040 Dr 9 (1%) 9 (1%) 18 (1%)

Page 3 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

SFC 50/250 FBC 4.5/160 Total Principal Investigator ID/ Country Investigator Name (N=694) (N=697) (N=1391) —————————————————————————————————————————————————————————————————————————————————————————

Ireland DR 3 (<1%) 2 (<1%) 5 (<1%) Dr. 5 (<1%) 5 (<1%) 10 (<1%) DR 1 (<1%) 0 1 (<1%) Dr 4 (<1%) 4 (<1%) 8 (<1%) Dr 0 1 (<1%) 1 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%)

Dr 1 (<1%) 0 1 (<1%) CONFIDENTIAL Dr 0 1 (<1%) 1 (<1%)

121 Italy 4 (<1%) 3 (<1%) 7 (<1%) 2 (<1%) 3 (<1%) 5 (<1%) 2 (<1%) 3 (<1%) 5 (<1%) 2 (<1%) 2 (<1%) 4 (<1%) 5 (<1%) 4 (<1%) 9 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%) Dr 3 (<1%) 4 (<1%) 7 (<1%) Dr 4 (<1%) 5 (<1%) 9 (<1%) Dr 0 1 (<1%) 1 (<1%) 2 (<1%) 3 (<1%) 5 (<1%)

Netherlands Dr 5 (<1%) 6 (<1%) 11 (<1%)

Dr 3 (<1%) 2 (<1%) 5 (<1%) GM2004/00056/00 Dr 1 (<1%) 1 (<1%) 2 (<1%) Dr 10 (1%) 10 (1%) 20 (1%) Dr 6 (<1%) 5 (<1%) 11 (<1%)

Dr 8 (1%) 7 (1%) 15 (1%) SAM40040 Dr 4 (<1%) 4 (<1%) 8 (<1%)

Page 4 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

Netherlands Drs 4 (<1%) 6 (<1%) 10 (<1%) Drs 2 (<1%) 0 2 (<1%) Drs 5 (<1%) 5 (<1%) 10 (<1%) 2 (<1%) 2 (<1%) 4 (<1%) Drs 6 (<1%) 7 (1%) 13 (<1%) Drs 4 (<1%) 5 (<1%) 9 (<1%)

Dr 2 (<1%) 3 (<1%) 5 (<1%) CONFIDENTIAL Drs 2 (<1%) 1 (<1%) 3 (<1%)

122 Norway 1 (<1%) 0 1 (<1%) Dr 6 (<1%) 4 (<1%) 10 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 0 2 (<1%) 2 (<1%) 3 (<1%) 2 (<1%) 5 (<1%)

Portugal Prof 7 (1%) 6 (<1%) 13 (<1%) DR 3 (<1%) 3 (<1%) 6 (<1%) Dr 9 (1%) 8 (1%) 17 (1%) Dr 4 (<1%) 4 (<1%) 8 (<1%) Dr 4 (<1%) 4 (<1%) 8 (<1%) Dr. 5 (<1%) 4 (<1%) 9 (<1%)

GM2004/00056/00 Russia Ac.,Prof.,MD 12 (2%) 12 (2%) 24 (2%) Prof 12 (2%) 12 (2%) 24 (2%) Prof. 6 (<1%) 6 (<1%) 12 (<1%)

Dr 13 (2%) 14 (2%) 27 (2%) SAM40040

Page 5 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator SFC 50/250 FBC 4.5/160 Total Principal Investigator ID/ Country Investigator Name (N=694) (N=697) (N=1391) ————————————————————————————————————————————————————————————————————————————————————————— Spain Dr 5 (<1%) 4 (<1%) 9 (<1%) DR. 12 (2%) 12 (2%) 24 (2%) dr. 4 (<1%) 4 (<1%) 8 (<1%) DR. 14 (2%) 14 (2%) 28 (2%) Dr. 0 1 (<1%) 1 (<1%) 8 (1%) 7 (1%) 15 (1%)

1 (<1%) 2 (<1%) 3 (<1%) CONFIDENTIAL 2 (<1%) 4 (<1%) 6 (<1%) Dr. 3 (<1%) 3 (<1%) 6 (<1%)

123 Dr. 7 (1%) 7 (1%) 14 (1%) Dr. 5 (<1%) 5 (<1%) 10 (<1%) Dr. 13 (2%) 12 (2%) 25 (2%) Dr. 2 (<1%) 3 (<1%) 5 (<1%) Dr. 1 (<1%) 2 (<1%) 3 (<1%) Sweden Dr 3 (<1%) 3 (<1%) 6 (<1%) Dr 3 (<1%) 2 (<1%) 5 (<1%) 5 (<1%) 5 (<1%) 10 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%) Dr 16 (2%) 16 (2%) 32 (2%) Dr 2 (<1%) 2 (<1%) 4 (<1%) GM2004/00056/00 GM2004/00056/00 Switzerland Dr med 3 (<1%) 2 (<1%) 5 (<1%) 2 (<1%) 0 2 (<1%) Prof. Dr. med. 4 (<1%) 4 (<1%) 8 (<1%)

Dr 16 (2%) 16 (2%) 32 (2%) SAM40040 Dr 1 (<1%) 1 (<1%) 2 (<1%) Page 6 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

United Kingdom Dr 0 2 (<1%) 2 (<1%) Dr 3 (<1%) 4 (<1%) 7 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 4 (<1%) 4 (<1%) 8 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 1 (<1%) 2 (<1%) 3 (<1%)

Dr 2 (<1%) 0 2 (<1%) CONFIDENTIAL Dr 5 (<1%) 5 (<1%) 10 (<1%) Dr 0 1 (<1%) 1 (<1%)

124 Dr 0 1 (<1%) 1 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 0 1 (<1%) 1 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 5 (<1%) 4 (<1%) 9 (<1%) Dr 6 (<1%) 7 (1%) 13 (<1%) Dr 2 (<1%) 2 (<1%) 4 (<1%) Dr 0 1 (<1%) 1 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%) Dr 0 1 (<1%) 1 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%)

Dr 1 (<1%) 0 1 (<1%) GM2004/00056/00 Dr 1 (<1%) 0 1 (<1%) Dr 3 (<1%) 2 (<1%) 5 (<1%) Dr 1 (<1%) 1 (<1%) 2 (<1%)

Dr 0 1 (<1%) 1 (<1%) SAM40040 Dr 2 (<1%) 1 (<1%) 3 (<1%)

Page 7 of 8 Protocol: SAM40040 Population: Intent-to-Treat Table 12.2 Summary of Randomised Subjects by Investigator

SFC 50/250 FBC 4.5/160 Total Principal Investigator ID/ Country Investigator Name (N=694) (N=697) (N=1391) —————————————————————————————————————————————————————————————————————————————————————————

United Kingdom Dr 2 (<1%) 4 (<1%) 6 (<1%) Dr 2 (<1%) 1 (<1%) 3 (<1%) Dr 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

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Page 8 of 8 Protocol: SAM40040 Population: Total Table 12.3 Summary of Withdrawals Prior to Randomisation

Total (N=1769) ————————————————————————————————————————————————————————————————

Withdrawals prior to randomisation 372 (21%)

Reason for withdrawal:

Adverse event 8 (<1%) Consent withdrawn 35 ( 2%) Lost to follow-up 15 (<1%)

Protocol violation 9 (<1%) CONFIDENTIAL Did not fulfil the entry criteria 282 (16%) Other 23 ( 1%)

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Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.4 Summary of Withdrawals After Randomisation

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) ————————————————————————————————————————————————————————————————————————————————————————

Completed 623 (90%) 635 (91%) 1258 (90%) Withdrawals after randomisation 71 (10%) 62 ( 9%) 133 (10%)

Reason for withdrawal: Adverse event 13 ( 2%) 10 ( 1%) 23 ( 2%) Consent withdrawn 11 ( 2%) 15 ( 2%) 26 ( 2%) Lost to follow-up 16 ( 2%) 13 ( 2%) 29 ( 2%)

Protocol violation 13 ( 2%) 12 ( 2%) 25 ( 2%) CONFIDENTIAL Lack of efficacy 5 (<1%) 2 (<1%) 7 (<1%) Did not fulfil the entry criteria 4 (<1%) 2 (<1%) 6 (<1%)

127 Other 9 ( 1%) 8 ( 1%) 17 ( 1%)

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Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.5 Summary of Withdrawals After Randomisation by Time

SFC 50/250 FBC 4.5/160 (N=694) (N=697) Days until ———————————————————————————— ———————————————————————————— Withdrawal Week n Total n Total ———————————————————————————————————————————————————————————————————————————————————————

<=7 1 3 (<1%) 3 (<1%) 2 (<1%) 2 (<1%) >7 to <=14 2 3 (<1%) 6 (<1%) 4 (<1%) 6 (<1%) >14 to <=28 4 6 (<1%) 12 (2%) 8 (1%) 14 (2%) >28 to <=56 8 24 (3%) 36 (5%) 18 (3%) 32 (5%) >56 to <=84 12 14 (2%) 50 (7%) 8 (1%) 40 (6%)

>84 to <=112 16 10 (1%) 60 (9%) 7 (1%) 47 (7%) CONFIDENTIAL >112 to <=140 20 4 (<1%) 64 (9%) 9 (1%) 56 (8%) >140 to <=168 24 5 (<1%) 69 (10%) 4 (<1%) 60 (9%)

128 >168 2 (<1%) 71 (10%) 2 (<1%) 62 (9%)

GM2004/00056/00

SAM40040 Note: The total is the cumulative total of subjects who were withdrawn from the study

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.6 Summary of Attendance at Each Clinic Visit

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) ———————————————————————————————————————————————————————————————————————————————

Clinic Visit 1 (Screening) 694 (100%) 697 (100%) 1391 (100%) Clinic Visit 2/2a (Randomisation) 694 (100%) 697 (100%) 1391 (100%) Clinic Visit 3 (Week 4) 666 (96%) 672 (96%) 1338 (96%) Clinic Visit 4 (Week 8) 649 (94%) 661 (95%) 1310 (94%) Clinic Visit 5 (Week 16) 630 (91%) 644 (92%) 1274 (92%) Clinic Visit 6 (Week 24) 622 (90%) 635 (91%) 1257 (90%) Follow-up 619 (89%) 627 (90%) 1246 (90%)

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Page 1 of 1 Protocol: SAM40040 Population: Total Table 12.7 Summary of Entry Criteria Failure

Total (N=1769) ———————————————————————————————————————————————————————————————————————————————

Number of Subjects Failing any Entry Criteria Visit 1 31 (2%)

Reason for failure

Exclusion Run-in Criteria = 1: Respiratiory infection 1 (<1%) Exclusion Run-in Criteria = 2: Exacerbation 2 (<1%) Exclusion Run-in Criteria = 3: Smoking history 5 (<1%)

Exclusion Run-in Criteria = 9: Non-compliance 1 (<1%) CONFIDENTIAL Exclusion Run-in Criteria = 11: Prohibited Medications 2 (<1%) Exclusion Run-in Criteria = 12: Oral/parenteral steroid use 2 (<1%)

130 Exclusion Run-in Criteria = 15: FEV1 <50% 8 (<1%) Exclusion Run-in Criteria = 16: Use of concurrent prohibited 1 (<1%) medication Inclusion Run-in Criteria = 1: Acceptable contraception 2 (<1%) Inclusion Run-in Criteria = 3: History of asthma 1 (<1%) Inclusion Run-in Criteria = 4: Change in asthma medication 1 (<1%) Inclusion Run-in Criteria = 5: Current ICS treatment 5 (<1%) Inclusion Run-in Criteria = 7: Able to comply with study 1 (<1%) procedures

Number of Subjects Failing any Randomisation Criteria Visit 2/2A 285 (16%)

Reason for failure GM2004/00056/00

Inclusion Treatment Period Criteria = 1: Reversibility 119 (7%) Inclusion Treatment Period Criteria = 2: Symptom scores 225 (13%)

Inclusion Treatment Period Criteria = 3: Diary card data 60 (3%) SAM40040

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.8 Summary of Reason For Exclusion From the Per-Protocol Population

SFC FBC Total 50/250 4.5/160 (N=694) (N=697) (N=1391) ——————————————————————————————————————————————————————————————————————————————————————————

Number of subjects totally excluded from the 202 (29%) 211 (30%) 413 (30%) Per-Protocol population

Reason for total exclusion

<4 of last 7 days of run-in with symptom score > 1 24 (3%) 40 (6%) 64 (5%)

CONFIDENTIAL <5 of last 7 days of run-in with complete DRC data 12 (2%) 15 (2%) 27 (2%)

131 Changed regular asthma medication within 4 weeks 7 (1%) 19 (3%) 26 (2%) before Visit 1

Compliance of < 80% or > 125% where all devices 67 (10%) 55 (8%) 122 (9%) returned

Compliance of < 80% where not all devices returned 64 (9%) 65 (9%) 129 (9%)

History of alcohol or medication abuse 1 (<1%) 0 1 (<1%)

Moderate exacerbation not treated with OCS 4 (<1%) 5 (<1%) 9 (<1%)

No reversible increase in FEV1 of at least 12% 10 (1%) 13 (2%) 23 (2%) GM2004/00056/00 and >=200ml at Visit 1/2/2a or documented within last 2 years

Not able to comply with therapy and complete DRC 0 1 (<1%) 1 (<1%) SAM40040 and questionnaires correctly

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 12.8 Summary of Reason For Exclusion From the Per-Protocol Population

Reason for total exclusion

Not receiving 1000-2000mg/day BDP or equivalent 3 (<1%) 3 (<1%) 6 (<1%) for at least 4 weeks prior to Visit 1

Of child-bearing potential with no negative 1 (<1%) 0 1 (<1%)

pregnancy test at entry or no acceptable CONFIDENTIAL contraceptive method

132 Pre-bronchodilator FEV1 of < 50% of predictive 8 (1%) 12 (2%) 20 (1%) normal value

Received high dose of BDP or equivalent within 4 8 (1%) 14 (2%) 22 (2%) weeks prior to visit 1

Smoking history of >= 10 pack years, likely to 0 1 (<1%) 1 (<1%) change smoking habits during study, or given up within 4 weeks of Visit 1

Took anti-cholinergic after Visit 1 5 (<1%) 3 (<1%) 8 (<1%)

Took beta-blockers after Visit 1 13 (2%) 7 (1%) 20 (1%) GM2004/00056/00

Took combination therapy containing 2 (<1%) 1 (<1%) 3 (<1%) bronchodilator after Visit 1

SAM40040 Took corticosteroid after Visit 1 5 (<1%) 8 (1%) 13 (<1%)

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 12.8 Summary of Reason For Exclusion From the Per-Protocol Population

Reason for total exclusion

Took inhaled corticosteriod after treatment start 2 (<1%) 7 (1%) 9 (<1%)

Took long-acting beta-agonist after Visit 1 0 2 (<1%) 2 (<1%)

Took nedocromil sodium after Visit 1 1 (<1%) 0 1 (<1%) CONFIDENTIAL

Took oral corticosteroids within 4 weeks of Visit 3 (<1%) 3 (<1%) 6 (<1%)

133 1

Took short-acting beta-agonist after Visit 1 1 (<1%) 3 (<1%) 4 (<1%)

Took theophylline after Visit 1 0 3 (<1%) 3 (<1%)

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Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 12.8 Summary of Reason For Exclusion From the Per-Protocol Population

Number of subjects partially excluded from the 30 (4%) 30 (4%) 60 (4%) Per-Protocol population

Reason for partial exclusion

Moderate exacerbation not treated with OCS 11 (2%) 6 (<1%) 17 (1%)

CONFIDENTIAL Took anti-cholinergic after Visit 1 3 (<1%) 2 (<1%) 5 (<1%)

134 Took beta-blockers after Visit 1 1 (<1%) 1 (<1%) 2 (<1%)

Took combination therapy containing 3 (<1%) 0 3 (<1%) bronchodilator after Visit 1

Took corticosteroid after Visit 1 11 (2%) 12 (2%) 23 (2%)

Took inhaled corticosteriod after treatment start 5 (<1%) 2 (<1%) 7 (<1%)

Took long-acting beta-agonist after Visit 1 1 (<1%) 1 (<1%) 2 (<1%)

Took short-acting beta-agonist after Visit 1 1 (<1%) 6 (<1%) 7 (<1%)

GM2004/00056/00 Took sodium cromoglycate after Visit 1 1 (<1%) 0 1 (<1%)

Took theophylline after Visit 1 2 (<1%) 1 (<1%) 3 (<1%)

SAM40040

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 12.9 Summary of Demographic and Baseline Characteristics Intent-to-Treat Population

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) ———————————————————————————————————————————————————————————————————————————————————

Age (y) n 694 697 1391 Mean 45.6 47.1 46.3 SD 15.1 14.5 14.8 Median 46.0 48.0 47.0 Min. 18 18 18 Max. 91 82 91

CONFIDENTIAL Group Age (y) n 694 697 1391 18-64 608 (88%) 608 (87%) 1216 (87%)

135 65-79 84 (12%) 87 (12%) 171 (12%) >=80 2 (<1%) 2 (<1%) 4 (<1%)

Sex n 694 697 1391 Female 387 (56%) 409 (59%) 796 (57%) Male 307 (44%) 288 (41%) 595 (43%)

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Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 12.9 Summary of Demographic and Baseline Characteristics Intent-to-Treat Population

Ethnic Origin n 694 697 1391 White 686 (99%) 691 (>99%) 1377 (99%) Black 1 (<1%) 2 (<1%) 3 (<1%) Asian 5 (<1%) 4 (<1%) 9 (<1%) Other 2 (<1%) 0 2 (<1%)

Height (cm) n 694 697 1391 CONFIDENTIAL Mean 167.8 167.3 167.5 SD 10.0 10.2 10.1

136 Median 167.0 167.0 167.0 Min. 142 140 140 Max. 198 204 204

Weight (kg) n 694 697 1391 Mean 76.22 76.42 76.32 SD 16.05 16.34 16.19 Median 75.00 75.00 75.00 Min. 35.0 40.0 35.0 Max. 150.0 153.8 153.8

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Page 2 of 2 Protocol: SAM40040 Population: Per Protocol Table 12.10 Summary of Demographic and Baseline Characteristics Per-Protocol Population

SFC 50/250 FBC 4.5/160 Total (N=492) (N=486) (N=978) ———————————————————————————————————————————————————————————————————————————————————

Age (y) n 492 486 978 Mean 45.3 47.3 46.3 SD 15.3 14.2 14.8 Median 45.0 49.0 47.0 Min. 18 18 18 Max. 91 82 91

CONFIDENTIAL Group Age (y) n 492 486 978 18-64 430 (87%) 427 (88%) 857 (88%)

137 65-79 60 (12%) 57 (12%) 117 (12%) >=80 2 (<1%) 2 (<1%) 4 (<1%)

Sex n 492 486 978 Female 277 (56%) 296 (61%) 573 (59%) Male 215 (44%) 190 (39%) 405 (41%)

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Page 1 of 2 Protocol: SAM40040 Population: Per Protocol Table 12.10 Summary of Demographic and Baseline Characteristics Per-Protocol Population

Ethnic Origin n 492 486 978 White 488 (>99%) 485 (>99%) 973 (>99%) Black 0 0 0 Asian 3 (<1%) 1 (<1%) 4 (<1%) Other 1 (<1%) 0 1 (<1%)

Height (cm) n 492 486 978 CONFIDENTIAL Mean 167.6 166.8 167.2 SD 10.0 10.2 10.1

138 Median 167.0 166.0 166.0 Min. 142 140 140 Max. 198 204 204

Weight (kg) n 492 486 978 Mean 75.73 77.01 76.37 SD 15.99 16.68 16.34 Median 74.00 75.10 75.00 Min. 35.0 40.0 35.0 Max. 150.0 153.8 153.8

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Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 12.11 Summary of Childbearing Potential

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) ——————————————————————————————————————————————————————————————————————————————————

Child bearing potential n 387 409 796 Premenarcheal 0 0 0 Sterile 41 (11%) 28 (7%) 69 (9%) Postmenopausal 168 (43%) 206 (50%) 374 (47%) Able to conceive 178 (46%) 175 (43%) 353 (44%)

Birth Control [1] CONFIDENTIAL n 178 175 353 Oral contraceptive 87 (49%) 72 (41%) 159 (45%)

139 Intrauterine contraceptive device 32 (18%) 37 (21%) 69 (20%) Depot contraceptive 3 (2%) 3 (2%) 6 (2%) Abstinence 34 (19%) 40 (23%) 74 (21%) Sterilisation of male partner 9 (5%) 17 (10%) 26 (7%) None 0 0 0 Other 25 (14%) 20 (11%) 45 (13%)

GM2004/00056/00

[1]: Consists of subjects who have childbearing potential of potentially able SAM40040 Subjects may use more than one method of birth control

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.12 Summary of Asthma History

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) ————————————————————————————————————————————————————————————————————————————————————

Duration of Asthma n 694 697 1391 < 6 months 0 0 0 >=6 months to <1yr 31 (4%) 31 (4%) 62 (4%) >=1yr to <5yrs 147 (21%) 128 (18%) 275 (20%) >=5yrs to <10yrs 125 (18%) 146 (21%) 271 (19%) >=10yrs to <15yrs 97 (14%) 108 (15%) 205 (15%) >=15yrs to <20yrs 77 (11%) 80 (11%) 157 (11%)

>=20yrs to <25yrs 72 (10%) 60 (9%) 132 (9%) CONFIDENTIAL >=25yrs 145 (21%) 144 (21%) 289 (21%)

140 Duration of Inhaled Cortisosteroid Use n 694 697 1391 < 6 months 55 (8%) 45 (6%) 100 (7%) >=6 months to <1yr 55 (8%) 57 (8%) 112 (8%) >=1yr to <5yrs 247 (36%) 230 (33%) 477 (34%) >=5yrs to <10yrs 178 (26%) 184 (26%) 362 (26%) >=10yrs to <15yrs 94 (14%) 98 (14%) 192 (14%) >=15yrs to <20yrs 37 (5%) 48 (7%) 85 (6%) >=20yrs to <25yrs 17 (2%) 17 (2%) 34 (2%) >=25yrs 11 (2%) 18 (3%) 29 (2%)

GM2004/00056/00

SAM40040

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.13 Summary of Asthma Exacerbations During The Last Year

Number of Exacerbations that required antibiotics and/or corticosteroids (not involving hospitalisation) n 694 697 1391 Mean 0.6 0.6 0.6 SD 1.0 1.1 1.1 Median 0.0 0.0 0.0

Min. 0 0 0 CONFIDENTIAL Max. 8 15 15

141 Distribution 0 454 (65%) 452 (65%) 906 (65%) 1 145 (21%) 140 (20%) 285 (20%) 2 59 (9%) 61 (9%) 120 (9%) 3 16 (2%) 26 (4%) 42 (3%) >3 20 (3%) 18 (3%) 38 (3%)

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 12.13 Summary of Asthma Exacerbations During The Last Year

Number of Exacerbations that required hospitalisation n 694 697 1391 Mean 0.1 0.1 0.1 SD 0.3 0.3 0.3 Median 0.0 0.0 0.0 Min. 0 0 0 Max. 4 3 4

CONFIDENTIAL Number of Exacerbations that required hospitalisation Distribution

142 0 650 (94%) 650 (93%) 1300 (93%) 1 39 (6%) 41 (6%) 80 (6%) 2 3 (<1%) 4 (<1%) 7 (<1%) 3 1 (<1%) 2 (<1%) 3 (<1%) >3 1 (<1%) 0 1 (<1%)

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 12.14 Summary of Smoking Status

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) —————————————————————————————————————————————————————————————————————————————

Smoking History n 694 697 1391 Never smoked 446 (64%) 440 (63%) 886 (64%) Current smoker 65 (9%) 73 (10%) 138 (10%) Former smoker 183 (26%) 184 (26%) 367 (26%)

CONFIDENTIAL

143

GM2004/00056/00

SAM40040

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.15 Summary of Baseline Lung Function Characteristics Intent-to-Treat Population

No of subjects with documented reversibility within the last 2 years [1] n 693 696 1389 Yes 377 (54%) 355 (51%) 732 (53%) No 316 (46%) 341 (49%) 657 (47%)

Pre-bronchodilator CONFIDENTIAL FEV1 (L) at Visit 1 n 689 690 1379 Mean 2.5 2.4 2.4

144 SD 0.83 0.78 0.81 Median 2.3 2.3 2.3 Min. 0.7 0.9 0.7 Max. 5.7 5.5 5.7

Post-bronchodilator FEV1 (L) at Visit 1 n 358 372 730 Mean 2.8 2.7 2.8 SD 0.90 0.86 0.88 Median 2.7 2.6 2.7 Min. 1.1 1.0 1.0 Max. 6.1 5.5 6.1

GM2004/00056/00

[1]: Documented evidence of reversibility of >=12% (and >=200mL) in FEV1, measured within SAM40040 last 2 years. Subjects may also have a reversibility measurement recorded.

Page 1 of 3 Protocol: SAM40040 Population: Intent-to-Treat Table 12.15 Summary of Baseline Lung Function Characteristics Intent-to-Treat Population

% Predicted FEV1 at Visit 1 n 689 690 1379 Mean 78.8 78.3 78.5 SD 16.50 16.42 16.45 Median 76.8 76.6 76.8 Min. 32.5 41.4 32.5

Max. 137.2 146.3 146.3 CONFIDENTIAL

Reversibility (%) at

145 Visit 1 n 358 372 730 Mean 21.4 22.3 21.8 SD 13.37 16.79 15.21 Median 17.3 18.8 17.9 Min. -5.0 -6.2 -6.2 Max. 90.2 151.9 151.9

Pre-bronchodilator FEV1 (L) at Visit 2/2a n 693 696 1389 Mean 2.5 2.4 2.4 SD 0.85 0.85 0.85 Median 2.3 2.3 2.3

Min. 0.6 0.8 0.6 GM2004/00056/00 Max. 5.4 5.6 5.6

[1]: Documented evidence of reversibility of >=12% (and >=200mL) in FEV1, measured within SAM40040 last 2 years. Subjects may also have a reversibility measurement recorded.

Page 2 of 3 Protocol: SAM40040 Population: Intent-to-Treat Table 12.15 Summary of Baseline Lung Function Characteristics Intent-to-Treat Population

Post-bronchodilator FEV1 (L) at Visit 2/2a n 90 104 194 Mean 2.7 2.6 2.7 SD 0.96 0.81 0.88 Median 2.8 2.6 2.7 Min. 1.2 0.9 0.9

Max. 5.6 4.8 5.6 CONFIDENTIAL

% Predicted FEV1 at

146 Visit 2/2a n 693 696 1389 Mean 78.7 78.5 78.6 SD 17.86 18.20 18.02 Median 77.4 77.5 77.4 Min. 25.7 30.8 25.7 Max. 133.2 142.5 142.5

Reversibility (%) at Visit 2/2a n 90 104 194 Mean 19.6 24.0 21.9 SD 10.83 14.78 13.25 Median 16.7 19.8 18.0

Min. 3.1 7.7 3.1 GM2004/00056/00 Max. 69.8 104.2 104.2

[1]: Documented evidence of reversibility of >=12% (and >=200mL) in FEV1, measured within SAM40040 last 2 years. Subjects may also have a reversibility measurement recorded.

Page 3 of 3 Protocol: SAM40040 Population: Per Protocol Table 12.16 Summary of Baseline Lung Function Characteristics Per-Protocol Population

SFC 50/250 FBC 4.5/160 Total (N=492) (N=486) (N=978) ————————————————————————————————————————————————————————————————————————————————————

No of subjects with documented reversibility within the last 2 years [1] n 492 486 978 Yes 262 (53%) 238 (49%) 500 (51%) No 230 (47%) 248 (51%) 478 (49%)

Pre-bronchodilator CONFIDENTIAL FEV1 (L) at Visit 1 n 467 468 935 Mean 2.4 2.4 2.4

147 SD 0.82 0.78 0.80 Median 2.3 2.3 2.3 Min. 0.7 0.9 0.7 Max. 5.7 5.5 5.7

Post-bronchodilator FEV1 (L) at Visit 1 n 247 264 511 Mean 2.9 2.7 2.8 SD 0.89 0.81 0.85 Median 2.7 2.7 2.7 Min. 1.1 1.1 1.1 Max. 6.1 5.5 6.1

GM2004/00056/00

[1]: Documented evidence of reversibility of >=12% (and >=200mL) in FEV1, measured within SAM40040 last 2 years. Subjects may also have a reversibility measurement recorded.

Page 1 of 3 Protocol: SAM40040 Population: Per Protocol Table 12.16 Summary of Baseline Lung Function Characteristics Per-Protocol Population

% Predicted FEV1 at Visit 1 n 467 468 935 Mean 78.5 79.1 78.8 SD 16.42 16.17 16.29 Median 76.8 77.5 77.1 Min. 50.0 50.0 50.0

Max. 137.2 137.2 137.2 CONFIDENTIAL

Reversibility (%) at

148 Visit 1 n 247 264 511 Mean 22.8 21.9 22.4 SD 14.42 13.96 14.18 Median 18.0 18.9 18.3 Min. -1.2 -5.0 -5.0 Max. 90.2 121.3 121.3

Pre-bronchodilator FEV1 (L) at Visit 2/2a n 449 453 902 Mean 2.4 2.4 2.4 SD 0.84 0.85 0.84 Median 2.3 2.3 2.3

Min. 0.6 0.8 0.6 GM2004/00056/00 Max. 5.4 5.3 5.4

[1]: Documented evidence of reversibility of >=12% (and >=200mL) in FEV1, measured within SAM40040 last 2 years. Subjects may also have a reversibility measurement recorded.

Page 2 of 3 Protocol: SAM40040 Population: Per Protocol Table 12.16 Summary of Baseline Lung Function Characteristics Per-Protocol Population

Post-bronchodilator FEV1 (L) at Visit 2/2a n 53 66 119 Mean 2.8 2.6 2.7 SD 0.92 0.74 0.82 Median 2.7 2.7 2.7 Min. 1.2 1.3 1.2

Max. 4.7 4.4 4.7 CONFIDENTIAL

% Predicted FEV1 at

149 Visit 2/2a n 449 453 902 Mean 78.4 79.3 78.8 SD 18.04 18.33 18.18 Median 77.1 77.6 77.4 Min. 25.7 30.8 25.7 Max. 133.2 139.2 139.2

Reversibility (%) at Visit 2/2a n 53 66 119 Mean 19.8 24.3 22.3 SD 11.80 15.68 14.21 Median 16.7 20.4 18.0

Min. 5.5 12.1 5.5 GM2004/00056/00 Max. 69.8 104.2 104.2

[1]: Documented evidence of reversibility of >=12% (and >=200mL) in FEV1, measured within SAM40040 last 2 years. Subjects may also have a reversibility measurement recorded.

Page 3 of 3 Protocol: SAM40040 Population: Intent-to-Treat Table 12.17 Summary of Current Medical Conditions

Condition SFC 50/250 FBC 4.5/160 Total Body System Present? (N=694) (N=697) (N=1391) ——————————————————————————————————————————————————————————————————————————————————————

Any condition 561 (81%) 555 (80%) 1116 (80%)

Ear,nose and throat n 694 696 1390 Yes 186 (27%) 172 (25%) 358 (26%) No 508 (73%) 524 (75%) 1032 (74%)

Eyes n 694 696 1390

Yes 82 (12%) 71 (10%) 153 (11%) CONFIDENTIAL No 612 (88%) 625 (90%) 1237 (89%)

150 Respiratory n 694 696 1390 Yes 18 (3%) 21 (3%) 39 (3%) No 676 (97%) 675 (97%) 1351 (97%)

Cardiovascular n 694 696 1390 Yes 155 (22%) 149 (21%) 304 (22%) No 539 (78%) 547 (79%) 1086 (78%)

Gastrointestinal n 694 696 1390 Yes 84 (12%) 92 (13%) 176 (13%) No 610 (88%) 604 (87%) 1214 (87%)

Hepatobiliary and pancreas n 694 696 1390 GM2004/00056/00 Yes 12 (2%) 14 (2%) 26 (2%) No 682 (98%) 682 (98%) 1364 (98%)

SAM40040

Page 1 of 3 Protocol: SAM40040 Population: Intent-to-Treat Table 12.17 Summary of Current Medical Conditions

Urinary system n 694 696 1390 Yes 25 (4%) 26 (4%) 51 (4%) No 669 (96%) 670 (96%) 1339 (96%)

Reproductive system n 694 696 1390 Yes 28 (4%) 31 (4%) 59 (4%) No 666 (96%) 665 (96%) 1331 (96%)

CONFIDENTIAL Neurology n 694 696 1390 Yes 43 (6%) 39 (6%) 82 (6%)

151 No 651 (94%) 657 (94%) 1308 (94%)

Blood and lymphatic n 694 696 1390 Yes 11 (2%) 16 (2%) 27 (2%) No 683 (98%) 680 (98%) 1363 (98%)

Endocrine and metabolic n 694 696 1390 Yes 72 (10%) 82 (12%) 154 (11%) No 622 (90%) 614 (88%) 1236 (89%)

Musculoskeletal n 694 696 1390 Yes 119 (17%) 114 (16%) 233 (17%)

No 575 (83%) 582 (84%) 1157 (83%) GM2004/00056/00

Skin n 694 696 1390 Yes 60 (9%) 72 (10%) 132 (9%)

No 634 (91%) 624 (90%) 1258 (91%) SAM40040

Page 2 of 3 Protocol: SAM40040 Population: Intent-to-Treat Table 12.17 Summary of Current Medical Conditions

Psychiatry n 694 696 1390 Yes 39 (6%) 44 (6%) 83 (6%) No 655 (94%) 652 (94%) 1307 (94%)

Allergies n 694 696 1390 Yes 331 (48%) 311 (45%) 642 (46%) No 363 (52%) 385 (55%) 748 (54%)

CONFIDENTIAL

152

GM2004/00056/00

SAM40040

Page 3 of 3 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Group Term SFC 50/250 FBC 4.5/160 Total Preferred Term (N=694) (N=697) (N=1391) ——————————————————————————————————————————————————————————————————————————————————————————

Any medication 694(100%) 697(100%) 1391(100%)

Corticosteroids 689(>99%) 696(>99%) 1385(>99%) Fluticasone propionate 316 (46%) 317 (45%) 633 (46%) Budesonide 292 (42%) 307 (44%) 599 (43%) Beclomethasone dipropionate 142 (20%) 144 (21%) 286 (21%) Prednisolone 45 (6%) 56 (8%) 101 (7%)

Prednisone 11 (2%) 12 (2%) 23 (2%) CONFIDENTIAL Medrol 6 (<1%) 6 (<1%) 12 (<1%) Dexamethasone 6 (<1%) 4 (<1%) 10 (<1%)

153 Polcortolon 3 (<1%) 3 (<1%) 6 (<1%) Hydrocortisone sodium succinate 4 (<1%) 1 (<1%) 5 (<1%) Urbason 2 (<1%) 3 (<1%) 5 (<1%) Mometasone 2 (<1%) 2 (<1%) 4 (<1%) Triamcinolone 0 4 (<1%) 4 (<1%) Steroid 1 (<1%) 2 (<1%) 3 (<1%) Betamethasone sodium phosphate 1 (<1%) 1 (<1%) 2 (<1%) Celestone 1 (<1%) 1 (<1%) 2 (<1%) Deflazacort 1 (<1%) 1 (<1%) 2 (<1%) Flunisolide 1 (<1%) 1 (<1%) 2 (<1%) Methylprednisolone sodium succinate 1 (<1%) 1 (<1%) 2 (<1%) Di-Adreson-F 0 1 (<1%) 1 (<1%)

Methylprednisolone 1 (<1%) 0 1 (<1%) GM2004/00056/00 Mometasone furoate 0 1 (<1%) 1 (<1%) Propiochrone 0 1 (<1%) 1 (<1%) Triamcinolone acetonide 1 (<1%) 0 1 (<1%)

SAM40040

Page 1 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Short acting beta-agonists 546 (79%) 524 (75%) 1070 (77%) Salbutamol sulphate 406 (59%) 380 (55%) 786 (57%) Terbutaline sulphate 109 (16%) 114 (16%) 223 (16%) Fenoterol hydrobromide 22 (3%) 26 (4%) 48 (3%) Berodual 18 (3%) 9 (1%) 27 (2%) Aarane 7 (1%) 8 (1%) 15 (1%) Allergospasmin 6 (<1%) 8 (1%) 14 (1%)

Combivent 4 (<1%) 10 (1%) 14 (1%) CONFIDENTIAL Terbutaline 6 (<1%) 8 (1%) 14 (1%) Berovent 6 (<1%) 3 (<1%) 9 (<1%)

154 Duovent 5 (<1%) 2 (<1%) 7 (<1%) Pirbuterol acetate 3 (<1%) 3 (<1%) 6 (<1%) Ditec 3 (<1%) 1 (<1%) 4 (<1%) Bronchodual 1 (<1%) 1 (<1%) 2 (<1%) Clenbuterol hydrochloride 2 (<1%) 0 2 (<1%) Spasmo-Mucosolvan 1 (<1%) 1 (<1%) 2 (<1%) Berodualin 1 (<1%) 0 1 (<1%) Dospir 0 1 (<1%) 1 (<1%)

Long acting beta-agonists 240 (35%) 265 (38%) 505 (36%) Formoterol 141 (20%) 150 (22%) 291 (21%) Salmeterol xinafoate 108 (16%) 124 (18%) 232 (17%)

Procaterol hydrochloride 2 (<1%) 0 2 (<1%) GM2004/00056/00 Bambuterol 0 1 (<1%) 1 (<1%)

SAM40040

Page 2 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Corticosteroids & bronchodilators combined 223 (32%) 236 (34%) 459 (33%) Fluticasone propionate+salmeterol 150 (22%) 149 (21%) 299 (21%) xinafoate Symbicort 62 (9%) 85 (12%) 147 (11%) Plusvent Accuhaler 7 (1%) 7 (1%) 14 (1%) Inaladuo 8 (1%) 4 (<1%) 12 (<1%)

Aliflus 0 3 (<1%) 3 (<1%) CONFIDENTIAL Clenil compositum 1 (<1%) 2 (<1%) 3 (<1%) Anasma 1 (<1%) 0 1 (<1%)

155 Assieme turbohaler 1 (<1%) 0 1 (<1%) Beclomethasone dipropionate + 1 (<1%) 0 1 (<1%) salbutamol sulphate Sinestic 1 (<1%) 0 1 (<1%)

Xanthines 62 (9%) 57 (8%) 119 (9%) Theophylline 52 (7%) 42 (6%) 94 (7%) Euphyllin 8 (1%) 10 (1%) 18 (1%) Theoplus 0 4 (<1%) 4 (<1%) Aminophylline 1 (<1%) 2 (<1%) 3 (<1%) Choline theophyllinate 2 (<1%) 0 2 (<1%) Euphyllin retard 2 (<1%) 0 2 (<1%)

Theospirex 0 1 (<1%) 1 (<1%) GM2004/00056/00

Montelukast sodium 62 (9%) 56 (8%) 118 (8%) Montelukast sodium 62 (9%) 56 (8%) 118 (8%)

SAM40040

Page 3 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Anti-cholinergics 29 (4%) 33 (5%) 62 (4%) Ipratropium bromide 26 (4%) 32 (5%) 58 (4%) Oxitropium bromide 3 (<1%) 1 (<1%) 4 (<1%)

Investigational drug 20 (3%) 24 (3%) 44 (3%) Blinded trial medication 20 (3%) 22 (3%) 42 (3%) Investigational drug, unspecified 0 2 (<1%) 2 (<1%)

CONFIDENTIAL Anti-tussives expectorants + mucolytics 18 (3%) 15 (2%) 33 (2%) Acetylcysteine 8 (1%) 9 (1%) 17 (1%)

156 Bronchospray 3 (<1%) 3 (<1%) 6 (<1%) Bromhexine 4 (<1%) 0 4 (<1%) Ambrobene 1 (<1%) 2 (<1%) 3 (<1%) Ambroxol 0 2 (<1%) 2 (<1%) Carbocisteine 1 (<1%) 0 1 (<1%) Eprazinone hydrochloride 1 (<1%) 0 1 (<1%) Sedotussin 1 (<1%) 0 1 (<1%)

Anti-histamines (h1 antagonists) 9 (1%) 13 (2%) 22 (2%) Cetirizine hydrochloride 7 (1%) 10 (1%) 17 (1%) Loratadine 2 (<1%) 2 (<1%) 4 (<1%) Desloratadine 0 1 (<1%) 1 (<1%)

Ebastine 1 (<1%) 0 1 (<1%) GM2004/00056/00 Hydroxyzine hydrochloride 0 1 (<1%) 1 (<1%)

SAM40040

Page 4 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Penicillins 11 (2%) 11 (2%) 22 (2%) Amoxicillin trihydrate + potassium 6 (<1%) 7 (1%) 13 (<1%) clavulanate Amoxicillin trihydrate 2 (<1%) 4 (<1%) 6 (<1%) Clavamel 3 (<1%) 0 3 (<1%) Phenoxymethylpenicillin potassium 1 (<1%) 0 1 (<1%)

Macrolides 10 (1%) 9 (1%) 19 (1%) CONFIDENTIAL Clarithromycin 5 (<1%) 8 (1%) 13 (<1%) Azithromycin 5 (<1%) 1 (<1%) 6 (<1%)

157 Erythromycin 1 (<1%) 0 1 (<1%)

Other asthma medication 7 (1%) 10 (1%) 17 (1%) Zafirlukast 7 (1%) 10 (1%) 17 (1%)

Quinolones 8 (1%) 5 (<1%) 13 (<1%) Moxifloxacin hydrochloride 5 (<1%) 2 (<1%) 7 (<1%) Ciprofloxacin 2 (<1%) 1 (<1%) 3 (<1%) Ciprofloxacin hydrochloride 1 (<1%) 1 (<1%) 2 (<1%) Levofloxacin 1 (<1%) 1 (<1%) 2 (<1%)

Nedocromil 8 (1%) 2 (<1%) 10 (<1%)

Nedocromil sodium 8 (1%) 2 (<1%) 10 (<1%) GM2004/00056/00

SAM40040

Page 5 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Cephalosporins & cephamycins 3 (<1%) 6 (<1%) 9 (<1%) Cefaclor 1 (<1%) 2 (<1%) 3 (<1%) Cefuroxime axetil 0 2 (<1%) 2 (<1%) Cephazolin sodium 1 (<1%) 1 (<1%) 2 (<1%) Cefadroxil 1 (<1%) 0 1 (<1%) Ceftibuten 0 1 (<1%) 1 (<1%) Cephalexin 0 1 (<1%) 1 (<1%)

CONFIDENTIAL Miscellaneous antibacterials 4 (<1%) 5 (<1%) 9 (<1%) Antibiotics 1 (<1%) 5 (<1%) 6 (<1%)

158 Telithromycin 2 (<1%) 0 2 (<1%) Pristinamycin 1 (<1%) 0 1 (<1%)

Tetracylines 1 (<1%) 4 (<1%) 5 (<1%) Doxycycline 1 (<1%) 3 (<1%) 4 (<1%) Doxycycline hydrochloride 0 1 (<1%) 1 (<1%)

Antidotes 0 1 (<1%) 1 (<1%) Glutathione 0 1 (<1%) 1 (<1%)

Ketotifen 0 1 (<1%) 1 (<1%) Ketotifen 0 1 (<1%) 1 (<1%)

GM2004/00056/00 Narcotic analgesics 0 1 (<1%) 1 (<1%) Codeine 0 1 (<1%) 1 (<1%)

SAM40040

Page 6 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.18 Summary of Asthma Medication Started Prior to Treatment Start Date

Nasal decongestants/cold cures 1 (<1%) 0 1 (<1%) Emser salz 1 (<1%) 0 1 (<1%)

Sodium cromoglycate 1 (<1%) 0 1 (<1%) Sodium cromoglycate 1 (<1%) 0 1 (<1%)

CONFIDENTIAL

159

GM2004/00056/00

SAM40040

Page 7 of 7 Protocol: SAM40040 Population: Intent-to-Treat Table 12.19 Summary of Asthma Medication Taken During the Treatment Period

Any medication 97 (14%) 115 (16%) 212 (15%)

Corticosteroids 67 (10%) 80 (11%) 147 (11%) Prednisolone 32 (5%) 44 (6%) 76 (5%) Prednisone 18 (3%) 14 (2%) 32 (2%) Urbason 4 (<1%) 8 (1%) 12 (<1%) Fluticasone propionate 2 (<1%) 9 (1%) 11 (<1%)

Beclomethasone dipropionate 3 (<1%) 2 (<1%) 5 (<1%) CONFIDENTIAL Medrol 3 (<1%) 2 (<1%) 5 (<1%) Budesonide 1 (<1%) 2 (<1%) 3 (<1%)

160 Betamethasone sodium phosphate 1 (<1%) 1 (<1%) 2 (<1%) Celestone 2 (<1%) 0 2 (<1%) Methylprednisolone 1 (<1%) 1 (<1%) 2 (<1%) Methylprednisolone sodium succinate 1 (<1%) 1 (<1%) 2 (<1%) Celestamine 0 1 (<1%) 1 (<1%) Cortisone 0 1 (<1%) 1 (<1%) Hydrocortisone acetate 0 1 (<1%) 1 (<1%) Hydrocortisone sodium phosphate 1 (<1%) 0 1 (<1%) Prednisolone acetate 0 1 (<1%) 1 (<1%) Prednisolone sodium succinate 1 (<1%) 0 1 (<1%) Triamcinolone 1 (<1%) 0 1 (<1%) Triamcinolone acetonide 1 (<1%) 0 1 (<1%)

GM2004/00056/00

SAM40040

Page 1 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.19 Summary of Asthma Medication Taken During the Treatment Period

Short acting beta-agonists 16 (2%) 21 (3%) 37 (3%) Salbutamol sulphate 15 (2%) 14 (2%) 29 (2%) Terbutaline sulphate 1 (<1%) 4 (<1%) 5 (<1%) Berodual 0 1 (<1%) 1 (<1%) Berovent 0 1 (<1%) 1 (<1%) Combivent 0 1 (<1%) 1 (<1%) Pirbuterol acetate 0 1 (<1%) 1 (<1%)

CONFIDENTIAL Penicillins 13 (2%) 9 (1%) 22 (2%) Amoxicillin trihydrate + potassium 8 (1%) 8 (1%) 16 (1%)

161 clavulanate Amoxicillin trihydrate 3 (<1%) 1 (<1%) 4 (<1%) Penglobe 1 (<1%) 0 1 (<1%) Phenoxymethylpenicillin potassium 1 (<1%) 0 1 (<1%)

Macrolides 11 (2%) 7 (1%) 18 (1%) Clarithromycin 4 (<1%) 4 (<1%) 8 (<1%) Roxithromycin 4 (<1%) 2 (<1%) 6 (<1%) Azithromycin 2 (<1%) 1 (<1%) 3 (<1%) Erythromycin 1 (<1%) 0 1 (<1%)

GM2004/00056/00

SAM40040

Page 2 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.19 Summary of Asthma Medication Taken During the Treatment Period

Anti-histamines (h1 antagonists) 6 (<1%) 9 (1%) 15 (1%) Cetirizine hydrochloride 3 (<1%) 6 (<1%) 9 (<1%) Loratadine 2 (<1%) 0 2 (<1%) Desloratadine 0 1 (<1%) 1 (<1%) Ebastine 1 (<1%) 0 1 (<1%) Hydroxyzine hydrochloride 0 1 (<1%) 1 (<1%) Levocetirizine hydrochloride 0 1 (<1%) 1 (<1%)

CONFIDENTIAL Anti-tussives expectorants + mucolytics 10 (1%) 5 (<1%) 15 (1%) Acetylcysteine 6 (<1%) 4 (<1%) 10 (<1%)

162 Ambroxol 1 (<1%) 0 1 (<1%) Carbocisteine 1 (<1%) 0 1 (<1%) Eprazinone hydrochloride 1 (<1%) 0 1 (<1%) Pulmotin 1 (<1%) 0 1 (<1%) Romilar 0 1 (<1%) 1 (<1%)

Corticosteroids & bronchodilators combined 5 (<1%) 3 (<1%) 8 (<1%) Fluticasone propionate+salmeterol 5 (<1%) 2 (<1%) 7 (<1%) xinafoate Symbicort 0 1 (<1%) 1 (<1%)

Cephalosporins & cephamycins 4 (<1%) 2 (<1%) 6 (<1%) GM2004/00056/00 Cefuroxime axetil 2 (<1%) 2 (<1%) 4 (<1%) Cefadroxil 1 (<1%) 0 1 (<1%) Cefixime 1 (<1%) 0 1 (<1%)

SAM40040

Page 3 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.19 Summary of Asthma Medication Taken During the Treatment Period

Xanthines 2 (<1%) 4 (<1%) 6 (<1%) Theophylline 1 (<1%) 3 (<1%) 4 (<1%) Aminophylline 0 1 (<1%) 1 (<1%) Theophylline glycinate 1 (<1%) 0 1 (<1%)

Quinolones 1 (<1%) 4 (<1%) 5 (<1%) Levofloxacin 1 (<1%) 2 (<1%) 3 (<1%)

Moxifloxacin hydrochloride 0 2 (<1%) 2 (<1%) CONFIDENTIAL

Tetracylines 3 (<1%) 2 (<1%) 5 (<1%)

163 Doxycycline 3 (<1%) 2 (<1%) 5 (<1%)

Anti-cholinergics 2 (<1%) 2 (<1%) 4 (<1%) Ipratropium bromide 2 (<1%) 2 (<1%) 4 (<1%)

Long acting beta-agonists 1 (<1%) 3 (<1%) 4 (<1%) Formoterol 0 2 (<1%) 2 (<1%) Salmeterol xinafoate 1 (<1%) 1 (<1%) 2 (<1%)

Miscellaneous antibacterials 1 (<1%) 1 (<1%) 2 (<1%) Antibiotics 0 1 (<1%) 1 (<1%) Pristinamycin 1 (<1%) 0 1 (<1%)

GM2004/00056/00 Montelukast sodium 1 (<1%) 1 (<1%) 2 (<1%) Montelukast sodium 1 (<1%) 1 (<1%) 2 (<1%)

SAM40040

Page 4 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.19 Summary of Asthma Medication Taken During the Treatment Period

Narcotic analgesics 2 (<1%) 0 2 (<1%) Codeine 1 (<1%) 0 1 (<1%) Codeine phosphate 1 (<1%) 0 1 (<1%)

Nasal decongestants/cold cures 2 (<1%) 0 2 (<1%) Emser salz 1 (<1%) 0 1 (<1%) Xylometazoline hydrochloride 1 (<1%) 0 1 (<1%)

CONFIDENTIAL Acids, salts, fluids, electrolytes 1 (<1%) 0 1 (<1%) Sodium chloride 1 (<1%) 0 1 (<1%)

164 Benzodiazepines 1 (<1%) 0 1 (<1%) Diazepam 1 (<1%) 0 1 (<1%)

Miscellaneous analgesics 0 1 (<1%) 1 (<1%) Propacetamol hydrochloride 0 1 (<1%) 1 (<1%)

Salicylates 1 (<1%) 0 1 (<1%) Aspirin 1 (<1%) 0 1 (<1%)

Sulfonamides 1 (<1%) 0 1 (<1%) Co-trimoxazole 1 (<1%) 0 1 (<1%)

GM2004/00056/00

SAM40040

Page 5 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Any medication 491 (71%) 486 (70%) 977 (70%)

Anti-histamines (h1 antagonists) 142 (20%) 105 (15%) 247 (18%) Cetirizine hydrochloride 47 (7%) 40 (6%) 87 (6%) Loratadine 51 (7%) 34 (5%) 85 (6%) Desloratadine 20 (3%) 8 (1%) 28 (2%) Fexofenadine hydrochloride 9 (1%) 13 (2%) 22 (2%)

Ebastine 8 (1%) 3 (<1%) 11 (<1%) CONFIDENTIAL Chlorpheniramine maleate 5 (<1%) 3 (<1%) 8 (<1%) Levocabastine hydrochloride 1 (<1%) 6 (<1%) 7 (<1%)

165 Mizolastine 5 (<1%) 2 (<1%) 7 (<1%) Azelastine hydrochloride 5 (<1%) 1 (<1%) 6 (<1%) Diphenhydramine hydrochloride 2 (<1%) 3 (<1%) 5 (<1%) Hydroxyzine hydrochloride 3 (<1%) 2 (<1%) 5 (<1%) Levocabastine 1 (<1%) 4 (<1%) 5 (<1%) Cinnarizine 2 (<1%) 2 (<1%) 4 (<1%) Rino-ebastel 3 (<1%) 1 (<1%) 4 (<1%) Clemastine fumarate 1 (<1%) 1 (<1%) 2 (<1%) Mepyramine maleate 1 (<1%) 1 (<1%) 2 (<1%) Tavegil 1 (<1%) 1 (<1%) 2 (<1%) Acrivastine 1 (<1%) 0 1 (<1%) Bisulepin hydrochloride 1 (<1%) 0 1 (<1%)

Chlorpheniramine 0 1 (<1%) 1 (<1%) GM2004/00056/00 Cirrus 1 (<1%) 0 1 (<1%) Cyclizine 1 (<1%) 0 1 (<1%) Cyproheptadine hydrochloride 1 (<1%) 0 1 (<1%)

Dexchlorpheniramine maleate 1 (<1%) 0 1 (<1%) SAM40040 Anti-histamines (h1 antagonists) continues ... Page 1 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Anti-histamines (h1 antagonists) Levocetirizine hydrochloride 1 (<1%) 0 1 (<1%) Mequitazine 1 (<1%) 0 1 (<1%) Narine (Spain) 0 1 (<1%) 1 (<1%) Promethazine hydrochloride 0 1 (<1%) 1 (<1%) Terfenadine 0 1 (<1%) 1 (<1%) Touristil 1 (<1%) 0 1 (<1%)

CONFIDENTIAL Miscellaneous analgesics 124 (18%) 111 (16%) 235 (17%) Paracetamol 118 (17%) 103 (15%) 221 (16%)

166 Benzydamine hydrochloride 0 2 (<1%) 2 (<1%) Finimal 1 (<1%) 1 (<1%) 2 (<1%) Mexavit 0 2 (<1%) 2 (<1%) Adolorin 0 1 (<1%) 1 (<1%) Afebryl 0 1 (<1%) 1 (<1%) Ataralgin 1 (<1%) 0 1 (<1%) Dialgine forte 0 1 (<1%) 1 (<1%) Dismenol 1 (<1%) 0 1 (<1%) Eudorlin (Paracetamol) 0 1 (<1%) 1 (<1%) Febrectal 0 1 (<1%) 1 (<1%) Floctafenine 0 1 (<1%) 1 (<1%) Neuranidal 0 1 (<1%) 1 (<1%)

Paracetamol + caffeine 1 (<1%) 0 1 (<1%) GM2004/00056/00 Phenacetin 1 (<1%) 0 1 (<1%) Sanalgin 1 (<1%) 0 1 (<1%) Sedergine C 1 (<1%) 0 1 (<1%)

Toximer 1 (<1%) 0 1 (<1%) SAM40040

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Corticosteroids 110 (16%) 115 (16%) 225 (16%) Mometasone furoate 28 (4%) 27 (4%) 55 (4%) Fluticasone propionate 23 (3%) 28 (4%) 51 (4%) Budesonide 19 (3%) 24 (3%) 43 (3%) Beclomethasone dipropionate 12 (2%) 10 (1%) 22 (2%) Triamcinolone acetonide 10 (1%) 3 (<1%) 13 (<1%) Hydrocortisone 3 (<1%) 5 (<1%) 8 (<1%)

Prednisolone 3 (<1%) 5 (<1%) 8 (<1%) CONFIDENTIAL Betamethasone valerate 3 (<1%) 3 (<1%) 6 (<1%) Prednisone 2 (<1%) 3 (<1%) 5 (<1%)

167 Hydrocortisone butyrate 1 (<1%) 3 (<1%) 4 (<1%) Betamethasone 1 (<1%) 2 (<1%) 3 (<1%) Celestamine 2 (<1%) 1 (<1%) 3 (<1%) Clobetasol propionate 2 (<1%) 1 (<1%) 3 (<1%) Prednicarbate 1 (<1%) 2 (<1%) 3 (<1%) Medrol 1 (<1%) 1 (<1%) 2 (<1%) Methylprednisolone aceponate 1 (<1%) 1 (<1%) 2 (<1%) Methylprednisolone acetate 1 (<1%) 1 (<1%) 2 (<1%) Advantan cream + glycerine 0 1 (<1%) 1 (<1%) Betamethasone sodium phosphate 0 1 (<1%) 1 (<1%) Celestamin 1 (<1%) 0 1 (<1%) Celestone 1 (<1%) 0 1 (<1%)

Cortisone 0 1 (<1%) 1 (<1%) GM2004/00056/00 Corto-Tavegil 1 (<1%) 0 1 (<1%) Dexa-phlogont 1 (<1%) 0 1 (<1%) Dexamethasone 1 (<1%) 0 1 (<1%)

Fluocinonide 1 (<1%) 0 1 (<1%) SAM40040 Corticosteroids continues ... Page 3 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Corticosteroids Hydrocortisone acetate 0 1 (<1%) 1 (<1%) Methylprednisolone 1 (<1%) 0 1 (<1%) Neurodavur Plus 0 1 (<1%) 1 (<1%) Scheriproct 1 (<1%) 0 1 (<1%) Thiovalone 0 1 (<1%) 1 (<1%) Triamcinolone 0 1 (<1%) 1 (<1%)

Urbason 1 (<1%) 0 1 (<1%) CONFIDENTIAL

NSAIDS 96 (14%) 88 (13%) 184 (13%)

168 Ibuprofen 41 (6%) 40 (6%) 81 (6%) Diclofenac sodium 14 (2%) 9 (1%) 23 (2%) Diclofenac 12 (2%) 9 (1%) 21 (2%) Nimesulide 7 (1%) 8 (1%) 15 (1%) Ketoprofen 5 (<1%) 4 (<1%) 9 (<1%) Dipyrone 3 (<1%) 4 (<1%) 7 (<1%) Meloxicam 5 (<1%) 2 (<1%) 7 (<1%) Naproxen sodium 4 (<1%) 3 (<1%) 7 (<1%) Piroxicam 4 (<1%) 3 (<1%) 7 (<1%) Mefenamic acid 2 (<1%) 4 (<1%) 6 (<1%) Metamizole magnesium 2 (<1%) 4 (<1%) 6 (<1%) Indomethacin 4 (<1%) 0 4 (<1%)

Naproxen 2 (<1%) 2 (<1%) 4 (<1%) GM2004/00056/00 Ketorolac trometamol 0 3 (<1%) 3 (<1%) Aceclofenac 1 (<1%) 1 (<1%) 2 (<1%) Deflamat 1 (<1%) 1 (<1%) 2 (<1%)

Flurbiprofen 2 (<1%) 0 2 (<1%) SAM40040 NSAIDS continues ... Page 4 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing NSAIDS Alpha amylase 1 (<1%) 0 1 (<1%) Aminophenazone 1 (<1%) 0 1 (<1%) Arthrotec 0 1 (<1%) 1 (<1%) Baralgin 1 (<1%) 0 1 (<1%) Benorylate 1 (<1%) 0 1 (<1%) Clonixin 0 1 (<1%) 1 (<1%)

Diclofenac potassium 1 (<1%) 0 1 (<1%) CONFIDENTIAL Etoricoxib 0 1 (<1%) 1 (<1%) Morniflumate 0 1 (<1%) 1 (<1%)

169 Neodolpasse 1 (<1%) 0 1 (<1%) Piroxicam beta cyclodextrine 0 1 (<1%) 1 (<1%) Proglumetacin maleate 0 1 (<1%) 1 (<1%) Tempalgin 1 (<1%) 0 1 (<1%) Tenoxicam 1 (<1%) 0 1 (<1%) Tolfenamic acid 1 (<1%) 0 1 (<1%)

GM2004/00056/00

SAM40040

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Estrogens & progestogens combined 83 (12%) 78 (11%) 161 (12%) Cileste 5 (<1%) 8 (1%) 13 (<1%) Marvelon 4 (<1%) 4 (<1%) 8 (<1%) Microgynon 5 (<1%) 3 (<1%) 8 (<1%) Yasmin 3 (<1%) 5 (<1%) 8 (<1%) Norethisterone acetate + oestradiol 3 (<1%) 3 (<1%) 6 (<1%) Tri-Minulet 4 (<1%) 2 (<1%) 6 (<1%)

Mercilon 2 (<1%) 3 (<1%) 5 (<1%) CONFIDENTIAL Activelle 1 (<1%) 3 (<1%) 4 (<1%) Microgynon 30 3 (<1%) 1 (<1%) 4 (<1%)

170 Minulet 2 (<1%) 2 (<1%) 4 (<1%) Nora Ratiopharm 2 (<1%) 2 (<1%) 4 (<1%) Oral contraceptive 2 (<1%) 2 (<1%) 4 (<1%) Adepal 0 3 (<1%) 3 (<1%) Femoston 2 (<1%) 1 (<1%) 3 (<1%) Gynera 2 (<1%) 1 (<1%) 3 (<1%) Kliofem 1 (<1%) 2 (<1%) 3 (<1%) Melodene 1 (<1%) 2 (<1%) 3 (<1%) Microdiol 2 (<1%) 1 (<1%) 3 (<1%) Arianna 2 (<1%) 0 2 (<1%) Cycleane 2 (<1%) 0 2 (<1%) Femoden 1 (<1%) 1 (<1%) 2 (<1%)

Femodene 1 (<1%) 1 (<1%) 2 (<1%) GM2004/00056/00 Gracial 2 (<1%) 0 2 (<1%) Klimonorm 1 (<1%) 1 (<1%) 2 (<1%) Leios 0 2 (<1%) 2 (<1%)

Meliane 0 2 (<1%) 2 (<1%) SAM40040 Estrogens & progestogens combined continues ... Page 6 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Estrogens & progestogens combined Minidril 1 (<1%) 1 (<1%) 2 (<1%) Minisiston 1 (<1%) 1 (<1%) 2 (<1%) Monostep 1 (<1%) 1 (<1%) 2 (<1%) Novynette 0 2 (<1%) 2 (<1%) Trinordiol 2 (<1%) 0 2 (<1%) Triquilar 1 (<1%) 1 (<1%) 2 (<1%)

Valette 0 2 (<1%) 2 (<1%) CONFIDENTIAL Belara 1 (<1%) 0 1 (<1%) Biviol 1 (<1%) 0 1 (<1%)

171 Climagest 1 (<1%) 0 1 (<1%) Climesse 1 (<1%) 0 1 (<1%) Contraceptive depot 0 1 (<1%) 1 (<1%) Desmin (Germany) 1 (<1%) 0 1 (<1%) Desolett 0 1 (<1%) 1 (<1%) Femanor 0 1 (<1%) 1 (<1%) Femodeen 1 (<1%) 0 1 (<1%) Femoston Conti 0 1 (<1%) 1 (<1%) Kliane 0 1 (<1%) 1 (<1%) Kliovance 1 (<1%) 0 1 (<1%) Marviol 0 1 (<1%) 1 (<1%) Meloden 1 (<1%) 0 1 (<1%)

Menova 1 (<1%) 0 1 (<1%) GM2004/00056/00 Microgynon 50 1 (<1%) 0 1 (<1%) Minigest 1 (<1%) 0 1 (<1%) Mirelle 1 (<1%) 0 1 (<1%)

Neogynon 1 (<1%) 0 1 (<1%) SAM40040 Estrogens & progestogens combined continues ... Page 7 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Estrogens & progestogens combined Nordiol 1 (<1%) 0 1 (<1%) NovaStep 0 1 (<1%) 1 (<1%) Ologyn 1 (<1%) 0 1 (<1%) Ovoplex 1 (<1%) 0 1 (<1%) Ovranette 1 (<1%) 0 1 (<1%) Perklimen 1 (<1%) 0 1 (<1%)

Phaeva 1 (<1%) 0 1 (<1%) CONFIDENTIAL Premella 0 1 (<1%) 1 (<1%) Premelle 0 1 (<1%) 1 (<1%)

172 Premelle cycle 0 1 (<1%) 1 (<1%) Premique 0 1 (<1%) 1 (<1%) Prempak-C 0 1 (<1%) 1 (<1%) Stediril-d 0 1 (<1%) 1 (<1%) Suavuret 0 1 (<1%) 1 (<1%) Synphasec 0 1 (<1%) 1 (<1%) Tri-Gynera 1 (<1%) 0 1 (<1%) Triagynon 1 (<1%) 0 1 (<1%) Triette 1 (<1%) 0 1 (<1%) Trigoa 0 1 (<1%) 1 (<1%) Trigynon 1 (<1%) 0 1 (<1%) Trinovum 1 (<1%) 0 1 (<1%)

Trionetta 28 1 (<1%) 0 1 (<1%) GM2004/00056/00 Varnoline 0 1 (<1%) 1 (<1%)

SAM40040

Page 8 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Penicillins 54 (8%) 60 (9%) 114 (8%) Amoxicillin trihydrate 24 (3%) 31 (4%) 55 (4%) Amoxicillin trihydrate + potassium 21 (3%) 19 (3%) 40 (3%) clavulanate Phenoxymethylpenicillin potassium 3 (<1%) 10 (1%) 13 (<1%) Flucloxacillin sodium 2 (<1%) 2 (<1%) 4 (<1%) Pivampicillin 1 (<1%) 1 (<1%) 2 (<1%)

Ampicillin trihydrate 0 1 (<1%) 1 (<1%) CONFIDENTIAL Britapen 0 1 (<1%) 1 (<1%) Clavamel 0 1 (<1%) 1 (<1%)

173 Clonamel 1 (<1%) 0 1 (<1%) Cloxacillin sodium 1 (<1%) 0 1 (<1%) Dicloxacillin sodium 1 (<1%) 0 1 (<1%) Phenoxymethylpenicillin calcium 1 (<1%) 0 1 (<1%) Piperacillin sodium 0 1 (<1%) 1 (<1%) Sultamicillin 1 (<1%) 0 1 (<1%)

Proton pump inhibitors 39 (6%) 50 (7%) 89 (6%) Omeprazole 18 (3%) 33 (5%) 51 (4%) Lansoprazole 12 (2%) 6 (<1%) 18 (1%) Esomeprazole 5 (<1%) 5 (<1%) 10 (<1%) Pantoprazole 3 (<1%) 5 (<1%) 8 (<1%)

Sodium rabeprazole 2 (<1%) 2 (<1%) 4 (<1%) GM2004/00056/00

SAM40040

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Calcium antagonists 40 (6%) 44 (6%) 84 (6%) Amlodipine 6 (<1%) 10 (1%) 16 (1%) Nifedipine 7 (1%) 8 (1%) 15 (1%) Verapamil hydrochloride 9 (1%) 3 (<1%) 12 (<1%) Diltiazem hydrochloride 3 (<1%) 8 (1%) 11 (<1%) Felodipine 4 (<1%) 6 (<1%) 10 (<1%) Amlodipine besylate 6 (<1%) 3 (<1%) 9 (<1%)

Verapamil 2 (<1%) 4 (<1%) 6 (<1%) CONFIDENTIAL Isradipine 2 (<1%) 0 2 (<1%) Nitrendipine 0 2 (<1%) 2 (<1%)

174 Lacidipine 0 1 (<1%) 1 (<1%) Lercanidipine 1 (<1%) 0 1 (<1%)

Salicylates 36 (5%) 46 (7%) 82 (6%) Aspirin 27 (4%) 31 (4%) 58 (4%) Anadin 3 (<1%) 1 (<1%) 4 (<1%) Lysine aspirin 2 (<1%) 2 (<1%) 4 (<1%) Anopyrin 0 2 (<1%) 2 (<1%) Carbaspirin calcium 1 (<1%) 1 (<1%) 2 (<1%) Mesalazine 0 2 (<1%) 2 (<1%) Treo 0 2 (<1%) 2 (<1%) Alka-seltzer 1 (<1%) 0 1 (<1%)

Aloxiprin 1 (<1%) 0 1 (<1%) GM2004/00056/00 Aspegic 1 (<1%) 0 1 (<1%) Aspirin + ascorbic acid 0 1 (<1%) 1 (<1%) Aspirin Plus 0 1 (<1%) 1 (<1%)

Aspirin plus C 0 1 (<1%) 1 (<1%) SAM40040 Salicylates continues ... Page 10 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Salicylates Citramon 1 (<1%) 0 1 (<1%) Godasal 0 1 (<1%) 1 (<1%) Norgesic 1 (<1%) 0 1 (<1%) Trolamine salicylate 0 1 (<1%) 1 (<1%)

Anti-tussives expectorants + mucolytics 49 (7%) 28 (4%) 77 (6%)

Acetylcysteine 19 (3%) 14 (2%) 33 (2%) CONFIDENTIAL Ambroxol 4 (<1%) 4 (<1%) 8 (<1%) Carbocisteine 5 (<1%) 2 (<1%) 7 (<1%)

175 Benylin 3 (<1%) 0 3 (<1%) Bromhexine 2 (<1%) 1 (<1%) 3 (<1%) Flutox 3 (<1%) 0 3 (<1%) Cocillana-etyfin 0 2 (<1%) 2 (<1%) Cough medication 1 (<1%) 1 (<1%) 2 (<1%) Ambrobene 0 1 (<1%) 1 (<1%) Ambrodoxy 0 1 (<1%) 1 (<1%) Balsoclase 1 (<1%) 0 1 (<1%) Bisolvon 0 1 (<1%) 1 (<1%) Bronchicum 1 (<1%) 0 1 (<1%) Bronchostop (capsules) 1 (<1%) 0 1 (<1%) Butamirate citrate 1 (<1%) 0 1 (<1%)

Codipront 1 (<1%) 0 1 (<1%) GM2004/00056/00 Dimethoxanate 1 (<1%) 0 1 (<1%) Guaiphenesin 0 1 (<1%) 1 (<1%) Herbal cough medication 1 (<1%) 0 1 (<1%)

Mollipect 1 (<1%) 0 1 (<1%) SAM40040 Anti-tussives expectorants + mucolytics continues ... Page 11 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Anti-tussives expectorants + mucolytics Muciclar 1 (<1%) 0 1 (<1%) Noscaflex 1 (<1%) 0 1 (<1%) Pholcodine 1 (<1%) 0 1 (<1%) Pulmotin 1 (<1%) 0 1 (<1%) Rhinotussal capsules 0 1 (<1%) 1 (<1%) Septolete 1 (<1%) 0 1 (<1%)

Tossamine plus 0 1 (<1%) 1 (<1%) CONFIDENTIAL Uniflu 1 (<1%) 0 1 (<1%) Venos expectorant 1 (<1%) 0 1 (<1%)

176 Wick Medinait 1 (<1%) 0 1 (<1%)

Macrolides 44 (6%) 29 (4%) 73 (5%) Clarithromycin 19 (3%) 12 (2%) 31 (2%) Azithromycin 11 (2%) 9 (1%) 20 (1%) Roxithromycin 10 (1%) 3 (<1%) 13 (<1%) Erythromycin 5 (<1%) 3 (<1%) 8 (<1%) Spiramycin 1 (<1%) 1 (<1%) 2 (<1%) Dirithromycin 0 1 (<1%) 1 (<1%) Miocamycin 1 (<1%) 0 1 (<1%)

GM2004/00056/00

SAM40040

Page 12 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Narcotic & other analgesics combined 42 (6%) 31 (4%) 73 (5%) Co-codamol 7 (1%) 3 (<1%) 10 (<1%) Co-proxamol 6 (<1%) 2 (<1%) 8 (<1%) Solpadeine 3 (<1%) 3 (<1%) 6 (<1%) Citodon minor 4 (<1%) 1 (<1%) 5 (<1%) Paracetamol + codeine 2 (<1%) 2 (<1%) 4 (<1%) Algidol 1 (<1%) 2 (<1%) 3 (<1%)

Co-dydramol 1 (<1%) 2 (<1%) 3 (<1%) CONFIDENTIAL Distalgesic 3 (<1%) 0 3 (<1%) Kapake 2 (<1%) 1 (<1%) 3 (<1%)

177 Algifen 0 2 (<1%) 2 (<1%) Analgilasa 0 2 (<1%) 2 (<1%) Antigrippine 1 (<1%) 1 (<1%) 2 (<1%) Efferalgan codeine 0 2 (<1%) 2 (<1%) Thomapyrin 0 2 (<1%) 2 (<1%) AC COD tablets 1 (<1%) 0 1 (<1%) Algostase 1 (<1%) 0 1 (<1%) Codoliprane 1 (<1%) 0 1 (<1%) Di-Antalvic 0 1 (<1%) 1 (<1%) Dolmen 1 (<1%) 0 1 (<1%) Dolocod 0 1 (<1%) 1 (<1%) Dolviran 1 (<1%) 0 1 (<1%)

Gelonida 1 (<1%) 0 1 (<1%) GM2004/00056/00 Kodamid 1 (<1%) 0 1 (<1%) Kodimagnyl 0 1 (<1%) 1 (<1%) Korylan 1 (<1%) 0 1 (<1%)

Lonarid 0 1 (<1%) 1 (<1%) SAM40040 Narcotic & other analgesics combined continues ... Page 13 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Narcotic & other analgesics combined Nurofen plus 1 (<1%) 0 1 (<1%) Panocod 0 1 (<1%) 1 (<1%) Paracod 0 1 (<1%) 1 (<1%) Paralgin forte 1 (<1%) 0 1 (<1%) Solpadol 1 (<1%) 0 1 (<1%) Spasmalgin 1 (<1%) 0 1 (<1%)

Syndol 1 (<1%) 0 1 (<1%) CONFIDENTIAL

Benzodiazepines 31 (4%) 37 (5%) 68 (5%)

178 Diazepam 10 (1%) 9 (1%) 19 (1%) Alprazolam 4 (<1%) 5 (<1%) 9 (<1%) Bromazepam 4 (<1%) 5 (<1%) 9 (<1%) Temazepam 3 (<1%) 6 (<1%) 9 (<1%) Tetrazepam 3 (<1%) 5 (<1%) 8 (<1%) Lorazepam 2 (<1%) 3 (<1%) 5 (<1%) Lormetazepam 3 (<1%) 1 (<1%) 4 (<1%) Clonazepam 1 (<1%) 1 (<1%) 2 (<1%) Clorazepate dipotassium 0 2 (<1%) 2 (<1%) Flunitrazepam 2 (<1%) 0 2 (<1%) Chlordiazepoxide 1 (<1%) 0 1 (<1%) Clobazam 0 1 (<1%) 1 (<1%)

Halazepam 0 1 (<1%) 1 (<1%) GM2004/00056/00 Ketazolam 1 (<1%) 0 1 (<1%) Loprazolam 0 1 (<1%) 1 (<1%) Nitrazepam 0 1 (<1%) 1 (<1%)

Oxazepam 1 (<1%) 0 1 (<1%) SAM40040 Benzodiazepines continues ... Page 14 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Benzodiazepines Prazepam 1 (<1%) 0 1 (<1%)

Diuretics 27 (4%) 38 (5%) 65 (5%) Frusemide 7 (1%) 8 (1%) 15 (1%) Hydrochlorothiazide 2 (<1%) 5 (<1%) 7 (<1%) Bendrofluazide 3 (<1%) 3 (<1%) 6 (<1%)

Indapamide 0 6 (<1%) 6 (<1%) CONFIDENTIAL Chlorthalidone 2 (<1%) 2 (<1%) 4 (<1%) Frumil 0 4 (<1%) 4 (<1%)

179 Torasemide 2 (<1%) 2 (<1%) 4 (<1%) Ameride 1 (<1%) 1 (<1%) 2 (<1%) Amicloton 1 (<1%) 1 (<1%) 2 (<1%) Centyl K 2 (<1%) 0 2 (<1%) Moduretic 2 (<1%) 0 2 (<1%) Spironolactone 1 (<1%) 1 (<1%) 2 (<1%) Aldactazine 0 1 (<1%) 1 (<1%) Amilorid comp 0 1 (<1%) 1 (<1%) Amiloride 0 1 (<1%) 1 (<1%) Amiloride + hydrochlorothiazide 1 (<1%) 0 1 (<1%) Co-amilofruse 0 1 (<1%) 1 (<1%) Comilorid 1 (<1%) 0 1 (<1%)

Diazide 0 1 (<1%) 1 (<1%) GM2004/00056/00 Diurex 1 (<1%) 0 1 (<1%) Piretanide 1 (<1%) 0 1 (<1%) Rhefluin 0 1 (<1%) 1 (<1%)

Triamterene 0 1 (<1%) 1 (<1%) SAM40040 Diuretics continues ... Page 15 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Diuretics Triamterene + hydrochlorothiazide 1 (<1%) 0 1 (<1%) Urea 0 1 (<1%) 1 (<1%)

Nasal decongestants/cold cures 34 (5%) 31 (4%) 65 (5%) Xylometazoline hydrochloride 6 (<1%) 5 (<1%) 11 (<1%) Phenylpropanolamine hydrochloride 2 (<1%) 4 (<1%) 6 (<1%)

Pseudoephedrine hydrochloride 2 (<1%) 4 (<1%) 6 (<1%) CONFIDENTIAL Dexa-Rhinaspray 4 (<1%) 1 (<1%) 5 (<1%) Actifed 2 (<1%) 1 (<1%) 3 (<1%)

180 Lemsip 2 (<1%) 1 (<1%) 3 (<1%) Oxymetazoline hydrochloride 2 (<1%) 1 (<1%) 3 (<1%) Coldrex 1 (<1%) 1 (<1%) 2 (<1%) Derinox 1 (<1%) 1 (<1%) 2 (<1%) Desenfriol 1 (<1%) 1 (<1%) 2 (<1%) Fervex 1 (<1%) 1 (<1%) 2 (<1%) Pseudoephedrine 1 (<1%) 1 (<1%) 2 (<1%) Rhinadvil 2 (<1%) 0 2 (<1%) Tramazoline hydrochloride 1 (<1%) 1 (<1%) 2 (<1%) Tylex 1 (<1%) 1 (<1%) 2 (<1%) Amidephrine 0 1 (<1%) 1 (<1%) Clarityne-D 1 (<1%) 0 1 (<1%)

Couldina 1 (<1%) 0 1 (<1%) GM2004/00056/00 Day nurse 1 (<1%) 0 1 (<1%) Decongestant 1 (<1%) 0 1 (<1%) Frenadol 1 (<1%) 0 1 (<1%)

Grippostad C 1 (<1%) 0 1 (<1%) SAM40040 Nasal decongestants/cold cures continues ... Page 16 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Nasal decongestants/cold cures Ilvico 0 1 (<1%) 1 (<1%) Influbene 0 1 (<1%) 1 (<1%) Neo Citran 0 1 (<1%) 1 (<1%) Propalgina plus 1 (<1%) 0 1 (<1%) Rhinaaxia 1 (<1%) 0 1 (<1%) Rhinofluimucil 1 (<1%) 0 1 (<1%)

Sinupret 1 (<1%) 0 1 (<1%) CONFIDENTIAL Sinutab 0 1 (<1%) 1 (<1%) Sofrasolone 0 1 (<1%) 1 (<1%)

181 Tetrahydrozoline hydrochloride 1 (<1%) 0 1 (<1%) Triofan 0 1 (<1%) 1 (<1%) Vibrocil 0 1 (<1%) 1 (<1%) Xylometazoline 0 1 (<1%) 1 (<1%)

Ace inhibitors 34 (5%) 26 (4%) 60 (4%) Enalapril maleate 7 (1%) 3 (<1%) 10 (<1%) Captopril 3 (<1%) 5 (<1%) 8 (<1%) Lisinopril 4 (<1%) 4 (<1%) 8 (<1%) Ramipril 5 (<1%) 3 (<1%) 8 (<1%) Enalapril 5 (<1%) 1 (<1%) 6 (<1%) Perindopril erbumine 1 (<1%) 3 (<1%) 4 (<1%)

Perindopril 1 (<1%) 2 (<1%) 3 (<1%) GM2004/00056/00 Quinapril hydrochloride 2 (<1%) 1 (<1%) 3 (<1%) Ednyt 0 2 (<1%) 2 (<1%) Renitec 2 (<1%) 0 2 (<1%)

Cilazapril 1 (<1%) 0 1 (<1%) SAM40040 Ace inhibitors continues ... Page 17 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Ace inhibitors Fosinopril 0 1 (<1%) 1 (<1%) Fosinopril sodium 1 (<1%) 0 1 (<1%) Moexipril 1 (<1%) 0 1 (<1%) Moexipril hydrochloride 0 1 (<1%) 1 (<1%) Spirapril hydrochloride 1 (<1%) 0 1 (<1%)

Thyroid preparations 21 (3%) 34 (5%) 55 (4%) CONFIDENTIAL Thyroxine sodium 21 (3%) 33 (5%) 54 (4%) Thyreotom forte 0 1 (<1%) 1 (<1%)

182 Angiotensin 11 antagonists 25 (4%) 24 (3%) 49 (4%) Valsartan 5 (<1%) 6 (<1%) 11 (<1%) Candesartan cilexetil 5 (<1%) 5 (<1%) 10 (<1%) Irbesartan 4 (<1%) 6 (<1%) 10 (<1%) Losartan potassium 5 (<1%) 3 (<1%) 8 (<1%) Telmisartan 4 (<1%) 3 (<1%) 7 (<1%) Eprosartan mesylate 1 (<1%) 1 (<1%) 2 (<1%) Atacand plus 1 (<1%) 0 1 (<1%) Cokenzen 0 1 (<1%) 1 (<1%)

Antifungals 28 (4%) 20 (3%) 48 (3%)

Nystatin 11 (2%) 6 (<1%) 17 (1%) GM2004/00056/00 Fluconazole 7 (1%) 4 (<1%) 11 (<1%) Miconazole 5 (<1%) 2 (<1%) 7 (<1%) Amphotericin 3 (<1%) 3 (<1%) 6 (<1%)

Itraconazole 3 (<1%) 2 (<1%) 5 (<1%) SAM40040 Antifungals continues ... Page 18 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Antifungals Clotrimazole 0 2 (<1%) 2 (<1%) Bifonazole 1 (<1%) 0 1 (<1%) Butoconazole nitrate 0 1 (<1%) 1 (<1%) Econazole nitrate 0 1 (<1%) 1 (<1%) Ketoconazole 1 (<1%) 0 1 (<1%) Terbinafine 1 (<1%) 0 1 (<1%)

CONFIDENTIAL Other anti-depressants 22 (3%) 26 (4%) 48 (3%) Citalopram hydrobromide 5 (<1%) 6 (<1%) 11 (<1%)

183 Paroxetine hydrochloride 4 (<1%) 6 (<1%) 10 (<1%) Fluoxetine hydrochloride 2 (<1%) 6 (<1%) 8 (<1%) Venlafaxine hydrochloride 2 (<1%) 4 (<1%) 6 (<1%) Fluoxetine 1 (<1%) 4 (<1%) 5 (<1%) Sertraline hydrochloride 3 (<1%) 0 3 (<1%) Sertraline 1 (<1%) 1 (<1%) 2 (<1%) Trazodone hydrochloride 2 (<1%) 0 2 (<1%) Citalopram 1 (<1%) 0 1 (<1%) Hypericum 1 (<1%) 0 1 (<1%) Lithium carbonate 0 1 (<1%) 1 (<1%) Mirtazapine 0 1 (<1%) 1 (<1%)

Anti-hyperlipidemics (affecting GM2004/00056/00 cholesterol/triglycerides) 25 (4%) 21 (3%) 46 (3%) Simvastatin 9 (1%) 8 (1%) 17 (1%) Atorvastatin calcium 8 (1%) 8 (1%) 16 (1%)

Pravastatin sodium 2 (<1%) 4 (<1%) 6 (<1%) SAM40040 Anti-hyperlipidemics (affecting cholesterol/triglycerides) continues ... Page 19 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Anti-hyperlipidemics (affecting cholesterol/triglycerides) Orlistat 3 (<1%) 0 3 (<1%) Fluvastatin sodium 1 (<1%) 1 (<1%) 2 (<1%) Lovastatin 1 (<1%) 1 (<1%) 2 (<1%) Bezafibrate 1 (<1%) 0 1 (<1%) Gemfibrozil 1 (<1%) 0 1 (<1%) Pravastatin 1 (<1%) 0 1 (<1%)

CONFIDENTIAL Vaccines + toxoids 22 (3%) 21 (3%) 43 (3%) Influenza vaccine 13 (2%) 12 (2%) 25 (2%)

184 Inactivated influenza vaccine 5 (<1%) 6 (<1%) 11 (<1%) Tetanus vaccine 1 (<1%) 1 (<1%) 2 (<1%) Diphtheria + tetanus vaccine 1 (<1%) 0 1 (<1%) Ditanrix 0 1 (<1%) 1 (<1%) Hepatitis B vaccine 0 1 (<1%) 1 (<1%) Klebsiella pneumoniae glycoproteins 1 (<1%) 0 1 (<1%) Luivac 0 1 (<1%) 1 (<1%) Poliomyelitis vaccine live oral 0 1 (<1%) 1 (<1%) Tick-borne Encephalitis vaccine 0 1 (<1%) 1 (<1%) Typhoid vaccine 1 (<1%) 0 1 (<1%) ViATIM 0 1 (<1%) 1 (<1%)

Cephalosporins & cephamycins 17 (2%) 17 (2%) 34 (2%) GM2004/00056/00 Cefuroxime axetil 9 (1%) 9 (1%) 18 (1%) Cefixime 4 (<1%) 2 (<1%) 6 (<1%) Cefaclor 2 (<1%) 1 (<1%) 3 (<1%)

Cephalexin 0 3 (<1%) 3 (<1%) SAM40040 Cephalosporins & cephamycins continues ... Page 20 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Cephalosporins & cephamycins Cefpodoxime proxetil 1 (<1%) 1 (<1%) 2 (<1%) Ceforanide 1 (<1%) 0 1 (<1%) Cefotiam hydrochloride 1 (<1%) 0 1 (<1%) Cefuroxime sodium 0 1 (<1%) 1 (<1%) Procef 0 1 (<1%) 1 (<1%)

Acids, salts, fluids, electrolytes 17 (2%) 16 (2%) 33 (2%) CONFIDENTIAL Calcium salt 5 (<1%) 4 (<1%) 9 (<1%) Calcioral 4 (<1%) 2 (<1%) 6 (<1%)

185 Dioralyte 2 (<1%) 1 (<1%) 3 (<1%) Magnesium aspartate 1 (<1%) 1 (<1%) 2 (<1%) Potassium chloride 0 2 (<1%) 2 (<1%) Sodium chloride 0 2 (<1%) 2 (<1%) Asparcam 0 1 (<1%) 1 (<1%) Cacit 1 (<1%) 0 1 (<1%) Calcium phosphate 1 (<1%) 0 1 (<1%) Calcium-Sandoz forte 1 (<1%) 0 1 (<1%) Magium K 0 1 (<1%) 1 (<1%) Magne-B6 1 (<1%) 0 1 (<1%) Magnesium pidolate 1 (<1%) 0 1 (<1%) Magnesium verla 0 1 (<1%) 1 (<1%)

Meridol (mouthwash) 1 (<1%) 0 1 (<1%) GM2004/00056/00 Potassium salt 0 1 (<1%) 1 (<1%)

SAM40040

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Miscellaneous antibacterials 15 (2%) 17 (2%) 32 (2%) Chloramphenicol 4 (<1%) 2 (<1%) 6 (<1%) Fusidic acid 2 (<1%) 2 (<1%) 4 (<1%) Trimethoprim 2 (<1%) 2 (<1%) 4 (<1%) Tonsillitis PMD 2 (<1%) 1 (<1%) 3 (<1%) Dalacin 2 (<1%) 0 2 (<1%) Fusafungine 1 (<1%) 1 (<1%) 2 (<1%)

Nitrofurantoin 1 (<1%) 1 (<1%) 2 (<1%) CONFIDENTIAL Pristinamycin 0 2 (<1%) 2 (<1%) Telithromycin 0 2 (<1%) 2 (<1%)

186 Adapalene 0 1 (<1%) 1 (<1%) Fosfomycin trometamol 1 (<1%) 0 1 (<1%) Fusidate sodium 0 1 (<1%) 1 (<1%) Solutricine 1 (<1%) 0 1 (<1%) Throat 0 1 (<1%) 1 (<1%) Tyrothricin 0 1 (<1%) 1 (<1%)

Vasodilators 14 (2%) 18 (3%) 32 (2%) Nitroglycerine 3 (<1%) 7 (1%) 10 (<1%) Isosorbide dinitrate 4 (<1%) 4 (<1%) 8 (<1%) Isosorbide mononitrate 2 (<1%) 4 (<1%) 6 (<1%) Molsidomine 1 (<1%) 4 (<1%) 5 (<1%)

Trimetazidine hydrochloride 3 (<1%) 1 (<1%) 4 (<1%) GM2004/00056/00 Vinpocetine 2 (<1%) 0 2 (<1%) Buflomedil hydrochloride 0 1 (<1%) 1 (<1%) Dipyridamole 0 1 (<1%) 1 (<1%)

Nicorandil 0 1 (<1%) 1 (<1%) SAM40040

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Narcotic analgesics 20 (3%) 10 (1%) 30 (2%) Tramadol hydrochloride 13 (2%) 4 (<1%) 17 (1%) Codeine phosphate 4 (<1%) 1 (<1%) 5 (<1%) Codeine 0 2 (<1%) 2 (<1%) Algesal 0 1 (<1%) 1 (<1%) Dextropropoxyphene napsylate 1 (<1%) 0 1 (<1%) Fentanyl 0 1 (<1%) 1 (<1%)

Ketogan 0 1 (<1%) 1 (<1%) CONFIDENTIAL Pentazocine hydrochloride 0 1 (<1%) 1 (<1%) Polery 1 (<1%) 0 1 (<1%)

187 Tilidine hydrochloride 1 (<1%) 0 1 (<1%)

Miscellaneous cardiovascular system drugs 10 (1%) 18 (3%) 28 (2%) Daflon 5 (<1%) 2 (<1%) 7 (<1%) Betahistine hydrochloride 2 (<1%) 2 (<1%) 4 (<1%) Oxpentifylline 1 (<1%) 3 (<1%) 4 (<1%) Aesculus 0 3 (<1%) 3 (<1%) Troxerutin 0 3 (<1%) 3 (<1%) Calcium dobesilate 0 2 (<1%) 2 (<1%) Diosmin 0 2 (<1%) 2 (<1%) Betahistine 1 (<1%) 0 1 (<1%)

Ginkor fort 1 (<1%) 0 1 (<1%) GM2004/00056/00 Reparil gel 0 1 (<1%) 1 (<1%)

SAM40040

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Quinolones 15 (2%) 12 (2%) 27 (2%) Ciprofloxacin 4 (<1%) 5 (<1%) 9 (<1%) Levofloxacin 3 (<1%) 2 (<1%) 5 (<1%) Moxifloxacin hydrochloride 2 (<1%) 2 (<1%) 4 (<1%) Norfloxacin 3 (<1%) 1 (<1%) 4 (<1%) Ciprofloxacin hydrochloride 1 (<1%) 1 (<1%) 2 (<1%) Ofloxacin 1 (<1%) 1 (<1%) 2 (<1%)

Pipemidic acid 1 (<1%) 0 1 (<1%) CONFIDENTIAL

Vitamins 18 (3%) 9 (1%) 27 (2%)

188 Bepanthen 2 (<1%) 1 (<1%) 3 (<1%) Alfacalcidol 2 (<1%) 0 2 (<1%) Calcitriol 2 (<1%) 0 2 (<1%) Colecalciferol 1 (<1%) 1 (<1%) 2 (<1%) Ideos 1 (<1%) 1 (<1%) 2 (<1%) Neurobion 2 (<1%) 0 2 (<1%) Pyridoxine 1 (<1%) 1 (<1%) 2 (<1%) Pyridoxine hydrochloride 1 (<1%) 1 (<1%) 2 (<1%) Calcichew-D3 1 (<1%) 0 1 (<1%) Evaton-T 1 (<1%) 0 1 (<1%) Hidroxil-B12-B6-B1 0 1 (<1%) 1 (<1%) Multivit-B-forte 1 (<1%) 0 1 (<1%)

Natecal D 1 (<1%) 0 1 (<1%) GM2004/00056/00 Neuromultivit 0 1 (<1%) 1 (<1%) Panthenol 1 (<1%) 0 1 (<1%) Thiamine hydrochloride 0 1 (<1%) 1 (<1%)

Vitamin B 0 1 (<1%) 1 (<1%) SAM40040 Vitamins continues ... Page 24 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Vitamins Vitamin E 1 (<1%) 0 1 (<1%) Vitamine B-complex Forte 1 (<1%) 0 1 (<1%)

H2 antagonists 16 (2%) 10 (1%) 26 (2%) Ranitidine hydrochloride 9 (1%) 10 (1%) 19 (1%) Cimetidine 3 (<1%) 0 3 (<1%)

Famotidine 2 (<1%) 0 2 (<1%) CONFIDENTIAL Nizatidine 1 (<1%) 0 1 (<1%) Pantecta 1 (<1%) 0 1 (<1%)

189 Miscellaneous hypoglycemics 15 (2%) 10 (1%) 25 (2%) Metformin hydrochloride 8 (1%) 4 (<1%) 12 (<1%) Glibenclamide 2 (<1%) 3 (<1%) 5 (<1%) Gliclazide 3 (<1%) 1 (<1%) 4 (<1%) Glimepiride 3 (<1%) 1 (<1%) 4 (<1%) Daopar 1 (<1%) 1 (<1%) 2 (<1%) Repaglinide 1 (<1%) 1 (<1%) 2 (<1%) Acarbose 0 1 (<1%) 1 (<1%) Glipizide 1 (<1%) 0 1 (<1%) Miglitol 0 1 (<1%) 1 (<1%)

GM2004/00056/00

SAM40040

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Tetracylines 15 (2%) 10 (1%) 25 (2%) Doxycycline 8 (1%) 6 (<1%) 14 (1%) Doxycycline hydrochloride 3 (<1%) 2 (<1%) 5 (<1%) Tetracycline 2 (<1%) 1 (<1%) 3 (<1%) Doxyhexal 1 (<1%) 0 1 (<1%) Lymecycline 1 (<1%) 0 1 (<1%) Oxytetracycline 0 1 (<1%) 1 (<1%)

CONFIDENTIAL Antacids 13 (2%) 10 (1%) 23 (2%) Gaviscon 2 (<1%) 2 (<1%) 4 (<1%)

190 Almagate 2 (<1%) 1 (<1%) 3 (<1%) Calcium carbonate 0 2 (<1%) 2 (<1%) Magaldrate 1 (<1%) 1 (<1%) 2 (<1%) Rennie 1 (<1%) 1 (<1%) 2 (<1%) Aluminium phosphate gel 1 (<1%) 0 1 (<1%) Anacid 0 1 (<1%) 1 (<1%) Andrews antacid 0 1 (<1%) 1 (<1%) Balancid 1 (<1%) 0 1 (<1%) Gaviscon advance 1 (<1%) 0 1 (<1%) Gaviscon liquid (UK) 1 (<1%) 0 1 (<1%) Gavison 1 (<1%) 0 1 (<1%) Moxydar 1 (<1%) 0 1 (<1%)

Simeco 1 (<1%) 0 1 (<1%) GM2004/00056/00 Titralac 0 1 (<1%) 1 (<1%)

SAM40040

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Miscellaneous drugs 7 (1%) 16 (2%) 23 (2%) Homeopathic medication 1 (<1%) 3 (<1%) 4 (<1%) Herbal medication 0 2 (<1%) 2 (<1%) Myrtol 1 (<1%) 1 (<1%) 2 (<1%) Simple linctus 0 2 (<1%) 2 (<1%) Throat medication 0 2 (<1%) 2 (<1%) Bearberry 0 1 (<1%) 1 (<1%)

Bronchipret 1 (<1%) 0 1 (<1%) CONFIDENTIAL Echinacea 0 1 (<1%) 1 (<1%) Glucosamine sulphate 0 1 (<1%) 1 (<1%)

191 Goldenrod 0 1 (<1%) 1 (<1%) Ivy 1 (<1%) 0 1 (<1%) Kamillan plus 0 1 (<1%) 1 (<1%) Kamillosan 1 (<1%) 0 1 (<1%) Laureth 9 0 1 (<1%) 1 (<1%) Nettle 0 1 (<1%) 1 (<1%) Spasmo-Urgenin 1 (<1%) 0 1 (<1%) Spiroflor 0 1 (<1%) 1 (<1%) Unknown 0 1 (<1%) 1 (<1%) Urgenin 1 (<1%) 0 1 (<1%)

Beta-blockers 14 (2%) 8 (1%) 22 (2%)

Metoprolol tartrate 4 (<1%) 1 (<1%) 5 (<1%) GM2004/00056/00 Atenolol 4 (<1%) 0 4 (<1%) Bisoprolol 1 (<1%) 1 (<1%) 2 (<1%) Timolol 1 (<1%) 1 (<1%) 2 (<1%)

Acecor 1 (<1%) 0 1 (<1%) SAM40040 Beta-blockers continues ... Page 27 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Beta-blockers Betaloc zok 1 (<1%) 0 1 (<1%) Betaxolol hydrochloride 1 (<1%) 0 1 (<1%) Carvedilol 0 1 (<1%) 1 (<1%) Cusimolol 0 1 (<1%) 1 (<1%) Metoprolol succinate 1 (<1%) 0 1 (<1%) Nebivolol hydrochloride 0 1 (<1%) 1 (<1%)

Propranolol hydrochloride 0 1 (<1%) 1 (<1%) CONFIDENTIAL Talinolol 0 1 (<1%) 1 (<1%)

192 Miscellaneous gastrointestinal 14 (2%) 7 (1%) 21 (2%) Metoclopramide hydrochloride 5 (<1%) 4 (<1%) 9 (<1%) Domperidone 4 (<1%) 3 (<1%) 7 (<1%) Activated charcoal 1 (<1%) 1 (<1%) 2 (<1%) Iberogast 1 (<1%) 0 1 (<1%) Lactic-acid-producing organisms 1 (<1%) 0 1 (<1%) Metoclopramide 1 (<1%) 0 1 (<1%) Modulanzime 1 (<1%) 0 1 (<1%) Xyloproct 1 (<1%) 0 1 (<1%)

Corticosteroids & anti-infectives combined 13 (2%) 7 (1%) 20 (1%)

Fucibet 1 (<1%) 2 (<1%) 3 (<1%) GM2004/00056/00 Gentisone HC 2 (<1%) 0 2 (<1%) Oropivalone Bacitracine 1 (<1%) 1 (<1%) 2 (<1%) Anusol HC 1 (<1%) 0 1 (<1%)

Betnovate-C 0 1 (<1%) 1 (<1%) SAM40040 Corticosteroids & anti-infectives combined continues ... Page 28 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Corticosteroids & anti-infectives combined Canesten HC 0 1 (<1%) 1 (<1%) Cortimyk 1 (<1%) 0 1 (<1%) Cortisporin 1 (<1%) 0 1 (<1%) Fucicort 0 1 (<1%) 1 (<1%) Fucidin H 1 (<1%) 0 1 (<1%) Locasalen 1 (<1%) 0 1 (<1%)

Lotriderm 1 (<1%) 0 1 (<1%) CONFIDENTIAL Maxitrol (drops) 1 (<1%) 0 1 (<1%) Otomize 1 (<1%) 0 1 (<1%)

193 Rinobanedif 1 (<1%) 0 1 (<1%) Synalar bi-otic 1 (<1%) 0 1 (<1%) Terracortril 0 1 (<1%) 1 (<1%)

Drugs affecting bone metabolism 12 (2%) 7 (1%) 19 (1%) Alendronate sodium 6 (<1%) 1 (<1%) 7 (<1%) Calcitonin 2 (<1%) 1 (<1%) 3 (<1%) Disodium etidronate 1 (<1%) 1 (<1%) 2 (<1%) Etidronic acid 0 2 (<1%) 2 (<1%) Salcatonin 1 (<1%) 1 (<1%) 2 (<1%) Hydroxyapatite 1 (<1%) 0 1 (<1%) Risedronic acid 1 (<1%) 0 1 (<1%)

Tridin 0 1 (<1%) 1 (<1%) GM2004/00056/00

SAM40040

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Estrogens 8 (1%) 11 (2%) 19 (1%) Oestradiol valerate 2 (<1%) 5 (<1%) 7 (<1%) Oestradiol 2 (<1%) 4 (<1%) 6 (<1%) Conjugated estrogens 4 (<1%) 1 (<1%) 5 (<1%) Estropipate 2 (<1%) 0 2 (<1%) Hormonin 0 1 (<1%) 1 (<1%)

Anti-androgens 10 (1%) 8 (1%) 18 (1%) CONFIDENTIAL Diane-35 5 (<1%) 3 (<1%) 8 (<1%) Diane 2 (<1%) 2 (<1%) 4 (<1%)

194 Dianette 1 (<1%) 2 (<1%) 3 (<1%) Climen 2 (<1%) 0 2 (<1%) Diane mite 0 1 (<1%) 1 (<1%)

Cyclo-oxygenase-2 inhibitors 9 (1%) 9 (1%) 18 (1%) Rofecoxib 7 (1%) 6 (<1%) 13 (<1%) Celecoxib 2 (<1%) 3 (<1%) 5 (<1%)

Other anxiolytics, sedatives & hypnotics 6 (<1%) 11 (2%) 17 (1%) Zolpidem 1 (<1%) 4 (<1%) 5 (<1%) Zopiclone 1 (<1%) 4 (<1%) 5 (<1%) Zolpidem tartrate 3 (<1%) 0 3 (<1%)

Valerian 1 (<1%) 1 (<1%) 2 (<1%) GM2004/00056/00 Mephenoxalone 0 1 (<1%) 1 (<1%) Natrasleep 0 1 (<1%) 1 (<1%) Sedacur Forte 0 1 (<1%) 1 (<1%)

SAM40040

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Ace inhibitors & diuretics combined 7 (1%) 8 (1%) 15 (1%) Zestoretic 1 (<1%) 2 (<1%) 3 (<1%) Co-Renitec 2 (<1%) 0 2 (<1%) Accuretic 0 1 (<1%) 1 (<1%) Co-Reniten 0 1 (<1%) 1 (<1%) Crinoretic 0 1 (<1%) 1 (<1%) Delix 1 (<1%) 0 1 (<1%)

Diurace 0 1 (<1%) 1 (<1%) CONFIDENTIAL Doneka Plus 0 1 (<1%) 1 (<1%) Innozide 1 (<1%) 0 1 (<1%)

195 Preterax 0 1 (<1%) 1 (<1%) Renacor 1 (<1%) 0 1 (<1%) Tritazide 1 (<1%) 0 1 (<1%)

Anticoagulants 8 (1%) 7 (1%) 15 (1%) Enoxaparin 3 (<1%) 2 (<1%) 5 (<1%) Fluindione 1 (<1%) 1 (<1%) 2 (<1%) Heparin 0 2 (<1%) 2 (<1%) Nicoumalone 1 (<1%) 1 (<1%) 2 (<1%) Phenprocoumon 1 (<1%) 1 (<1%) 2 (<1%) Dalteparin sodium 0 1 (<1%) 1 (<1%) Heparin sodium 1 (<1%) 0 1 (<1%)

Warfarin sodium 1 (<1%) 0 1 (<1%) GM2004/00056/00

SAM40040

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Tricyclic anti-depressants 7 (1%) 8 (1%) 15 (1%) Desipramine hydrochloride 1 (<1%) 2 (<1%) 3 (<1%) Amitriptyline 2 (<1%) 0 2 (<1%) Dothiepin 1 (<1%) 1 (<1%) 2 (<1%) Amitriptyline hydrochloride 1 (<1%) 0 1 (<1%) Clomipramine hydrochloride 0 1 (<1%) 1 (<1%) Coaxil 0 1 (<1%) 1 (<1%)

Deanxit 1 (<1%) 0 1 (<1%) CONFIDENTIAL Doxepin 0 1 (<1%) 1 (<1%) Lofepramine 1 (<1%) 0 1 (<1%)

196 Lofepramine hydrochloride 0 1 (<1%) 1 (<1%) Trimipramine maleate 0 1 (<1%) 1 (<1%)

Alpha 1-adrenoceptor antagonists 7 (1%) 7 (1%) 14 (1%) Doxazosin mesylate 2 (<1%) 3 (<1%) 5 (<1%) Terazosin hydrochloride 1 (<1%) 2 (<1%) 3 (<1%) Alfuzosin hydrochloride 2 (<1%) 0 2 (<1%) Urapidil 0 2 (<1%) 2 (<1%) Doxazosin 1 (<1%) 0 1 (<1%) Prazosin hydrochloride 1 (<1%) 0 1 (<1%)

Anti-migraine preparations 4 (<1%) 10 (1%) 14 (1%)

Rizatriptan benzoate 2 (<1%) 1 (<1%) 3 (<1%) GM2004/00056/00 Migraleve 1 (<1%) 1 (<1%) 2 (<1%) Naratriptan hydrochloride 0 2 (<1%) 2 (<1%) Sumatriptan succinate 1 (<1%) 1 (<1%) 2 (<1%)

Tonopan 0 2 (<1%) 2 (<1%) SAM40040 Anti-migraine preparations continues ... Page 32 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Anti-migraine preparations Dihydroergotamine mesylate 0 1 (<1%) 1 (<1%) Venotop 0 1 (<1%) 1 (<1%) Zolmitriptan 0 1 (<1%) 1 (<1%)

Anti-cholinergics 8 (1%) 5 (<1%) 13 (<1%) Hyoscine butylbromide 4 (<1%) 2 (<1%) 6 (<1%)

Detrusitol 1 (<1%) 2 (<1%) 3 (<1%) CONFIDENTIAL Benzhexol hydrochloride 0 1 (<1%) 1 (<1%) Dicyclomine hydrochloride 1 (<1%) 0 1 (<1%)

197 Otilonium bromide 1 (<1%) 0 1 (<1%) Oxybutynin hydrochloride 1 (<1%) 0 1 (<1%)

Anti-gout (affecting uric acid metabolism) 5 (<1%) 8 (1%) 13 (<1%) Allopurinol 4 (<1%) 8 (1%) 12 (<1%) Colchicine 1 (<1%) 0 1 (<1%)

Hematinics 4 (<1%) 9 (1%) 13 (<1%) Ferrous sulfate 2 (<1%) 4 (<1%) 6 (<1%) Folic acid 0 4 (<1%) 4 (<1%) Cyanocobalamin 0 1 (<1%) 1 (<1%)

Fero-gradumet 1 (<1%) 0 1 (<1%) GM2004/00056/00 Hydroxocobalamin 0 1 (<1%) 1 (<1%) Tardyferon 1 (<1%) 0 1 (<1%)

SAM40040

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Local antiseptics & disinfectants 6 (<1%) 7 (1%) 13 (<1%) Neo-Angin 2 (<1%) 2 (<1%) 4 (<1%) Strepsils 1 (<1%) 1 (<1%) 2 (<1%) Chloraseptic 0 1 (<1%) 1 (<1%) Chlorhexidine gluconate 0 1 (<1%) 1 (<1%) Eludril 1 (<1%) 0 1 (<1%) Hexetidine 0 1 (<1%) 1 (<1%)

Ictasol 1 (<1%) 0 1 (<1%) CONFIDENTIAL Jox 0 1 (<1%) 1 (<1%) Lemocin 0 1 (<1%) 1 (<1%)

198 Phenol 1 (<1%) 0 1 (<1%)

Sodium cromoglycate 8 (1%) 5 (<1%) 13 (<1%) Sodium cromoglycate 7 (1%) 5 (<1%) 12 (<1%) Lodoxamide trometamol 1 (<1%) 0 1 (<1%)

Antipsychotics 4 (<1%) 8 (1%) 12 (<1%) Thiethylperazine maleate 2 (<1%) 1 (<1%) 3 (<1%) Clozapine 0 1 (<1%) 1 (<1%) Fluopromazine 1 (<1%) 0 1 (<1%) Flupenthixol hydrochloride 0 1 (<1%) 1 (<1%) Fluspirilene 0 1 (<1%) 1 (<1%)

Methotrimeprazine 0 1 (<1%) 1 (<1%) GM2004/00056/00 Olanzapine 0 1 (<1%) 1 (<1%) Prazine 0 1 (<1%) 1 (<1%) Prochlorperazine maleate 0 1 (<1%) 1 (<1%)

Sulpiride 1 (<1%) 0 1 (<1%) SAM40040 Antipsychotics continues ... Page 34 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Antipsychotics Thioridazine 0 1 (<1%) 1 (<1%)

Antispasmodics/anticholinergics 8 (1%) 4 (<1%) 12 (<1%) Drotaverine 3 (<1%) 2 (<1%) 5 (<1%) Duspatal 1 (<1%) 2 (<1%) 3 (<1%) Mebeverine 2 (<1%) 0 2 (<1%)

Colofac 1 (<1%) 0 1 (<1%) CONFIDENTIAL Denaverine hydrochloride 1 (<1%) 0 1 (<1%) Spasmalgon 1 (<1%) 0 1 (<1%)

199 Trospium chloride 1 (<1%) 0 1 (<1%)

Drugs acting on heart muscle 6 (<1%) 6 (<1%) 12 (<1%) Digoxin 5 (<1%) 5 (<1%) 10 (<1%) Digitoxin 1 (<1%) 1 (<1%) 2 (<1%)

Progestogens 7 (1%) 5 (<1%) 12 (<1%) Medroxyprogesterone acetate 2 (<1%) 2 (<1%) 4 (<1%) Levonorgestrel 2 (<1%) 1 (<1%) 3 (<1%) Nomegestrol acetate 0 2 (<1%) 2 (<1%) Etonogestrel 1 (<1%) 0 1 (<1%) Lynoestrenol 1 (<1%) 0 1 (<1%)

Norethisterone 1 (<1%) 0 1 (<1%) GM2004/00056/00 Primolut 1 (<1%) 0 1 (<1%)

SAM40040

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Antidiarrheals 5 (<1%) 6 (<1%) 11 (<1%) Loperamide hydrochloride 5 (<1%) 4 (<1%) 9 (<1%) Diosmectite 0 1 (<1%) 1 (<1%) Herbal antidiarrheal medication 0 1 (<1%) 1 (<1%) Saccharomyces boulardii 0 1 (<1%) 1 (<1%)

Miscellaneous endocrine & metabolic 5 (<1%) 6 (<1%) 11 (<1%)

Latanoprost 2 (<1%) 2 (<1%) 4 (<1%) CONFIDENTIAL Potassium iodide 2 (<1%) 0 2 (<1%) Sodium chondroitin sulfate 0 2 (<1%) 2 (<1%)

200 Prostakan 0 1 (<1%) 1 (<1%) Simepar 1 (<1%) 0 1 (<1%) Tamsulosin hydrochloride 0 1 (<1%) 1 (<1%)

Local anesthetics 5 (<1%) 5 (<1%) 10 (<1%) Lignocaine hydrochloride 1 (<1%) 2 (<1%) 3 (<1%) Trachitol 1 (<1%) 2 (<1%) 3 (<1%) Amethocaine 1 (<1%) 0 1 (<1%) Intralgin 1 (<1%) 0 1 (<1%) Merocaine 1 (<1%) 0 1 (<1%) Septanest 0 1 (<1%) 1 (<1%)

Miscellaneous skin, ear & eye GM2004/00056/00 preparations 3 (<1%) 7 (1%) 10 (<1%) Chloroxine 0 3 (<1%) 3 (<1%) Calcipotriene 0 1 (<1%) 1 (<1%)

Creme rap 0 1 (<1%) 1 (<1%) SAM40040 Miscellaneous skin, ear & eye preparations continues ... Page 36 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Miscellaneous skin, ear & eye preparations Magistrale preparations 1 (<1%) 0 1 (<1%) Ointment 0 1 (<1%) 1 (<1%) Oxyquinolone sulfate 1 (<1%) 0 1 (<1%) Piascledine 0 1 (<1%) 1 (<1%) Topical skin preparation 1 (<1%) 0 1 (<1%) Tretinoin 1 (<1%) 0 1 (<1%)

CONFIDENTIAL Ophthalmological preparations (including diagnostic agents) 6 (<1%) 4 (<1%) 10 (<1%)

201 Antasten-priven 3 (<1%) 3 (<1%) 6 (<1%) Brinzolamide 1 (<1%) 1 (<1%) 2 (<1%) Dorzolamide hydrochloride 1 (<1%) 0 1 (<1%) Spersallerg 1 (<1%) 0 1 (<1%)

Other hypotensives 4 (<1%) 6 (<1%) 10 (<1%) Moxonidine 1 (<1%) 1 (<1%) 2 (<1%) Tarka 1 (<1%) 1 (<1%) 2 (<1%) Adelphane 0 1 (<1%) 1 (<1%) Clonidine 0 1 (<1%) 1 (<1%) Clonidine hydrochloride 0 1 (<1%) 1 (<1%) Co-dergocrine mesylate 1 (<1%) 0 1 (<1%)

Rilmenidine 1 (<1%) 0 1 (<1%) GM2004/00056/00 Trirezid K 0 1 (<1%) 1 (<1%)

SAM40040

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Other immunologicals 3 (<1%) 6 (<1%) 9 (<1%) Grass pollen hyposensitization 1 (<1%) 2 (<1%) 3 (<1%) Alk-depot SQ 0 2 (<1%) 2 (<1%) Asthma + hayfever immunotherapy 1 (<1%) 0 1 (<1%) Dust mite hyposensitization 1 (<1%) 0 1 (<1%) Hyposensitization therapy 0 1 (<1%) 1 (<1%) Phostal 0 1 (<1%) 1 (<1%)

CONFIDENTIAL Sulfonamides 1 (<1%) 8 (1%) 9 (<1%) Co-trimoxazole 1 (<1%) 5 (<1%) 6 (<1%)

202 Cotrim forte von ct 0 1 (<1%) 1 (<1%) Sulphamethizole 0 1 (<1%) 1 (<1%) Sulphasalazine 0 1 (<1%) 1 (<1%)

Anti-arrhythmics 2 (<1%) 6 (<1%) 8 (<1%) Amiodarone hydrochloride 1 (<1%) 3 (<1%) 4 (<1%) Amiodarone 0 1 (<1%) 1 (<1%) Cibenzoline succinate 0 1 (<1%) 1 (<1%) Detajmium bitartrate 0 1 (<1%) 1 (<1%) Flecainide acetate 1 (<1%) 0 1 (<1%)

Dermatological vehicles, bases,

emollients & protectives 3 (<1%) 5 (<1%) 8 (<1%) GM2004/00056/00 Diprobase 1 (<1%) 1 (<1%) 2 (<1%) Alpha-Keri 1 (<1%) 0 1 (<1%) Aqueous cream 1 (<1%) 0 1 (<1%)

Balneum plus bath oil 0 1 (<1%) 1 (<1%) SAM40040 Dermatological vehicles, bases, emollients & protectives continues ... Page 38 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

... continuing Dermatological vehicles, bases, emollients & protectives Cetomacrogol cream 1 (<1%) 0 1 (<1%) Emulsifying ointment + oily cream 0 1 (<1%) 1 (<1%) Emulsifying wax 0 1 (<1%) 1 (<1%) Kaolin Poultice 0 1 (<1%) 1 (<1%)

Laxatives 1 (<1%) 7 (1%) 8 (<1%)

Psyllium husk 1 (<1%) 3 (<1%) 4 (<1%) CONFIDENTIAL Lactulose 0 1 (<1%) 1 (<1%) Magnesium sulfate 0 1 (<1%) 1 (<1%)

203 Mineral oil 0 1 (<1%) 1 (<1%) Sennosides 1 (<1%) 0 1 (<1%) Sodium picosulphate 0 1 (<1%) 1 (<1%)

Other hypotensives & diuretics combined 5 (<1%) 3 (<1%) 8 (<1%) Coaprovel 4 (<1%) 0 4 (<1%) Co-diovan 1 (<1%) 1 (<1%) 2 (<1%) Briserin N 0 1 (<1%) 1 (<1%) Cozaar comp 0 1 (<1%) 1 (<1%)

Antiprotozoals 4 (<1%) 3 (<1%) 7 (<1%) Metronidazole 3 (<1%) 1 (<1%) 4 (<1%)

Chloroquine phosphate 1 (<1%) 0 1 (<1%) GM2004/00056/00 Malarone 0 1 (<1%) 1 (<1%) Quinine 0 1 (<1%) 1 (<1%)

SAM40040

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Enzymes, choleretics & related substances 4 (<1%) 3 (<1%) 7 (<1%) Amylase 1 (<1%) 2 (<1%) 3 (<1%) Pancreatin 2 (<1%) 1 (<1%) 3 (<1%) Allochol 1 (<1%) 0 1 (<1%) Hymecromone 1 (<1%) 0 1 (<1%)

Nedocromil 3 (<1%) 4 (<1%) 7 (<1%) CONFIDENTIAL Nedocromil sodium 3 (<1%) 4 (<1%) 7 (<1%)

204 Anti-estrogens 3 (<1%) 3 (<1%) 6 (<1%) Raloxifene hydrochloride 3 (<1%) 3 (<1%) 6 (<1%)

Antivirals 3 (<1%) 3 (<1%) 6 (<1%) Acyclovir 2 (<1%) 0 2 (<1%) Alpha-anilino phenyl acetamide 0 1 (<1%) 1 (<1%) Brivudine 0 1 (<1%) 1 (<1%) Inosine diphosphate 0 1 (<1%) 1 (<1%) Tromantadine hydrochloride 1 (<1%) 0 1 (<1%)

Anticonvulsants (non-barbiturate, non-benzodiazepine) 3 (<1%) 2 (<1%) 5 (<1%)

Carbamazepine 1 (<1%) 1 (<1%) 2 (<1%) GM2004/00056/00 Valproate sodium 1 (<1%) 1 (<1%) 2 (<1%) Gabapentin 1 (<1%) 0 1 (<1%) Primidone 0 1 (<1%) 1 (<1%)

SAM40040

Page 40 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Insulins 1 (<1%) 4 (<1%) 5 (<1%) Intermediate/long-acting insulin 0 3 (<1%) 3 (<1%) Human short-acting insulin 0 1 (<1%) 1 (<1%) Insulin 0 1 (<1%) 1 (<1%) Insulin lispro 1 (<1%) 0 1 (<1%)

Muscle relaxants 3 (<1%) 2 (<1%) 5 (<1%)

Cyclobenzaprine hydrochloride 1 (<1%) 1 (<1%) 2 (<1%) CONFIDENTIAL Thiocolchicoside 1 (<1%) 1 (<1%) 2 (<1%) Chlorzoxazone 1 (<1%) 0 1 (<1%)

205 Nasal decongestants/cold cures contd. 3 (<1%) 2 (<1%) 5 (<1%) Alca-C 0 1 (<1%) 1 (<1%) Beechams powders capsule 1 (<1%) 0 1 (<1%) Dimotane Co 1 (<1%) 0 1 (<1%) Lasa Con Codeina 1 (<1%) 0 1 (<1%) Lemsip Cold + Flu Breathe Easy 0 1 (<1%) 1 (<1%) Sudafed Dual Relief Non-Drowsy 0 1 (<1%) 1 (<1%)

Antiplatelet drugs 2 (<1%) 2 (<1%) 4 (<1%) Clopidogrel bisulphate 1 (<1%) 1 (<1%) 2 (<1%) Clopidogrel 0 1 (<1%) 1 (<1%)

Iscover 1 (<1%) 0 1 (<1%) GM2004/00056/00

Miscellaneous cytotoxic agents 3 (<1%) 1 (<1%) 4 (<1%) Altretamine 3 (<1%) 1 (<1%) 4 (<1%)

SAM40040

Page 41 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Miscellaneous nervous system 2 (<1%) 2 (<1%) 4 (<1%) Acetylleucine 1 (<1%) 0 1 (<1%) Adalgur 0 1 (<1%) 1 (<1%) Anacervix 0 1 (<1%) 1 (<1%) Nicotine 1 (<1%) 0 1 (<1%)

Operations 2 (<1%) 2 (<1%) 4 (<1%)

Cryosurgery 1 (<1%) 1 (<1%) 2 (<1%) CONFIDENTIAL Surgery 0 1 (<1%) 1 (<1%) Surgical removal of tooth 1 (<1%) 0 1 (<1%)

206 Vitamins & trace elements combined 3 (<1%) 1 (<1%) 4 (<1%) Centrum 2 (<1%) 0 2 (<1%) Berocca 0 1 (<1%) 1 (<1%) Cacit Vit D3 1 (<1%) 0 1 (<1%)

Aminoglycosides 2 (<1%) 1 (<1%) 3 (<1%) Gentamicin sulphate 0 1 (<1%) 1 (<1%) Polyspectran 1 (<1%) 0 1 (<1%) Tobramycin 1 (<1%) 0 1 (<1%)

Androgens 1 (<1%) 2 (<1%) 3 (<1%)

Tibolone 1 (<1%) 1 (<1%) 2 (<1%) GM2004/00056/00 Testosterone enanthate 0 1 (<1%) 1 (<1%)

SAM40040

Page 42 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Hemostatics 1 (<1%) 2 (<1%) 3 (<1%) Tranexamic acid 1 (<1%) 1 (<1%) 2 (<1%) Naftazone 0 1 (<1%) 1 (<1%)

Miscellaneous anti-infectives/immunologicals 1 (<1%) 2 (<1%) 3 (<1%) Rodogyl 0 2 (<1%) 2 (<1%)

Blastoestimulina ovulos 1 (<1%) 0 1 (<1%) CONFIDENTIAL

Miscellaneous nutrition 2 (<1%) 1 (<1%) 3 (<1%)

207 Additiva superform 1 (<1%) 0 1 (<1%) Quatral 1 (<1%) 0 1 (<1%) Revitalose 1 (<1%) 0 1 (<1%) Vivioptal 0 1 (<1%) 1 (<1%)

Short acting beta-agonists 2 (<1%) 1 (<1%) 3 (<1%) Spasmo-Mucosolvan 1 (<1%) 0 1 (<1%) Terbutaline sulphate 0 1 (<1%) 1 (<1%) Tussoretard 1 (<1%) 0 1 (<1%)

Vasoconstrictors 1 (<1%) 2 (<1%) 3 (<1%) Etilefrine hydrochloride 1 (<1%) 1 (<1%) 2 (<1%)

Norfenefrine hydrochloride 1 (<1%) 1 (<1%) 2 (<1%) GM2004/00056/00

5-alpha-reductase inhibitors 2 (<1%) 0 2 (<1%) Finasteride 2 (<1%) 0 2 (<1%)

SAM40040

Page 43 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Astringents 2 (<1%) 0 2 (<1%) Arnica flower 2 (<1%) 0 2 (<1%)

Carminatives (antiflatulants) 1 (<1%) 1 (<1%) 2 (<1%) Flatoril 1 (<1%) 1 (<1%) 2 (<1%)

Otological preparations 0 2 (<1%) 2 (<1%)

Cerumol 0 1 (<1%) 1 (<1%) CONFIDENTIAL Ritiometan 0 1 (<1%) 1 (<1%)

208 Pesticides 1 (<1%) 1 (<1%) 2 (<1%) Malathion 0 1 (<1%) 1 (<1%) Permethrin 1 (<1%) 0 1 (<1%)

Anorectics 0 1 (<1%) 1 (<1%) Sibutramine hydrochloride 0 1 (<1%) 1 (<1%)

Anti-allergic compounds 1 (<1%) 0 1 (<1%) Homeopathic allergy medication 1 (<1%) 0 1 (<1%)

Anti-thyroid preparations 0 1 (<1%) 1 (<1%) Carbimazole 0 1 (<1%) 1 (<1%)

GM2004/00056/00 Antidiuretics 0 1 (<1%) 1 (<1%) Desmopressin 0 1 (<1%) 1 (<1%)

SAM40040

Page 44 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Antihelminthics 0 1 (<1%) 1 (<1%) Mebendazole 0 1 (<1%) 1 (<1%)

Beta-blockers & diuretics combined 0 1 (<1%) 1 (<1%) Co-dilatrend 0 1 (<1%) 1 (<1%)

Dopaminergic compounds 0 1 (<1%) 1 (<1%)

Sinemet 0 1 (<1%) 1 (<1%) CONFIDENTIAL

General anesthetics 0 1 (<1%) 1 (<1%)

209 Entonox 0 1 (<1%) 1 (<1%)

Immunosuppressants 0 1 (<1%) 1 (<1%) Tacrolimus 0 1 (<1%) 1 (<1%)

Miscellaneous non-drug products 1 (<1%) 0 1 (<1%) Sea water 1 (<1%) 0 1 (<1%)

Non-drug contraceptive devices 0 1 (<1%) 1 (<1%) Intrauterine device 0 1 (<1%) 1 (<1%)

Other asthma medication 1 (<1%) 0 1 (<1%)

Herbal bronchitis medication 1 (<1%) 0 1 (<1%) GM2004/00056/00

Posterior pituitary preparations (including oxytocics) 1 (<1%) 0 1 (<1%)

Prostaglandin F2 alpha 1 (<1%) 0 1 (<1%) SAM40040

Page 45 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.20 Summary of Non-Asthma Medication Taken During the Treatment Period

Rubifacients 0 1 (<1%) 1 (<1%) Ambene 0 1 (<1%) 1 (<1%)

Stimulants 1 (<1%) 0 1 (<1%) Caffeine 1 (<1%) 0 1 (<1%)

Trace elements 1 (<1%) 0 1 (<1%)

Selenium 1 (<1%) 0 1 (<1%) CONFIDENTIAL

210

GM2004/00056/00

SAM40040

Page 46 of 46 Protocol: SAM40040 Population: Intent-to-Treat Table 12.21 Summary of Baseline Diary Card (Day -7 to -1) Intent-to-Treat Population

SFC 50/250 FBC 4.5/160 Total (N=694) (N=697) (N=1391) ———————————————————————————————————————————————————————————————————————————————————————

Mean Morning PEF (L/min) n 694 696 1390 Mean 357.6 348.4 353.0 SD 112.45 111.47 112.01 Median 346.9 338.5 341.4 Min. 64 99 64 Max. 721 741 741

CONFIDENTIAL Mean Evening PEF (L/min) n 694 695 1389 Mean 368.2 359.8 364.0

211 SD 112.66 111.74 112.24 Median 355.7 351.4 354.3 Min. 80 108 80 Max. 773 744 773

GM2004/00056/00

SAM40040

Page 1 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.21 Summary of Baseline Diary Card (Day -7 to -1) Intent-to-Treat Population

Mean % Predicted Morning PEF n 694 696 1390 Mean 78.9 78.2 78.6 SD 19.28 19.42 19.35 Median 78.2 78.0 78.0 Min. 20 30 20 Max. 146 132 146

CONFIDENTIAL Mean % Predicted Evening PEF n 694 695 1389 Mean 81.2 80.8 81.0

212 SD 18.91 19.14 19.02 Median 80.7 81.0 81.0 Min. 28 26 26 Max. 146 133 146

GM2004/00056/00

SAM40040

Page 2 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.21 Summary of Baseline Diary Card (Day -7 to -1) Intent-to-Treat Population

Mean Day-Time Symptom Scores n 694 695 1389 Mean 1.8 1.8 1.8 SD 0.75 0.73 0.74 Median 1.7 1.7 1.7 Min. 0 0 0 Max. 5 4 5

CONFIDENTIAL Mean Night-Time Symptom Scores n 694 696 1390 Mean 1.0 0.9 0.9

213 SD 0.68 0.69 0.68 Median 1.0 1.0 1.0 Min. 0 0 0 Max. 4 4 4

GM2004/00056/00

SAM40040

Page 3 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.21 Summary of Baseline Diary Card (Day -7 to -1) Intent-to-Treat Population

% Symptom-Free Days n 694 695 1389 Mean 8.2 7.3 7.8 SD 16.98 16.32 16.65 Median 0.0 0.0 0.0 Min. 0 0 0 Max. 100 100 100

CONFIDENTIAL % Symptom-Free Nights n 694 696 1390 Mean 31.5 35.0 33.3

214 SD 35.77 37.64 36.75 Median 14.0 25.0 14.0 Min. 0 0 0 Max. 100 100 100

GM2004/00056/00

SAM40040

Page 4 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.21 Summary of Baseline Diary Card (Day -7 to -1) Intent-to-Treat Population

% Rescue-Free Days n 693 694 1387 Mean 25.7 24.6 25.2 SD 36.08 35.34 35.70 Median 0.0 0.0 0.0 Min. 0 0 0 Max. 100 100 100

CONFIDENTIAL % Rescue-Free Nights n 693 694 1387 Mean 50.7 52.3 51.5

215 SD 40.86 40.84 40.84 Median 57.0 57.0 57.0 Min. 0 0 0 Max. 100 100 100

Mean Circadian Variation in PEF (%) n 694 694 1388 Mean 8.8 9.2 9.0 SD 6.74 6.65 6.69 Median 7.0 7.2 7.1 Min. 0 0 0 Max. 61 38 61

GM2004/00056/00

SAM40040

Page 5 of 5 Protocol: SAM40040 Population: Per Protocol Table 12.22 Summary of Baseline Diary Card (Day -7 to -1) Per-Protocol Population

SFC 50/250 FBC 4.5/160 Total (N=492) (N=486) (N=978) ———————————————————————————————————————————————————————————————————————————————————————

Mean Morning PEF (L/min) n 464 453 917 Mean 358.8 352.1 355.5 SD 110.61 110.07 110.33 Median 350.7 344.3 350.0 Min. 90 100 90 Max. 676 741 741

CONFIDENTIAL Mean Evening PEF (L/min) n 408 395 803 Mean 371.5 363.7 367.6

216 SD 111.44 109.49 110.49 Median 363.1 356.7 360.0 Min. 80 100 80 Max. 698 744 744

GM2004/00056/00

SAM40040

Page 1 of 5 Protocol: SAM40040 Population: Per Protocol Table 12.22 Summary of Baseline Diary Card (Day -7 to -1) Per-Protocol Population

Mean % Predicted Morning PEF n 464 453 917 Mean 79.3 79.7 79.5 SD 18.89 19.12 18.99 Median 78.5 79.7 78.7 Min. 31 30 30 Max. 134 132 134

CONFIDENTIAL Mean % Predicted Evening PEF n 408 395 803 Mean 81.7 82.5 82.1

217 SD 18.86 18.68 18.76 Median 81.5 82.8 82.1 Min. 28 29 28 Max. 143 133 143

GM2004/00056/00

SAM40040

Page 2 of 5 Protocol: SAM40040 Population: Per Protocol Table 12.22 Summary of Baseline Diary Card (Day -7 to -1) Per-Protocol Population

Mean Day-Time Symptom Scores n 408 395 803 Mean 1.5 1.6 1.5 SD 0.74 0.72 0.73 Median 1.4 1.5 1.4 Min. 0 0 0 Max. 4 4 4

CONFIDENTIAL Mean Night-Time Symptom Scores n 464 453 917 Mean 0.8 0.7 0.8

218 SD 0.64 0.60 0.62 Median 0.8 0.8 0.8 Min. 0 0 0 Max. 4 3 4

GM2004/00056/00

SAM40040

Page 3 of 5 Protocol: SAM40040 Population: Per Protocol Table 12.22 Summary of Baseline Diary Card (Day -7 to -1) Per-Protocol Population

% Symptom-Free Days n 408 395 803 Mean 12.1 10.0 11.1 SD 23.33 21.76 22.58 Median 0.0 0.0 0.0 Min. 0 0 0 Max. 100 100 100

CONFIDENTIAL % Symptom-Free Nights n 464 453 917 Mean 39.6 40.7 40.1

219 SD 39.26 40.78 40.00 Median 29.0 29.0 29.0 Min. 0 0 0 Max. 100 100 100

GM2004/00056/00

SAM40040

Page 4 of 5 Protocol: SAM40040 Population: Per Protocol Table 12.22 Summary of Baseline Diary Card (Day -7 to -1) Per-Protocol Population

% Rescue-Free Days n 408 395 803 Mean 37.1 35.6 36.4 SD 41.89 41.37 41.61 Median 14.0 14.0 14.0 Min. 0 0 0 Max. 100 100 100

CONFIDENTIAL % Rescue-Free Nights n 464 453 917 Mean 60.6 63.5 62.0

220 SD 41.94 41.19 41.57 Median 75.0 83.0 80.0 Min. 0 0 0 Max. 100 100 100

Mean Circadian Variation in PEF (%) n 385 369 754 Mean 7.1 7.8 7.4 SD 5.51 6.99 6.28 Median 5.7 5.7 5.7 Min. 0 0 0 Max. 33 46 46

GM2004/00056/00

SAM40040

Page 5 of 5 Protocol: SAM40040 Population: Intent-to-Treat Table 12.23 Summary of Asthma Control Assessment Using The Asthma Control Questionnaire at Baseline

Mean Total Score n 689 691 1380 Mean 2.07 2.05 2.06 SD 0.84 0.86 0.85 Median 2.00 2.00 2.00 Min. 0.0 0.0 0.0 Max. 4.9 4.9 4.9

CONFIDENTIAL Distribution =>0 - <1 61 (9%) 64 (9%) 125 (9%) =>1 - <2 246 (36%) 257 (37%) 503 (36%)

221 =>2 - <3 271 (39%) 254 (37%) 525 (38%) =>3 - <4 101 (15%) 103 (15%) 204 (15%) =>4 - <5 10 (1%) 13 (2%) 23 (2%) =>5 - <6 0 0 0 6 0 0 0

GM2004/00056/00

SAM40040

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 12.24 Summary of Percentage Compliance

Compliance (%) n 693 695 1388 Mean 89.2 89.3 89.3 SD 27.23 22.59 25.00 Median 96.6 96.5 96.5 Min. 0 0 0 Max. 356 189 356

Range <20% 25 (4%) 18 (3%) 43 (3%) CONFIDENTIAL 20% to <50% 26 (4%) 28 (4%) 54 (4%) 50% to <80% 99 (14%) 99 (14%) 198 (14%)

222 80% to <100% 368 (53%) 368 (53%) 736 (53%) 100% to <120% 159 (23%) 165 (24%) 324 (23%) >=120% 16 (2%) 17 (2%) 33 (2%)

GM2004/00056/00

SAM40040

Page 1 of 1 CONFIDENTIAL GM2004/00056/00 SAM40040

Efficacy Data Source Figures and Tables

Page Figure 13.1 Plot of Cumulative Number of Exacerbations by Study Day Using Protocol Defined Exacerbations All Exacerbations...... 226 Figure 13.2 Plot of Cumulative Number of Exacerbations by Study Day Using Protocol Defined Exacerbations Moderate and Severe Exacerbations ...... 227 Figure 13.3 Kaplan Meier Survival Curve of Time to First Exacerbation. . . . . 228 Table 13.1 Summary of the Rate of Exacerbations Intent-to-Treat Population ...... 229 Table 13.2 Summary of the Rate of Exacerbations Per-Protocol Population . 230 Table 13.3 Statistical Analysis of the Rate of Exacerbations Intent-to-Treat Population ...... 231 Table 13.4 Statistical Analysis of the Rate of Exacerbations Per-Protocol Population ...... 232 Table 13.5 Statistical Analysis of the Rate of Exacerbations Negative Binomial Model Intent-to-Treat Population ...... 233 Table 13.6 Statistical Analysis of the Rate of Moderate/Severe Exacerbations ...... 234 Table 13.7 Statistical Analysis of the Rate of All Exacerbations Adjusting for Interval...... 235 Table 13.8 Statistical Analysis of the Rate of Moderate/Severe Exacerbations Adjusting for Interval ...... 236 Table 13.9 Statistical Analysis of the Rate of Protocol Defined Moderate/Severe Exacerbations Adjusting for Interval ...... 237 Table 13.10 Summary of the Number of Exacerbations ...... 241 Table 13.11 Statistical Analysis of the Proportion of Subjects With At Least One Exacerbation ...... 242 Table 13.12 Summary of the Severity of Exacerbations ...... 243 Table 13.13 Summary of Time to First Exacerbation ...... 244 Table 13.14 Survival Analysis of Time To First Exacerbation Cox's Proportional Hazards ...... 245

223 CONFIDENTIAL GM2004/00056/00 SAM40040

Table 13.15 Summary of Mean Morning PEF (L/min): Raw Values and Change From Baseline ...... 246 Table 13.16 Statistical Analysis of Mean Change in Morning PEF (L/min) . . . 248 Table 13.17 Summary of Mean Evening PEF (L/min): Raw Values and Change From Baseline ...... 252 Table 13.18 Statistical Analysis of Mean Change in Evening PEF (L/min) . . . 254 Table 13.19 Summary of Percentage Predicted Morning PEF (L/min): Raw Values and Change from Baseline ...... 258 Table 13.20 Statistical Analysis of Percentage Predicted Morning PEF (L/min) (Weeks 1-24) ...... 260 Table 13.21 Summary of Percentage Predicted Evening PEF (L/min): Raw Values and Change from Baseline ...... 264 Table 13.22 Statistical Analysis of Percentage Predicted Evening PEF (L/min) (Weeks 1-24) ...... 266 Table 13.23 Summary of Circadian Variation in Peak Flow (Weeks 1-24) . . . 270 Table 13.24 Summary of Clinic FEV1 (L) ...... 272 Table 13.25 Summary of Clinic FEV1 (L): Raw Values and Change from Baseline to Week 24 ...... 273 Table 13.26 Statistical Analysis of Mean Change in Clinic FEV1 (L) (Week 24) ...... 275 Table 13.27 Summary of Daytime Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24) ...... 276 Table 13.28 Statistical Analysis of Mean Change in Daytime Symptom Scores ...... 278 Table 13.29 Summary of Night-time Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24) ...... 282 Table 13.30 Statistical Analysis of Mean Change in Night-time Symptom Scores (Weeks 1-24) ...... 284 Table 13.31 Summary of Percentage of Symptom-Free Days (Weeks 1-24) . 288 Table 13.32 Statistical Analysis of Percentage of Symptom-Free Days (Weeks 1-24)...... 290 Table 13.33 Summary of Percentage of Symptom-Free Nights (Weeks 1-24) ...... 291

224 CONFIDENTIAL GM2004/00056/00 SAM40040

Table 13.34 Statistical Analysis of Percentage of Symptom-Free Nights (Weeks 1-24)...... 293 Table 13.35 Summary of Percentage of Days with No Relief Medication (Weeks 1-24)...... 294 Table 13.36 Statistical Analysis of Percentage of Days with No Relief Medication (Weeks 1-24) ...... 296 Table 13.37 Summary of Percentage of Nights with No Relief Medication (Weeks 1-24)...... 297 Table 13.38 Statistical Analysis of Percentage of Nights with No Relief Medication (Weeks 1-24) ...... 299 Table 13.39 Summary of Mean Daily Ventolin Use...... 300 Table 13.40 Summary and Analysis of the Number of Withdrawals Due to Lack of Efficacy ...... 302 Table 13.41 Summary and Analysis of the Proportion of Subjects with Well-Controlled Asthma ...... 303 Table 13.42 Summary of Number of Weeks With Well-Controlled Asthma . . 304 Table 13.43 Summary of Asthma Control Questionnaire (ACQ)...... 305 Table 13.44 Summary of Asthma Control Questionnaire: Raw Values and Change from Baseline...... 309 Table 13.45 Statistical Analysis of Mean Change in Asthma Control Questionnaire Score (Week 24) ...... 311

225 CONFIDENTIAL GM2004/00056/00 SAM40040

226 CONFIDENTIAL GM2004/00056/00 SAM40040

227 CONFIDENTIAL GM2004/00056/00 SAM40040

228 Protocol: SAM40040 Population: Intent-to-Treat Table 13.1 Summary of the Rate of Exacerbations Intent-to-Treat Population

Exacerbation Rate per 24 SFC 50/250 FBC 4.5/160 week treatment period [1] (N=694) (N=697) ——————————————————————————————————————————————————————

Number of Subjects 694 697 Mean 3.06 3.07 SD 4.44 4.27 Median 1 1 Min. 0 0 Max. 34 25

CONFIDENTIAL

229

GM2004/00056/00

[1]: Exacerbation data imputed for all subjects withdrawing prior to end of SAM40040 treatment period.

Page 1 of 1 Protocol: SAM40040 Population: Per Protocol Table 13.2 Summary of the Rate of Exacerbations Per-Protocol Population

Exacerbation Rate per 24 SFC 50/250 FBC 4.5/160 week treatment period [1] (N=492) (N=486) ——————————————————————————————————————————————————————

Number of Subjects 492 486 Mean 2.99 2.90 SD 4.43 4.13 Median 1 1 Min. 0 0 Max. 34 25

CONFIDENTIAL

230

GM2004/00056/00

[1]: Exacerbation data imputed for all subjects withdrawing prior to end of SAM40040 treatment period.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.3 Statistical Analysis of the Rate of Exacerbations Intent-to-Treat Population

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ————————————————————————————————————————————————————————————————————————————————————

Mean Rate Per 24 weeks from Poisson Model 2.69 2.79

Treatment Comparison (SFC/FBC) [1] Ratio 0.96 95% CL 0.84, 1.10 p-value 0.571

CONFIDENTIAL

231

GM2004/00056/00

SAM40040 [1]: Model adjusted for main effects of gender, country grouping and age.

Page 1 of 1 Protocol: SAM40040 Population: Per Protocol Table 13.4 Statistical Analysis of the Rate of Exacerbations Per-Protocol Population

SFC 50/250 FBC 4.5/160 (N=492) (N=486) ————————————————————————————————————————————————————————————————————————————————————

Mean Rate Per 24 weeks from Poisson Model 2.68 2.65

Treatment Comparison (SFC/FBC) [1] Ratio 1.01 95% CL 0.86, 1.18 p-value 0.921

CONFIDENTIAL

232

GM2004/00056/00

SAM40040 [1]: Model adjusted for main effects of gender, country grouping and age.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.5 Statistical Analysis of the Rate of Exacerbations Negative Binomial Model Intent-to-Treat Population

Mean Rate Per 24 weeks from Negative Binomial Mode 2.72 2.83

Treatment Comparison (SFC/FBC) [1] Ratio 0.96 95% CL 0.83, 1.12

p-value 0.628 CONFIDENTIAL

233

GM2004/00056/00

SAM40040 [1]: Model adjusted for main effects of gender, country grouping and age.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.6 Statistical Analysis of the Rate of Moderate/Severe Exacerbations

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ————————————————————————————————————————————————————————————————————————

Adjusted Mean Rate Per 24 Weeks [1] 0.08 0.11

Treatment Comparison (SFC/FBC) [1] Ratio 0.75 95% CL 0.53, 1.05 p-value 0.095

CONFIDENTIAL

234

GM2004/00056/00

SAM40040 [1]: Poisson model adjusted for main effects of gender, country grouping and age

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.7 Statistical Analysis of the Rate of All Exacerbations Adjusting for Interval

Adjusted Mean Rate Per Year [1] 5.87 6.07

Treatment Comparison (SFC/FBC) [1] Ratio 0.97 95% CL 0.84, 1.11 p-value 0.645

CONFIDENTIAL

235

GM2004/00056/00

[1]: GEE model (using negative binomial distribution and unstructured working correlation matrix) adjusted for main effects of gender, country

grouping, age and interval. SAM40040 LOCF used to account for withdrawn subjects.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.8 Statistical Analysis of the Rate of Moderate/Severe Exacerbations Adjusting for Interval

Adjusted Mean Rate Per Year [1] 0.18 0.25

Treatment Comparison (SFC/FBC) [1] Ratio 0.71 95% CL 0.51, 1.00 p-value 0.052

CONFIDENTIAL

236

GM2004/00056/00

[1]: GEE model (using Poisson distribution and unstructured working correlation matrix)

adjusted for main effects of gender, country grouping, age and interval. SAM40040 LOCF used to account for for withdrawn subjects

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.9 Statistical Analysis of the Rate of Protocol Defined Moderate/Severe Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 Weeks 1-24 (N=694) (N=697) ————————————————————————————————————————————————————————————————————————

Adjusted Mean Rate Per Year [1] 0.155 0.223

Treatment Comparison [1] Ratio 0.70 95% CL 0.48, 1.01 p-value 0.059

CONFIDENTIAL

237

GM2004/00056/00 [1]: GEE model (using Poisson distribution and unstructured working correlation matrix) adjusted for main effects of gender, country grouping, age and interval and interaction of treatment-by-interval.

P-value for treatment-by-interval interaction = 0.055 SAM40040 LOCF used to account for withdrawn subjects Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.9 Statistical Analysis of the Rate of Protocol Defined Moderate/Severe Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 Weeks 1-8 (N=694) (N=697) ————————————————————————————————————————————————————————————————————————

Adjusted Mean Rate Per Year [1] 0.227 0.224

Treatment Comparison [1] Ratio 1.01 95% CL 0.61, 1.67 p-value 0.960

CONFIDENTIAL

238

P-value for treatment-by-interval interaction = 0.055 SAM40040 LOCF used to account for withdrawn subjects Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.9 Statistical Analysis of the Rate of Protocol Defined Moderate/Severe Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 Weeks 9-16 (N=694) (N=697) ————————————————————————————————————————————————————————————————————————

Adjusted Mean Rate Per Year [1] 0.157 0.202

Treatment Comparison [1] Ratio 0.78 95% CL 0.45, 1.35 p-value 0.371

CONFIDENTIAL

239

P-value for treatment-by-interval interaction = 0.055 SAM40040 LOCF used to account for withdrawn subjects Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.9 Statistical Analysis of the Rate of Protocol Defined Moderate/Severe Exacerbations Adjusting for Interval

SFC 50/250 FBC 4.5/160 Weeks 17-24 (N=694) (N=697) ————————————————————————————————————————————————————————————————————————

Adjusted Mean Rate Per Year [1] 0.105 0.244

Treatment Comparison [1] Ratio 0.43 95% CL 0.23, 0.79 p-value 0.006

CONFIDENTIAL

240

P-value for treatment-by-interval interaction = 0.055 SAM40040 LOCF used to account for withdrawn subjects Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.10 Summary of the Number of Exacerbations

SFC 50/250 FBC 4.5/160 Number of Exacerbations [1] (N=694) (N=697) ——————————————————————————————————————————————————————————

Number of Subjects 694 697 0 258 (37%) 246 (35%) 1 127 (18%) 113 (16%) 2 54 (8%) 83 (12%) 3 45 (6%) 53 (8%) >3 210 (30%) 202 (29%)

SFC / FBC [2] CONFIDENTIAL Odds Ratio 1.05 95% CI 0.869, 1.275

241 p-value 0.599

GM2004/00056/00 [1]: The number of exacerbations for each subject during their time in the study. Imputation is used to estimate the number of exacerbations for subjects who withdrew early.

[2]: Logistic regression (proportional odds) adjusted for gender, country grouping SAM40040 and age.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.11 Statistical Analysis of the Proportion of Subjects With At Least One Exacerbation

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ————————————————————————————————————————————————————————————————

No Exacerbations 258 (37%) 246 (35%) At Least One Exacerbation 436 (63%) 451 (65%)

SFC - FBC Difference (se) -1.88% (2.58%) 95% CI -6.93%, 3.17% p-value [1] 0.454

CONFIDENTIAL

242

GM2004/00056/00

SAM40040 [1]: Based on Cochran-Mantel-Haenszel Test stratified by country grouping.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.12 Summary of the Severity of Exacerbations

SFC 50/250 FBC 4.5/160 Severity [1] (N=694) (N=697) ————————————————————————————————————————————————————————————————

Number of Subjects with Exacerbations Classed as: Severe 4 (<1%) 1 (<1%) Moderate 63 (9%) 79 (11%) Mild 369 (53%) 371 (53%) No Exacerbation 258 (37%) 246 (35%)

SFC / FBC [2] CONFIDENTIAL Odds Ratio 1.11 95% CL 0.90, 1.36

243 p-value 0.317

GM2004/00056/00

[1]: Maximum severity of exacerbation experienced by subjects.

[2]: Logistic regression (proportional odds) adjusted for gender, country grouping SAM40040 and age.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.13 Summary of Time to First Exacerbation

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ————————————————————————————————————— ———————————————————————————————————— Survival Survival Interval N Exacerbation Censored Estimate N Exacerbation Censored Estimate ——————————————————————————————————————————————————————————————————————————————————————————

Weeks 0 - 4 694 310 7 0.551 697 301 10 0.566 Weeks 5 - 8 377 59 10 0.464 386 57 9 0.481 Weeks 9 - 12 308 26 8 0.424 320 34 3 0.430 Weeks 13 - 16 274 14 4 0.402 283 21 2 0.398

Weeks 17 - 20 256 17 1 0.376 260 17 3 0.372 CONFIDENTIAL Weeks 21 - 24 238 10 228 0.355 240 21 219 0.337

244 Number of 436 451 subjects with exacerbation

Note: N=number of subjects remaining in the study at the start of the interval who are yet experience an exacerbation

Exacerbation=no. of subjects that experienced their first exacerbation in this GM2004/00056/00 period Censored=number of subjects who withdrew from the study in this period or completed the study without experiencing a first exacerbation

Survival Estimate=Kaplan-Meier estimates of the probability of surviving to the SAM40040 end of the interval without experiencing a first exacerbation

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.14 Survival Analysis of Time To First Exacerbation Cox’s Proportional Hazards

n 436 451 median 40 47 min/max 0, 174 0, 167 SFC/FBC Hazard Ratio 1.03 95% CL 0.91, 1.18

p-value [1] 0.617 CONFIDENTIAL

245

GM2004/00056/00

[1]: Hazard ratio for treatment groups, p-value and 95% CL based on Cox’s Proportional SAM40040 Hazards model, adjusted for sex and age and stratified by country grouping.

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.15 Summary of Mean Morning PEF (L/min): Raw Values and Change From Baseline

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ———————————————————— ———————————————————— Study Period Raw Change Raw Change ——————————————————————————————————————————————————————————————————————————

Run-in (baseline) n 694 696 Mean 357.6 348.4 SD 112.45 111.47 Median 346.9 338.5 Min. 64 99

Max. 721 741 CONFIDENTIAL

Weeks 1-24 n 686 686 692 691

246 Mean 396.5 39.0 386.5 38.6 SD 110.90 46.88 112.86 46.68 Median 388.2 30.4 378.4 31.8 Min. 91 -113 138 -106 Max. 750 280 771 224

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.15 Summary of Mean Morning PEF (L/min): Raw Values and Change From Baseline

Weeks 1-8 n 686 686 692 691 Mean 391.8 34.3 382.0 34.0 SD 110.81 41.85 112.10 42.01 Median 385.4 27.3 373.3 28.8 Min. 90 -95 129 -130

Max. 742 236 771 194 CONFIDENTIAL

Weeks 9-16 n 648 648 661 660

247 Mean 398.5 42.4 388.1 40.9 SD 111.96 51.63 113.93 51.34 Median 391.6 33.5 380.7 34.4 Min. 93 -134 128 -136 Max. 752 323 777 233

Weeks 17-24 n 630 630 644 643 Mean 398.9 43.9 389.2 42.3 SD 112.66 53.22 113.99 53.40 Median 391.6 35.9 384.5 35.0 Min. 91 -136 123 -141 Max. 756 311 767 250

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.16 Statistical Analysis of Mean Change in Morning PEF (L/min)

SFC 50/250 FBC 4.5/160 Weeks 1-24 (N=694) (N=697) ———————————————————————————————————————————————————————————————————————————

Number of subjects 686 691 Baseline raw mean (sd) 357.5 (112.75) 348.3 (111.64) Raw mean (sd) 396.5 (110.90) 386.8 (112.66) Adjusted mean (se) 394.6 (1.74) 394.3 (1.75) Adjusted mean change (se) [1] 41.8 (1.74) 41.4 (1.75)

SFC - FBC CONFIDENTIAL Difference (se) 0.34 (2.37) 95% CL -4.30, 4.99

248 p-value 0.885

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 morning PEF.

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.16 Statistical Analysis of Mean Change in Morning PEF (L/min)

SFC 50/250 FBC 4.5/250 Weeks 1-8 (N=694) (N=697) ———————————————————————————————————————————————————————————————————————————

Number of subjects 686 691 Baseline raw mean (sd) 357.5 (112.75) 348.3 (111.64) Raw mean (sd) 391.8 (110.81) 382.3 (111.94) Adjusted mean (se) 389.7 (1.58) 389.5 (1.58) Adjusted mean change (se) [1] 36.8 (1.58) 36.6 (1.58)

SFC - FBC CONFIDENTIAL Difference (se) 0.20 (2.14) 95% CL -4.00, 4.40

249 p-value 0.926

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 morning PEF.

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.16 Statistical Analysis of Mean Change in Morning PEF (L/min)

SFC 50/250 FBC 4.5/160 Weeks 9-16 (N=694) (N=697) ———————————————————————————————————————————————————————————————————————————

Number of subjects 648 660 Baseline raw mean (sd) 356.1 (112.36) 347.5 (110.82) Raw mean (sd) 398.5 (111.96) 388.4 (113.70) Adjusted mean (se) 397.1 (1.98) 395.6 (1.97) Adjusted mean change (se) [1] 45.4 (1.98) 43.9 (1.97)

SFC - FBC CONFIDENTIAL Difference (se) 1.50 (2.67) 95% CL -3.74, 6.74

250 p-value 0.575

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 morning PEF.

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.16 Statistical Analysis of Mean Change in Morning PEF (L/min)

SFC 50/250 FBC 4.5/160 Weeks 17-24 (N=694) (N=697) ———————————————————————————————————————————————————————————————————————————

Number of subjects 630 643 Baseline raw mean (sd) 355.0 (112.84) 347.2 (111.29) Raw mean (sd) 398.9 (112.66) 389.6 (113.73) Adjusted mean (se) 397.9 (2.07) 396.4 (2.06) Adjusted mean change (se) [1] 46.9 (2.07) 45.4 (2.06)

SFC - FBC CONFIDENTIAL Difference (se) 1.52 (2.80) 95% CL -3.98, 7.02

251 p-value 0.589

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 morning PEF.

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.17 Summary of Mean Evening PEF (L/min): Raw Values and Change From Baseline

Run-in (baseline) n 694 695 Mean 368.2 359.8 SD 112.66 111.74 Median 355.7 351.4 Min. 80 108

Max. 773 744 CONFIDENTIAL

Weeks 1-24 n 686 686 692 691

252 Mean 401.0 32.7 392.4 32.9 SD 111.16 46.13 112.73 45.72 Median 391.7 25.4 386.6 25.0 Min. 101 -176 136 -107 Max. 729 273 774 317

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.17 Summary of Mean Evening PEF (L/min): Raw Values and Change From Baseline

Weeks 1-8 n 686 686 692 691 Mean 396.9 28.6 388.5 28.9 SD 111.26 41.31 112.65 40.94 Median 388.1 22.4 382.8 22.2 Min. 101 -148 125 -102

Max. 714 233 772 213 CONFIDENTIAL

Weeks 9-16 n 647 647 661 660

253 Mean 403.1 36.0 393.6 34.7 SD 111.99 50.29 113.38 50.73 Median 395.6 28.3 389.3 27.3 Min. 102 -208 127 -114 Max. 725 311 782 367

Weeks 17-24 n 630 630 644 643 Mean 402.7 36.6 394.6 36.0 SD 112.78 52.12 112.93 52.26 Median 394.4 29.6 389.2 28.1 Min. 99 -173 123 -146 Max. 748 298 770 372

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.18 Statistical Analysis of Mean Change in Evening PEF (L/min)

Number of subjects 686 691 Baseline raw mean (sd) 368.3 (112.92) 359.8 (111.96) Raw mean (sd) 401.0 (111.16) 392.7 (112.54) Adjusted mean (se) 399.1 (1.72) 399.4 (1.72) Adjusted mean change (se) [1] 35.1 (1.72) 35.4 (1.72)

SFC - FBC CONFIDENTIAL Difference (se) -0.33 (2.33) 95% CL -4.90, 4.24

254 p-value 0.887

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 evening PEF.

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.18 Statistical Analysis of Mean Change in Evening PEF (L/min)

Number of subjects 686 691 Baseline raw mean (sd) 368.3 (112.92) 359.8 (111.96) Raw mean (sd) 396.9 (111.26) 388.7 (112.50) Adjusted mean (se) 394.7 (1.55) 395.2 (1.56) Adjusted mean change (se) [1] 30.7 (1.55) 31.2 (1.56)

SFC - FBC CONFIDENTIAL Difference (se) -0.45 (2.11) 95% CL -4.58, 3.69

255 p-value 0.833

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 evening PEF.

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.18 Statistical Analysis of Mean Change in Evening PEF (L/min)

Number of subjects 647 660 Baseline raw mean (sd) 367.2 (112.93) 359.2 (111.20) Raw mean (sd) 403.1 (111.99) 393.9 (113.18) Adjusted mean (se) 401.7 (1.94) 400.5 (1.93) Adjusted mean change (se) [1] 38.6 (1.94) 37.4 (1.93)

SFC - FBC CONFIDENTIAL Difference (se) 1.22 (2.62) 95% CL -3.93, 6.36

256 p-value 0.643

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 evening PEF.

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.18 Statistical Analysis of Mean Change in Evening PEF (L/min)

Number of subjects 630 643 Baseline raw mean (sd) 366.1 (113.20) 359.0 (111.75) Raw mean (sd) 402.7 (112.78) 394.9 (112.68) Adjusted mean (se) 401.6 (2.03) 401.0 (2.02) Adjusted mean change (se) [1] 39.1 (2.03) 38.5 (2.02)

SFC - FBC CONFIDENTIAL Difference (se) 0.52 (2.74) 95% CL -4.86, 5.89

257 p-value 0.851

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 evening PEF.

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.19 Summary of Percentage Predicted Morning PEF (L/min): Raw Values and Change from Baseline

Run-in (baseline) n 694 696 Mean 78.9 78.2 SD 19.28 19.42 Median 78.2 78.0 Min. 20 30

Max. 146 132 CONFIDENTIAL

Weeks 1-24 n 686 686 692 691

258 Mean 87.9 9.0 87.1 8.9 SD 18.97 10.90 19.13 10.74 Median 88.1 7.0 88.1 7.5 Min. 28 -21 34 -24 Max. 142 59 147 60

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.19 Summary of Percentage Predicted Morning PEF (L/min): Raw Values and Change from Baseline

Weeks 1-8 n 686 686 692 691 Mean 86.8 7.9 86.1 7.9 SD 18.83 9.72 18.98 9.64 Median 87.0 6.2 87.0 6.6 Min. 27 -18 35 -20

Max. 139 57 144 54 CONFIDENTIAL

Weeks 9-16 n 648 648 661 660

259 Mean 88.8 9.8 87.6 9.5 SD 19.43 11.99 19.53 11.75 Median 89.8 7.6 88.3 7.8 Min. 28 -32 34 -26 Max. 143 68 149 62

Weeks 17-24 n 630 630 644 643 Mean 88.9 10.1 87.8 9.8 SD 19.44 12.42 19.54 12.35 Median 90.2 8.3 88.8 8.2 Min. 28 -33 30 -34 Max. 144 66 150 66

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.20 Statistical Analysis of Percentage Predicted Morning PEF (L/min) (Weeks 1-24)

Number of subjects 686 691 Baseline raw mean (sd) 78.9 (19.26) 78.3 (19.42) Raw mean (sd) 87.9 (18.97) 87.2 (19.07) Adjusted mean (se) 87.8 (0.40) 87.6 (0.40) Adjusted mean change (se) [1] 9.2 (0.40) 9.0 (0.40)

SFC - FBC CONFIDENTIAL Difference (se) 0.22 (0.54) 95% CL -0.84, 1.28

260 p-value 0.683

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted morning PEF.

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.20 Statistical Analysis of Percentage Predicted Morning PEF (L/min) (Weeks 1-24)

Number of subjects 686 691 Baseline raw mean (sd) 78.9 (19.26) 78.3 (19.42) Raw mean (sd) 86.8 (18.83) 86.1 (18.94) Adjusted mean (se) 86.7 (0.36) 86.6 (0.36) Adjusted mean change (se) [1] 8.1 (0.36) 8.0 (0.36)

SFC - FBC CONFIDENTIAL Difference (se) 0.16 (0.49) 95% CL -0.80, 1.12

261 p-value 0.743

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted morning PEF.

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.20 Statistical Analysis of Percentage Predicted Morning PEF (L/min) (Weeks 1-24)

Number of subjects 648 660 Baseline raw mean (sd) 79.1 (19.37) 78.2 (19.39) Raw mean (sd) 88.8 (19.43) 87.7 (19.47) Adjusted mean (se) 88.6 (0.45) 88.1 (0.45) Adjusted mean change (se) [1] 10.0 (0.45) 9.5 (0.45)

SFC - FBC CONFIDENTIAL Difference (se) 0.46 (0.61) 95% CL -0.74, 1.65

262 p-value 0.452

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted morning PEF.

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.20 Statistical Analysis of Percentage Predicted Morning PEF (L/min) (Weeks 1-24)

Number of subjects 630 643 Baseline raw mean (sd) 78.8 (19.29) 78.1 (19.50) Raw mean (sd) 88.9 (19.44) 87.9 (19.47) Adjusted mean (se) 88.8 (0.47) 88.3 (0.47) Adjusted mean change (se) [1] 10.3 (0.47) 9.8 (0.47)

SFC - FBC CONFIDENTIAL Difference (se) 0.51 (0.64) 95% CL -0.75, 1.77

263 p-value 0.427

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted morning PEF.

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.21 Summary of Percentage Predicted Evening PEF (L/min): Raw Values and Change from Baseline

Run-in (baseline) n 694 695 Mean 81.2 80.8 SD 18.91 19.14 Median 80.7 81.0 Min. 28 26

Max. 146 133 CONFIDENTIAL

Weeks 1-24 n 686 686 692 691

264 Mean 88.9 7.6 88.4 7.6 SD 18.75 10.70 18.87 10.46 Median 88.8 5.6 88.9 5.7 Min. 29 -33 34 -21 Max. 145 58 148 64

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.21 Summary of Percentage Predicted Evening PEF (L/min): Raw Values and Change from Baseline

Weeks 1-8 n 686 686 692 691 Mean 87.9 6.6 87.5 6.7 SD 18.69 9.55 18.84 9.33 Median 87.7 4.6 88.2 5.0 Min. 29 -28 36 -16

Max. 144 49 144 57 CONFIDENTIAL

Weeks 9-16 n 647 647 661 660

265 Mean 89.8 8.3 88.8 8.0 SD 19.08 11.66 19.24 11.59 Median 90.0 6.2 89.1 5.9 Min. 29 -39 34 -25 Max. 145 66 150 69

Weeks 17-24 n 630 630 644 643 Mean 89.7 8.5 89.0 8.3 SD 19.24 12.18 19.13 12.04 Median 90.4 6.6 89.6 6.3 Min. 29 -33 30 -28 Max. 146 63 152 70

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.22 Statistical Analysis of Percentage Predicted Evening PEF (L/min) (Weeks 1-24)

Number of subjects 686 691 Baseline raw mean (sd) 81.3 (18.89) 80.9 (19.14) Raw mean (sd) 88.9 (18.75) 88.5 (18.82) Adjusted mean (se) 88.8 (0.39) 88.8 (0.39) Adjusted mean change (se) [1] 7.8 (0.39) 7.7 (0.39)

SFC - FBC CONFIDENTIAL Difference (se) 0.07 (0.53) 95% CL -0.97, 1.10

266 p-value 0.902

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted evening PEF.

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.22 Statistical Analysis of Percentage Predicted Evening PEF (L/min) (Weeks 1-24)

Number of subjects 686 691 Baseline raw mean (sd) 81.3 (18.89) 80.9 (19.14) Raw mean (sd) 87.9 (18.69) 87.5 (18.80) Adjusted mean (se) 87.9 (0.35) 87.8 (0.35) Adjusted mean change (se) [1] 6.8 (0.35) 6.8 (0.35)

SFC - FBC CONFIDENTIAL Difference (se) 0.03 (0.48) 95% CL -0.91, 0.97

267 p-value 0.947

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted evening PEF.

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.22 Statistical Analysis of Percentage Predicted Evening PEF (L/min) (Weeks 1-24)

Number of subjects 647 660 Baseline raw mean (sd) 81.5 (19.01) 80.8 (19.14) Raw mean (sd) 89.8 (19.08) 88.9 (19.18) Adjusted mean (se) 89.6 (0.44) 89.2 (0.44) Adjusted mean change (se) [1] 8.5 (0.44) 8.1 (0.44)

SFC - FBC CONFIDENTIAL Difference (se) 0.39 (0.59) 95% CL -0.78, 1.55

268 p-value 0.515

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted evening PEF.

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.22 Statistical Analysis of Percentage Predicted Evening PEF (L/min) (Weeks 1-24)

Number of subjects 630 643 Baseline raw mean (sd) 81.2 (18.87) 80.8 (19.27) Raw mean (sd) 89.7 (19.24) 89.1 (19.06) Adjusted mean (se) 89.6 (0.46) 89.3 (0.46) Adjusted mean change (se) [1] 8.6 (0.46) 8.3 (0.46)

SFC - FBC CONFIDENTIAL Difference (se) 0.28 (0.63) 95% CL -0.95, 1.52

269 p-value 0.656

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 percentage predicted evening PEF.

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.23 Summary of Circadian Variation in Peak Flow (Weeks 1-24)

Run-in (baseline) n 694 694 Mean 8.8 9.2 SD 6.74 6.65 Median 7.0 7.2 Min. 0 0

Max. 61 38 CONFIDENTIAL

Weeks 1-24 n 685 685 692 690

270 Mean 5.6 -3.1 6.2 -2.9 SD 3.83 5.56 4.31 5.44 Median 4.7 -2.0 5.1 -1.8 Min. 0 -39 0 -32 Max. 30 15 33 21

GM2004/00056/00

SAM40040 [1]: Baseline mean has been derived over last 7 days of run-in.

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.23 Summary of Circadian Variation in Peak Flow (Weeks 1-24)

Weeks 1-8 n 685 685 692 690 Mean 6.3 -2.5 6.8 -2.4 SD 4.13 5.48 4.41 5.29 Median 5.4 -1.4 5.7 -1.5 Min. 0 -37 0 -32

Max. 34 13 31 20 CONFIDENTIAL

Weeks 9-16 n 648 648 661 659

271 Mean 5.4 -3.3 6.1 -3.0 SD 4.32 5.91 4.66 5.73 Median 4.3 -2.2 4.8 -2.1 Min. 0 -35 0 -32 Max. 40 25 37 18

Weeks 17-24 n 630 630 644 642 Mean 5.0 -3.7 5.7 -3.4 SD 3.94 5.85 4.76 5.98 Median 3.8 -2.6 4.6 -2.2 Min. 0 -44 0 -33 Max. 33 18 42 32

GM2004/00056/00

SAM40040 [1]: Baseline mean has been derived over last 7 days of run-in.

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.24 Summary of Clinic FEV1 (L)

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ——————————————————————————————————————— ——————————————————————————————————————— n Mean SD Med Min Max n Mean SD Med Min Max ——————————————————————————————————————————————————————————————————————————————————————————

Run-in 689 2.46 0.83 2.32 0.74 5.73 690 2.38 0.78 2.27 0.91 5.51 Baseline 693 2.45 0.85 2.33 0.61 5.42 697 2.40 0.85 2.27 0.75 5.56 Week 4 667 2.68 0.88 2.55 0.82 5.85 667 2.62 0.87 2.52 0.78 6.14 Week 8 649 2.68 0.89 2.58 0.90 6.01 661 2.63 0.89 2.52 0.95 5.94 Week 16 632 2.70 0.90 2.58 0.92 5.57 643 2.65 0.89 2.54 0.81 6.03

Week 24 626 2.71 0.91 2.62 0.80 6.21 635 2.64 0.89 2.57 0.82 6.19 CONFIDENTIAL Follow-up 113 2.44 0.79 2.36 0.89 4.59 98 2.57 0.84 2.44 1.11 5.38

272

GM2004/00056/00

SAM40040

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.25 Summary of Clinic FEV1 (L): Raw Values and Change from Baseline to Week 24

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ———————————————————————————————— ———————————————————————————————— Raw Change Raw Change —————————————————————————————————————————————————————————————————————————————————————————

Baseline n 693 697 Mean 2.45 2.40 SD 0.85 0.85 Median 2.33 2.27 Min 0.61 0.75

Max 5.42 5.56 CONFIDENTIAL

273 Week 4 n 667 666 667 667 Mean 2.68 0.23 2.62 0.22 SD 0.88 0.38 0.87 0.38 Median 2.55 0.19 2.52 0.18 Min 0.82 -2.16 0.78 -1.80 Max 5.85 2.02 6.14 2.41

Week 8 n 649 648 661 661 Mean 2.68 0.25 2.63 0.24 SD 0.89 0.41 0.89 0.41 Median 2.58 0.21 2.52 0.20

Min 0.90 -2.36 0.95 -1.94 GM2004/00056/00 Max 6.01 2.07 5.94 2.49

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.25 Summary of Clinic FEV1 (L): Raw Values and Change from Baseline to Week 24

Week 16 n 632 631 643 643 Mean 2.70 0.28 2.65 0.25 SD 0.90 0.42 0.89 0.43 Median 2.58 0.21 2.54 0.22 Min 0.92 -1.92 0.81 -1.94

Max 5.57 2.78 6.03 2.44 CONFIDENTIAL

274 Week 24 n 626 625 635 635 Mean 2.71 0.28 2.64 0.24 SD 0.91 0.45 0.89 0.41 Median 2.62 0.23 2.57 0.20 Min 0.80 -1.50 0.82 -2.02 Max 6.21 2.58 6.19 2.46

Follow-up n 113 113 98 98 Mean 2.44 0.21 2.57 0.30 SD 0.79 0.48 0.84 0.38 Median 2.36 0.16 2.44 0.20

Min 0.89 -2.56 1.11 -0.41 GM2004/00056/00 Max 4.59 1.80 5.38 1.37

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.26 Statistical Analysis of Mean Change in Clinic FEV1 (L) (Week 24)

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ——————————————————————————————————————————————————————————

Number of subjects 625 635 Baseline raw mean (sd) 2.43 (0.83) 2.40 (0.85) Raw mean (sd) 2.71 (0.91) 2.64 (0.89) Adjusted mean (se) 2.71 (0.02) 2.68 (0.02) Adjusted mean change (se) 0.29 (0.02) 0.27 (0.02)

SFC - FBC CONFIDENTIAL Difference (se) 0.03 (0.022) 95% CL -0.02, 0.07

275 p-value 0.221

GM2004/00056/00

SAM40040 [1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline FEV1

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.27 Summary of Daytime Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24)

Run-in (baseline) n 694 695 Mean 1.8 1.8 SD 0.75 0.73 Median 1.7 1.7 Min. 0.0 0.0

Max. 4.6 4.1 CONFIDENTIAL

Weeks 1-24 n 685 685 692 690

276 Mean 0.8 -1.0 0.8 -1.0 SD 0.79 0.81 0.78 0.79 Median 0.5 -1.0 0.5 -1.0 Min. 0.0 -3.7 0.0 -4.0 Max. 4.9 2.6 4.0 2.0

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.27 Summary of Daytime Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24)

Weeks 1-8 n 685 685 692 690 Mean 0.9 -0.9 0.9 -0.9 SD 0.81 0.80 0.81 0.82 Median 0.7 -0.8 0.7 -0.9 Min. 0.0 -3.7 0.0 -3.9

Max. 4.9 2.6 4.0 1.6 CONFIDENTIAL

Weeks 9-16 n 647 647 660 659

277 Mean 0.7 -1.1 0.7 -1.1 SD 0.82 0.85 0.85 0.85 Median 0.3 -1.0 0.4 -1.0 Min. 0.0 -4.0 0.0 -4.0 Max. 4.8 2.5 4.1 2.3

Weeks 17-24 n 630 630 644 643 Mean 0.7 -1.1 0.7 -1.1 SD 0.84 0.87 0.81 0.83 Median 0.3 -1.1 0.3 -1.1 Min. 0.0 -4.0 0.0 -4.0 Max. 5.0 2.7 4.0 2.3

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.28 Statistical Analysis of Mean Change in Daytime Symptom Scores

Number of subjects 685 690 Baseline raw mean (sd) 1.8 (0.75) 1.8 (0.73) Raw mean (sd) 0.8 (0.79) 0.8 (0.78) Adjusted mean (se) 0.8 (0.03) 0.7 (0.03) Adjusted mean change (se) [1] -1.0 (0.03) -1.1 (0.03)

SFC - FBC CONFIDENTIAL Difference (se) 0.03 (0.04) 95% CL -0.04, 0.10

278 p-value 0.425

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 daytime symptom score.

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.28 Statistical Analysis of Mean Change in Daytime Symptom Scores

Number of subjects 685 690 Baseline raw mean (sd) 1.8 (0.75) 1.8 (0.73) Raw mean (sd) 0.9 (0.81) 0.9 (0.81) Adjusted mean (se) 0.9 (0.03) 0.8 (0.03) Adjusted mean change (se) [1] -0.9 (0.03) -0.9 (0.03)

SFC - FBC CONFIDENTIAL Difference (se) 0.03 (0.04) 95% CL -0.04, 0.10

279 p-value 0.428

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 daytime symptom score.

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.28 Statistical Analysis of Mean Change in Daytime Symptom Scores

Number of subjects 647 659 Baseline raw mean (sd) 1.8 (0.74) 1.8 (0.71) Raw mean (sd) 0.7 (0.82) 0.7 (0.85) Adjusted mean (se) 0.7 (0.03) 0.7 (0.03) Adjusted mean change (se) [1] -1.1 (0.03) -1.1 (0.03)

SFC - FBC CONFIDENTIAL Difference (se) 0.00 (0.04) 95% CL -0.08, 0.08

280 p-value 0.955

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 daytime symptom score.

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.28 Statistical Analysis of Mean Change in Daytime Symptom Scores

Number of subjects 630 643 Baseline raw mean (sd) 1.8 (0.73) 1.8 (0.72) Raw mean (sd) 0.7 (0.84) 0.7 (0.81) Adjusted mean (se) 0.7 (0.03) 0.6 (0.03) Adjusted mean change (se) [1] -1.1 (0.03) -1.2 (0.03)

SFC - FBC CONFIDENTIAL Difference (se) 0.03 (0.04) 95% CL -0.05, 0.10

281 p-value 0.535

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 daytime symptom score.

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.29 Summary of Night-time Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24)

Run-in (baseline) n 694 696 Mean 1.0 0.9 SD 0.68 0.69 Median 1.0 1.0 Min. 0.0 0.0

Max. 4.0 4.0 CONFIDENTIAL

Weeks 1-24 n 686 686 692 691

282 Mean 0.4 -0.5 0.4 -0.5 SD 0.56 0.64 0.56 0.66 Median 0.2 -0.5 0.2 -0.4 Min. 0.0 -2.7 0.0 -3.8 Max. 3.8 1.4 3.3 1.7

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.29 Summary of Night-time Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24)

Weeks 1-8 n 686 686 692 691 Mean 0.5 -0.5 0.5 -0.4 SD 0.59 0.62 0.58 0.65 Median 0.3 -0.4 0.2 -0.4 Min. 0.0 -2.6 0.0 -3.7

Max. 3.6 1.8 3.1 1.6 CONFIDENTIAL

Weeks 9-16 n 648 648 661 660

283 Mean 0.4 -0.6 0.4 -0.5 SD 0.59 0.68 0.60 0.69 Median 0.1 -0.6 0.1 -0.4 Min. 0.0 -3.6 0.0 -3.9 Max. 3.9 1.9 3.7 1.7

Weeks 17-24 n 630 630 644 643 Mean 0.4 -0.6 0.4 -0.5 SD 0.59 0.69 0.59 0.70 Median 0.0 -0.6 0.1 -0.4 Min. 0.0 -3.6 0.0 -4.0 Max. 4.0 1.4 3.7 1.9

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.30 Statistical Analysis of Mean Change in Night-time Symptom Scores (Weeks 1-24)

Number of subjects 686 691 Baseline raw mean (sd) 1.0 (0.68) 0.9 (0.69) Raw mean (sd) 0.4 (0.56) 0.4 (0.56) Adjusted mean (se) 0.4 (0.02) 0.4 (0.02) Adjusted mean change (se) [1] -0.6 (0.02) -0.5 (0.02)

SFC - FBC CONFIDENTIAL Difference (se) -0.02 (0.03) 95% CL -0.07, 0.03

284 p-value 0.383

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 night-time symptom score.

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.30 Statistical Analysis of Mean Change in Night-time Symptom Scores (Weeks 1-24)

Number of subjects 686 691 Baseline raw mean (sd) 1.0 (0.68) 0.9 (0.69) Raw mean (sd) 0.5 (0.59) 0.5 (0.58) Adjusted mean (se) 0.5 (0.02) 0.5 (0.02) Adjusted mean change (se) [1] -0.5 (0.02) -0.5 (0.02)

SFC - FBC CONFIDENTIAL Difference (se) -0.01 (0.03) 95% CL -0.06, 0.04

285 p-value 0.775

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 night-time symptom score.

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.30 Statistical Analysis of Mean Change in Night-time Symptom Scores (Weeks 1-24)

Number of subjects 648 660 Baseline raw mean (sd) 1.0 (0.68) 0.9 (0.69) Raw mean (sd) 0.4 (0.59) 0.4 (0.60) Adjusted mean (se) 0.4 (0.02) 0.4 (0.02) Adjusted mean change (se) [1] -0.6 (0.02) -0.5 (0.02)

SFC - FBC CONFIDENTIAL Difference (se) -0.05 (0.03) 95% CL -0.10, 0.01

286 p-value 0.087

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 night-time symptom score.

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.30 Statistical Analysis of Mean Change in Night-time Symptom Scores (Weeks 1-24)

Number of subjects 630 643 Baseline raw mean (sd) 1.0 (0.68) 0.9 (0.69) Raw mean (sd) 0.4 (0.59) 0.4 (0.59) Adjusted mean (se) 0.3 (0.02) 0.4 (0.02) Adjusted mean change (se) [1] -0.6 (0.02) -0.6 (0.02)

SFC - FBC CONFIDENTIAL Difference (se) -0.05 (0.03) 95% CL -0.11, 0.00

287 p-value 0.061

GM2004/00056/00

[1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline SAM40040 night-time symptom score.

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.31 Summary of Percentage of Symptom-Free Days (Weeks 1-24)

Run-in (baseline) n 694 695 Mean 8.2 7.3 SD 16.98 16.32 Median 0.0 0.0 Min. 0 0

Max. 100 100 CONFIDENTIAL

Weeks 1-24 n 685 685 692 690

288 Mean 52.4 44.2 52.0 44.7 SD 38.99 38.03 38.53 37.57 Median 63.0 46.0 60.0 43.0 Min. 0 -99 0 -75 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.31 Summary of Percentage of Symptom-Free Days (Weeks 1-24)

Weeks 1-8 n 685 685 692 690 Mean 45.8 37.6 45.8 38.5 SD 38.29 36.95 38.33 37.06 Median 46.0 32.0 45.0 31.0 Min. 0 -98 0 -84

Max. 100 100 100 100 CONFIDENTIAL

Weeks 9-16 n 644 644 659 658

289 Mean 56.0 48.0 54.6 47.7 SD 41.91 41.03 41.87 40.83 Median 71.0 52.0 64.0 48.5 Min. 0 -100 0 -77 Max. 100 100 100 100

Weeks 17-24 n 626 626 642 641 Mean 57.8 50.0 56.4 49.7 SD 42.92 42.07 42.22 41.30 Median 77.0 57.0 71.0 55.0 Min. 0 -100 0 -65 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.32 Statistical Analysis of Percentage of Symptom-Free Days (Weeks 1-24)

Number of subjects 685 692 Median 63.0 60.0

Frequency Distribution of Symptom-Free Days (%) 0% - <=25% 236 (34%) 235 (34%) >25% - <=50% 67 (10%) 88 (13%)

>50% - <=75% 109 (16%) 89 (13%) CONFIDENTIAL >75% - <=100% 273 (40%) 280 (40%)

290 SFC / FBC [1] Odds Ratio 1.03 95% CL 0.84, 1.25 p-value 0.800

GM2004/00056/00

SAM40040 [1]: Logistic regression (proportional odds) adjusted for gender, country grouping and age

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.33 Summary of Percentage of Symptom-Free Nights (Weeks 1-24)

Run-in (baseline) n 694 696 Mean 31.5 35.0 SD 35.77 37.64 Median 14.0 25.0 Min. 0 0

Max. 100 100 CONFIDENTIAL

Weeks 1-24 n 686 686 692 691

291 Mean 68.0 36.7 67.2 32.2 SD 35.91 38.75 36.71 40.14 Median 85.0 33.0 86.0 27.0 Min. 0 -83 0 -99 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.33 Summary of Percentage of Symptom-Free Nights (Weeks 1-24)

Weeks 1-8 n 686 686 692 691 Mean 63.2 31.8 63.6 28.5 SD 37.06 37.58 37.59 39.05 Median 78.0 25.0 80.0 22.0 Min. 0 -100 0 -98

Max. 100 100 100 100 CONFIDENTIAL

Weeks 9-16 n 645 645 660 659

292 Mean 70.9 39.6 68.4 33.6 SD 38.01 41.50 39.00 42.55 Median 93.0 38.0 89.0 27.0 Min. 0 -100 0 -100 Max. 100 100 100 100

Weeks 17-24 n 626 626 642 641 Mean 73.2 41.8 69.2 35.0 SD 37.77 42.50 39.36 43.43 Median 96.0 43.0 94.0 29.0 Min. 0 -100 0 -100 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.34 Statistical Analysis of Percentage of Symptom-Free Nights (Weeks 1-24)

Number of subjects 686 692 Median 85.0 86.0

Frequency Distribution of Symptom-Free Nights (%) 0% - <=25% 134 (20%) 148 (21%) >25% - <=50% 49 ( 7%) 54 ( 8%)

>50% - <=75% 102 (15%) 88 (13%) CONFIDENTIAL >75% - <=100% 401 (58%) 402 (58%)

293 SFC / FBC [1] Odds Ratio 0.97 95% CL 0.78, 1.19 p-value 0.758

GM2004/00056/00

SAM40040 [1]: Logistic regression (proportional odds) adjusted for gender, country grouping and age

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.35 Summary of Percentage of Days with No Relief Medication (Weeks 1-24)

Run-in (baseline) n 693 694 Mean 25.7 24.6 SD 36.08 35.34 Median 0.0 0.0 Min. 0 0

Max. 100 100 CONFIDENTIAL

Weeks 1-24 n 686 685 690 688

294 Mean 66.4 40.6 64.8 40.3 SD 36.69 38.97 36.27 39.15 Median 82.0 38.0 81.0 37.5 Min. 0 -99 0 -100 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.35 Summary of Percentage of Days with No Relief Medication (Weeks 1-24)

Weeks 1-8 n 685 684 689 687 Mean 61.9 36.1 59.6 35.0 SD 37.57 37.98 38.09 38.66 Median 76.0 30.5 73.0 29.0 Min. 0 -98 0 -100

Max. 100 100 100 100 CONFIDENTIAL

Weeks 9-16 n 644 644 656 655

295 Mean 69.1 43.6 67.2 43.1 SD 38.80 41.55 38.50 41.96 Median 91.0 41.0 89.0 41.0 Min. 0 -100 0 -100 Max. 100 100 100 100

Weeks 17-24 n 625 625 641 640 Mean 70.3 44.7 69.0 44.9 SD 38.08 41.44 37.72 42.35 Median 93.0 43.0 91.0 43.0 Min. 0 -100 0 -100 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.36 Statistical Analysis of Percentage of Days with No Relief Medication (Weeks 1-24)

Number of subjects 686 690 Median 82.0 81.0

Frequency Distribution of Rescue-Free Days (%) 0% - <=25% 149 (22%) 149 (22%) >25% - <=50% 51 ( 7%) 77 (11%)

>50% - <=75% 98 (14%) 87 (13%) CONFIDENTIAL >75% - <=100% 388 (57%) 377 (55%)

296 SFC / FBC [1] Odds Ratio 0.95 95% CL 0.77, 1.17 p-value 0.620

GM2004/00056/00

SAM40040 [1]: Logistic regression (proportional odds) adjusted for gender, country grouping and age

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.37 Summary of Percentage of Nights with No Relief Medication (Weeks 1-24)

Run-in (baseline) n 693 694 Mean 50.7 52.3 SD 40.86 40.84 Median 57.0 57.0 Min. 0 0

Max. 100 100 CONFIDENTIAL

Weeks 1-24 n 684 684 690 689

297 Mean 80.4 29.4 78.7 26.4 SD 29.50 38.05 30.66 39.94 Median 95.0 17.5 95.0 15.0 Min. 0 -100 0 -100 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.37 Summary of Percentage of Nights with No Relief Medication (Weeks 1-24)

Weeks 1-8 n 684 684 689 688 Mean 77.1 26.2 75.1 22.8 SD 31.35 36.43 33.41 39.27 Median 93.0 13.5 93.0 12.0 Min. 0 -100 0 -100

Max. 100 100 100 100 CONFIDENTIAL

Weeks 9-16 n 644 644 655 654

298 Mean 82.5 31.8 80.2 28.2 SD 30.63 40.24 31.73 41.97 Median 98.0 21.5 98.0 15.0 Min. 0 -100 0 -100 Max. 100 100 100 100

Weeks 17-24 n 624 624 640 639 Mean 83.3 32.5 81.8 30.4 SD 30.39 40.67 31.15 42.08 Median 100.0 19.0 100.0 16.0 Min. 0 -100 0 -100 Max. 100 100 100 100

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.38 Statistical Analysis of Percentage of Nights with No Relief Medication (Weeks 1-24)

Number of subjects 684 690 Median 95.0 95.0

Frequency Distribution of Rescue-Free Nights (%) 0% - <=25% 67 (10%) 79 (11%) >25% - <=50% 33 ( 5%) 39 ( 6%)

>50% - <=75% 75 (11%) 67 (10%) CONFIDENTIAL >75% - <=100% 509 (74%) 505 (73%)

299 SFC / FBC [1] Odds Ratio 0.92 95% CL 0.73, 1.17 p-value 0.512

GM2004/00056/00

SAM40040 [1]: Logistic regression (proportional odds) adjusted for gender, country grouping and age

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.39 Summary of Mean Daily Ventolin Use

SFC 50/250 FBC 4.5/160 Time Period (N=694) (N=697) ——————————————————————————————————————————————————————————————————————————

Run-in (baseline) n 693 694 Mean 2.28 2.34 SD 1.80 1.83 Median 2.0 2.0 Min 0.0 0.0 Max 10.7 12.6

Weeks 1-24 n 684 688 CONFIDENTIAL Mean 0.90 0.94 SD 1.30 1.34

300 Median 0.3 0.4 Min 0.0 0.0 Max 8.9 13.1

p-value [1] 0.321

Weeks 1-8 n 684 686 Mean 1.01 1.09 SD 1.33 1.47 Median 0.4 0.5 Min 0.0 0.0 Max 9.3 14.6

GM2004/00056/00 p-value [1] 0.365

SAM40040 [1]: Derived from Wilcoxon Rank Sum Test

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.39 Summary of Mean Daily Ventolin Use

Weeks 9-16 n 643 653 Mean 0.82 0.89 SD 1.34 1.45 Median 0.2 0.2 Min 0.0 0.0 Max 8.6 13.9

p-value [1] 0.239 CONFIDENTIAL

Weeks 17-24 n 624 640

301 Mean 0.80 0.82 SD 1.38 1.33 Median 0.2 0.2 Min 0.0 0.0 Max 11.9 11.1

p-value [1] 0.424

GM2004/00056/00

SAM40040 [1]: Derived from Wilcoxon Rank Sum Test

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.40 Summary and Analysis of the Number of Withdrawals Due to Lack of Efficacy

N 694 697 Yes 5 (<1%) 2 (<1%) No 689 (>99%) 695 (>99%)

SFC - FBC Difference in % (se) 0.4% (0.38%) 95% CI -0.3%, 1.2%

p-value [1] 0.287 CONFIDENTIAL

302

GM2004/00056/00

SAM40040 [1]: Based on Fisher’s Exact 2-sided test

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.41 Summary and Analysis of the Proportion of Subjects with Well-Controlled Asthma

Well Controlled [1] 483 (70%) 486 (70%) Not Well Controlled 211 (30%) 211 (30%)

SFC - FBC -0.1% (2.47%) Difference (se) -5.0%, 4.7% p-value [2] 1.000

CONFIDENTIAL

303

GM2004/00056/00

[1]: A subject is classified as well-controlled if they achieve well-controlled status

at any point during the treatment period. SAM40040 [2]: Derived from Fisher’s Exact Test

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.42 Summary of Number of Weeks With Well-Controlled Asthma

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ——————————————————————————————————————————————————————————————————

Weeks 1-24 n 686 692 Mean 10.2 9.6 SD 9.2 9.1 Median 9.0 7.0 Min. 0 0 Max. 24 24

p-value [1] 0.3905 CONFIDENTIAL

304

GM2004/00056/00

SAM40040 [1]: Derived from Wilcoxon Rank Sum Test

Page 1 of 1 Protocol: SAM40040 Population: Intent-to-Treat Table 13.43 Summary of Asthma Control Questionnaire (ACQ)

SFC 50/250 FBC 4.5/160 (N=694) (N=697) —————————————————————————————————————————————————————————————————— Week 4

Mean Total Score n 664 666 Mean 1.26 1.26 SD 0.88 0.84 Median 1.14 1.14 Min. 0.0 0.0 Max. 5.3 4.7

CONFIDENTIAL Distribution =>0 - <1 283 (43%) 269 (40%) =>1 - <2 247 (37%) 257 (39%)

305 =>2 - <3 105 (16%) 112 (17%) =>3 - <4 23 (3%) 25 (4%) =>4 - <5 4 (<1%) 3 (<1%) =>5 - <6 2 (<1%) 0 6 0 0

GM2004/00056/00

SAM40040

Page 1 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.43 Summary of Asthma Control Questionnaire (ACQ)

SFC 50/250 FBC 4.5/160 (N=694) (N=697) —————————————————————————————————————————————————————————————————— Week 8

Mean Total Score n 643 658 Mean 1.12 1.13 SD 0.85 0.88 Median 1.00 1.00 Min. 0.0 0.0 Max. 4.6 4.6

CONFIDENTIAL Distribution =>0 - <1 308 (48%) 321 (49%) =>1 - <2 226 (35%) 216 (33%)

306 =>2 - <3 87 (14%) 92 (14%) =>3 - <4 17 (3%) 26 (4%) =>4 - <5 5 (<1%) 3 (<1%) =>5 - <6 0 0 6 0 0

GM2004/00056/00

SAM40040

Page 2 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.43 Summary of Asthma Control Questionnaire (ACQ)

SFC 50/250 FBC 4.5/160 (N=694) (N=697) —————————————————————————————————————————————————————————————————— Week 16

Mean Total Score n 626 637 Mean 1.06 1.06 SD 0.87 0.87 Median 0.86 0.86 Min. 0.0 0.0 Max. 4.7 4.7

CONFIDENTIAL Distribution =>0 - <1 331 (53%) 327 (51%) =>1 - <2 202 (32%) 201 (32%)

307 =>2 - <3 69 (11%) 87 (14%) =>3 - <4 20 (3%) 19 (3%) =>4 - <5 4 (<1%) 3 (<1%) =>5 - <6 0 0 6 0 0

GM2004/00056/00

SAM40040

Page 3 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.43 Summary of Asthma Control Questionnaire (ACQ)

SFC 50/250 FBC 4.5/160 (N=694) (N=697) —————————————————————————————————————————————————————————————————— Week 24

Mean Total Score n 615 629 Mean 1.02 1.03 SD 0.85 0.86 Median 0.86 0.86 Min. 0.0 0.0 Max. 4.3 4.7

CONFIDENTIAL Distribution =>0 - <1 338 (55%) 340 (54%) =>1 - <2 188 (31%) 194 (31%)

308 =>2 - <3 69 (11%) 75 (12%) =>3 - <4 17 (3%) 17 (3%) =>4 - <5 3 (<1%) 3 (<1%) =>5 - <6 0 0 6 0 0

GM2004/00056/00

SAM40040

Page 4 of 4 Protocol: SAM40040 Population: Intent-to-Treat Table 13.44 Summary of Asthma Control Questionnaire: Raw Values and Change from Baseline

SFC 50/250 FBC 4.5/160 (N=694) (N=697) —————————————————————— —————————————————————— Time Period Raw Change Raw Change ————————————————————————————————————————————————————————————————————————

Baseline n 689 691 Mean 2.07 2.05 SD 0.84 0.86 Median 2.00 2.00 Min. 0.0 0.0

Max. 4.9 4.9 CONFIDENTIAL

Week 4 n 664 660 666 661

309 Mean 1.26 -0.82 1.26 -0.79 SD 0.88 0.86 0.84 0.86 Median 1.14 -0.71 1.14 -0.71 Min. 0.0 -3.7 0.0 -4.1 Max. 5.3 2.3 4.7 2.0

Week 8 n 643 638 658 653 Mean 1.12 -0.96 1.13 -0.92 SD 0.85 0.87 0.88 0.91 Median 1.00 -0.86 1.00 -0.86 Min. 0.0 -3.4 0.0 -4.1 Max. 4.6 2.9 4.6 1.6

GM2004/00056/00

SAM40040

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.44 Summary of Asthma Control Questionnaire: Raw Values and Change from Baseline

Week 16 n 626 621 637 633 Mean 1.06 -1.01 1.06 -1.00 SD 0.87 0.86 0.87 0.92 Median 0.86 -1.00 0.86 -0.86 Min. 0.0 -3.7 0.0 -4.1

Max. 4.7 2.4 4.7 2.3 CONFIDENTIAL

Week 24 n 615 610 629 625

310 Mean 1.02 -1.04 1.03 -1.03 SD 0.85 0.87 0.86 0.92 Median 0.86 -1.00 0.86 -1.00 Min. 0.0 -3.6 0.0 -4.1 Max. 4.3 1.4 4.7 1.7

GM2004/00056/00

SAM40040

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 13.45 Statistical Analysis of Mean Change in Asthma Control Questionnaire Score (Week 24)

Number of subjects 610 625 Baseline raw mean (SD) 2.06 (0.832) 2.06 (0.869) Raw mean (SD) 1.02 (0.847) 1.03 (0.857) Adjusted mean (SE) 1.00 (0.031) 1.01 (0.031) Adjusted mean change (SE) [1] -1.06 (0.031) -1.05 (0.031)

SFC - FBC

Difference -0.01 (0.042) CONFIDENTIAL 95% CL -0.09, 0.07 p-value 0.829

311

GM2004/00056/00

SAM40040 [1]: ANCOVA adjusted for main effects of gender, country grouping, age and baseline score.

Page 1 of 1 CONFIDENTIAL GM2004/00056/00 SAM40040

Safety Data Source Tables

Page Table 14.1 Summary of Unscheduled Asthma Related Healthcare Contacts During the Treatment Period ...... 313 Table 14.2 Summary of Time Missed from Work or Usual Activities During the Treatment Period ...... 315

312 Protocol: SAM40040 Population: Intent-to-Treat Table 14.1 Summary of Unscheduled Asthma Related Healthcare Contacts During the Treatment Period

SFC 50/250 FBC 4.5/160 Contact method (N=694) (N=697) ——————————————————————————————————————————————————————————————————————————————

Telephone Number of units consumed 37 52 Number of subjects 32 41 Rate per 10000 [1] 3.3 4.6

Home/Day Number of units consumed 6 4 Number of subjects 4 3 Rate per 10000 [1] 0.5 0.4

CONFIDENTIAL Home/Night Number of units consumed 0 0 Number of subjects 0 0

313 Rate per 10000 [1] 0.0 0.0

Office/Practice Number of units consumed 55 50 Number of subjects 37 38 Rate per 10000 [1] 5.0 4.4

Outpatients Clinic Number of units consumed 28 29 Number of subjects 17 21 Rate per 10000 [1] 2.5 2.6

Emergency Room/A&E Dept. Number of units consumed 8 10 Number of subjects 6 9

Rate per 10000 [1] 0.7 0.9 GM2004/00056/00

[1]: Rate per 10000: SAM40040 Rate of contact per treatment days=(No of Units/Length of Treatment)*10000

Page 1 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 14.1 Summary of Unscheduled Asthma Related Healthcare Contacts During the Treatment Period

Hospital ICU Number of units consumed 7 0 Number of subjects 2 0 Rate per 10000 [1] 0.6 0.0

Hospital Gen. Ward Number of units consumed 16 4 Number of subjects 4 1 Rate per 10000 [1] 1.4 0.4

CONFIDENTIAL No. of Hospitalisations Number of hospitalisations 5 1 Number of subjects 5 1

314 Rate per 10000 [1] 0.5 0.1

GM2004/00056/00

[1]: Rate per 10000: SAM40040 Rate of contact per treatment days=(No of Units/Length of Treatment)*10000

Page 2 of 2 Protocol: SAM40040 Population: Intent-to-Treat Table 14.2 Summary of Time Missed from Work or Usual Activities During the Treatment Period

SFC 50/250 FBC 4.5/160 Weeks 1-24 (N=694) (N=697) ———————————————————————————————————————————————————————————————————————————————————

No. of days lost / No. of subjects in each category Days with no time off 89302 / 635 90180 / 637 Half days lost 3098 / 203 3985 / 211 Complete days lost 1149 / 88 979 / 96 Total days lost [1] 2698 / 645 2971.5 / 647 Days unknown 17418 / 655 17614 / 658

Number of Days Missed from Work CONFIDENTIAL n 645 647 median 0.0 0.0

315 mean 4.2 4.6 sd 15.58 15.27 min 0.0 0.0 max 136.0 142.0

Percentage of Days with No Time off Work [2] n 694 697 median 95.6 95.9 mean 79.0 78.7 sd 32.72 32.75 min 0.0 0.0 max 100.0 100.0

GM2004/00056/00

[1]: Total days lost = 0.5 * (total half days lost) + (total complete days lost) [2]: The denominator in the calculation of percentage of days with no time off is the

study duration for each subject. Unknown days are included and not classified SAM40040 as ’no time off’.

Page 1 of 1 CONFIDENTIAL GM2004/00056/00 SAM40040

Safety Data Source Tables

Page Table 15.1 Summary of Exposure to Study Medication ...... 317 Table 15.2 Overall Summary of Adverse Events...... 318 Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment) ...... 319 Table 15.4 Summary of All Adverse Events (Starting During Treatment) . . . . 325 Table 15.5 Summary of All Adverse Events (Started Post-Treatment) ...... 338 Table 15.6 Summary of Drug-Related Adverse Events ...... 341 Table 15.7 Summary of Serious Adverse Events ...... 346 Table 15.8 Summary of Adverse Events Leading to Withdrawal ...... 349 Table 15.9 Summary of the Most Common Adverse Events During Treatment ...... 352

316 Protocol: SAM40040 Population: Intent-to-Treat Table 15.1 Summary of Exposure to Study Medication

SFC 50/250 FBC 4.5/160 (N=694) (N=697) ———————————————————————————————————————————————————————————————————————————————————

Treatment Exposure (Days) [1] n 694 697 Mean 159.9 161.8 SD 35.9 33.5 Median 169.0 169.0 Min. 4 5 Max. 216 217

Range of Exposure n 694 697 CONFIDENTIAL <=14 days 6 (<1%) 6 (<1%) 15-28 days 6 (<1%) 8 (1%)

317 29-56 days 24 (3%) 18 (3%) 57-112 days 24 (3%) 15 (2%) 113-168 days 242 (35%) 261 (37%) >168 days 392 (56%) 389 (56%)

GM2004/00056/00

SAM40040 [1]: Calculated as ((date treatment stopped - date treatment started) + 1) days

Page 1 of 1 Protocol: SAM40040 Population: Safety Table 15.2 Overall Summary of Adverse Events

SFC 50/250 FBC 4.5/160 (N=697) (N=700) n % events n % events ————————————————————————————————————————————————————————————————————————————————————

Number of subjects with an adverse event 400 (57%) 1562 395 (56%) 1312

Number of subjects with a serious 20 (3%) 29 12 (2%) 13 adverse event

Number of subjects with a drug-related 58 (8%) 111 61 (9%) 124 CONFIDENTIAL adverse event

318 Number of subjects with an adverse 14 (2%) 21 10 (1%) 11 event leading to withdrawal

Number of subjects with a serious 3 (<1%) 6 1 (<1%) 1 adverse event leading to withdrawal

Number of subjects with an ongoing 54 (8%) 62 69 (10%) 96 adverse event at the end of study/withdrawal

GM2004/00056/00

SAM40040

Page 1 of 1 Protocol: SAM40040 Population: Safety Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment)

BODY SYSTEM SFC 50/250 FBC 4.5/160 Event (N=697) (N=700) ——————————————————————————————————————————————————————————————————————————————————————————

ANY EVENT 101 (14%) 111 (16%)

NEUROLOGY Any event 49 (7%) 47 (7%) Headaches 46 (7%) 43 (6%) Migraines 3 (<1%) 0 Allergic neurological 0 1 (<1%)

disorders CONFIDENTIAL Disturbances of sense of 0 1 (<1%) smell

319 Dizziness 0 1 (<1%) Neuralgia 0 1 (<1%) Vertigo 0 1 (<1%)

EAR NOSE & THROAT Any event 23 (3%) 35 (5%) Upper respiratory tract 7 (1%) 18 (3%) infection (URTI) Rhinitis 4 (<1%) 6 (<1%) Throat irritation 3 (<1%) 4 (<1%) Epistaxis 0 3 (<1%) Nasal congestion/blockage 1 (<1%) 1 (<1%)

Sinusitis 2 (<1%) 0 GM2004/00056/00 Upper respiratory 1 (<1%) 1 (<1%) inflammation Viral ear nose & throat 1 (<1%) 1 (<1%)

infections SAM40040 EAR NOSE & THROAT continues ...

Page 1 of 6 Protocol: SAM40040 Population: Safety Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment)

... continuing EAR NOSE & THROAT Ear signs & symptoms 0 1 (<1%) Ear,nose & throat 1 (<1%) 0 infections External otitis 1 (<1%) 0 Hearing loss 0 1 (<1%) Hoarseness/dysphonia 0 1 (<1%)

Laryngitis 1 (<1%) 0 CONFIDENTIAL Otitis 1 (<1%) 0 Pharyngitis/throat 1 (<1%) 0

320 infection Rhinorrhea/post nasal drip 1 (<1%) 0

GASTROINTESTINAL Any event 14 (2%) 20 (3%) Dental discomfort & pain 4 (<1%) 4 (<1%) Diarrhea 1 (<1%) 4 (<1%) Gastrointestinal 3 (<1%) 2 (<1%) discomfort & pain Abdominal discomfort & 1 (<1%) 2 (<1%) pain Nausea & vomiting 2 (<1%) 1 (<1%)

Candidiasis mouth/throat 0 2 (<1%) GM2004/00056/00 Gastric ulcers 1 (<1%) 1 (<1%) Gastroenteritis 0 2 (<1%) Dyspeptic symptoms 1 (<1%) 0

GASTROINTESTINAL continues ... SAM40040

Page 2 of 6 Protocol: SAM40040 Population: Safety Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment)

... continuing GASTROINTESTINAL Gastrointestinal 0 1 (<1%) hemorrhage Gastrointestinal 0 1 (<1%) infections Gastrointestinal signs & 1 (<1%) 0 symptoms

Oral discomfort & pain 0 1 (<1%) CONFIDENTIAL

MUSCULOSKELETAL

321 Any event 7 (1%) 13 (2%) Musculoskeletal pain 3 (<1%) 6 (<1%) Muscle pain 4 (<1%) 1 (<1%) Arthralgia & articular 0 4 (<1%) rheumatism Bone & skeletal pain 0 1 (<1%) Degenerative arthritis 0 1 (<1%) Musculoskeletal 0 1 (<1%) inflammation

LOWER RESPIRATORY Any event 10 (1%) 7 (1%)

Breathing disorders 3 (<1%) 2 (<1%) GM2004/00056/00 Cough 3 (<1%) 1 (<1%) Viral respiratory 3 (<1%) 1 (<1%) infections

LOWER RESPIRATORY continues ... SAM40040

Page 3 of 6 Protocol: SAM40040 Population: Safety Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment)

... continuing LOWER RESPIRATORY Lower respiratory 0 3 (<1%) infections Asthma 1 (<1%) 0

NON-SITE SPECIFIC Any event 7 (1%) 9 (1%)

Fever 0 4 (<1%) CONFIDENTIAL Pain 1 (<1%) 2 (<1%) Chest symptoms 2 (<1%) 0

322 Edema & swelling 2 (<1%) 0 Viral infections 1 (<1%) 1 (<1%) Allergies & allergic 0 1 (<1%) reactions Cramps 1 (<1%) 0 Inflammation 0 1 (<1%) Malaise & fatigue 0 1 (<1%) Non-specific conditions 1 (<1%) 0

CARDIOVASCULAR Any event 3 (<1%) 6 (<1%) Angina pectoris 1 (<1%) 2 (<1%)

Arrhythmias 0 1 (<1%) GM2004/00056/00 Flushing 1 (<1%) 0 Hypertension 0 1 (<1%) Impaired peripheral 1 (<1%) 0

circulation SAM40040 CARDIOVASCULAR continues ...

Page 4 of 6 Protocol: SAM40040 Population: Safety Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment)

... continuing CARDIOVASCULAR Shock 0 1 (<1%) Tachycardia 0 1 (<1%)

SKIN Any event 5 (<1%) 3 (<1%) Skin rashes 1 (<1%) 1 (<1%)

Acne & folliculitis 0 1 (<1%) CONFIDENTIAL Dermatitis & dermatosis 1 (<1%) 0 Fungal skin infections 1 (<1%) 0

323 Photodermatitis 0 1 (<1%) Pruritus 1 (<1%) 0 Skin infections 1 (<1%) 0

DRUG INTERACTION OVERDOSE & TRAUMA Any event 3 (<1%) 1 (<1%) Contusions & hematomas 1 (<1%) 1 (<1%) Ligament tendon or 2 (<1%) 0 cartilage injuries

EYE

Any event 3 (<1%) 0 GM2004/00056/00 Keratitis & conjunctivitis 2 (<1%) 0 Eye infections 1 (<1%) 0

SAM40040

Page 5 of 6 Protocol: SAM40040 Population: Safety Table 15.3 Summary of All Adverse Events (Starting Pre-Treatment)

PSYCHIATRY Any event 2 (<1%) 1 (<1%) Anxiety 0 1 (<1%) Depressive disorders 1 (<1%) 0 Intoxication & hangover 1 (<1%) 0

UROLOGY

Any event 0 2 (<1%) CONFIDENTIAL Bladder inflammation 0 2 (<1%)

324 HEPATOBILIARY TRACT & PANCREAS Any event 0 1 (<1%) Cholangitis 0 1 (<1%) Hepatobiliary symptoms 0 1 (<1%)

REPRODUCTION Any event 0 1 (<1%) Fungal reproductive 0 1 (<1%) infections

GM2004/00056/00

SAM40040

Page 6 of 6 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

ANY EVENT 384 (55%) 377 (54%)

EAR NOSE & THROAT Any event 203 (29%) 181 (26%) Upper respiratory tract 101 (14%) 94 (13%) infection (URTI) Rhinitis 45 (6%) 34 (5%)

Throat irritation 32 (5%) 23 (3%) CONFIDENTIAL Hoarseness/dysphonia 17 (2%) 16 (2%) Pharyngitis/throat 12 (2%) 10 (1%)

325 infection Sinusitis 10 (1%) 10 (1%) Ear,nose & throat 9 (1%) 5 (<1%) infections Tonsillitis 5 (<1%) 5 (<1%) Laryngitis 7 (1%) 2 (<1%) Upper respiratory 6 (<1%) 3 (<1%) inflammation Rhinorrhea/post nasal drip 6 (<1%) 2 (<1%) Ear signs & symptoms 3 (<1%) 2 (<1%) Ear nose & throat polyps 1 (<1%) 2 (<1%) Nasal congestion/blockage 1 (<1%) 2 (<1%)

Otitis 0 3 (<1%) GM2004/00056/00 Fungal infection mouth & 1 (<1%) 1 (<1%) throat Sneezing 0 2 (<1%)

EAR NOSE & THROAT continues ... SAM40040

Page 1 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing EAR NOSE & THROAT Viral ear nose & throat 1 (<1%) 1 (<1%) infections Epistaxis 0 1 (<1%) Hearing loss 0 1 (<1%) Labyrinthitis 0 1 (<1%) Larynx signs & symptoms 1 (<1%) 0

Mastoiditis & eustachian 1 (<1%) 0 CONFIDENTIAL salpingitis Nasal sinus disorders 0 1 (<1%)

326 Sinusitis/sinus infection 1 (<1%) 0 Throat & tonsil signs & 0 1 (<1%) symptoms Vocal cord disorders 0 1 (<1%)

NEUROLOGY Any event 114 (16%) 112 (16%) Headaches 101 (14%) 95 (14%) Sleep disorders 6 (<1%) 3 (<1%) Dizziness 4 (<1%) 4 (<1%) Tremors 0 8 (1%) Vertigo 6 (<1%) 2 (<1%)

Migraines 4 (<1%) 2 (<1%) GM2004/00056/00 Disorders of equilibrium 2 (<1%) 1 (<1%) Convulsions 0 2 (<1%) Compressed nerve syndromes 0 1 (<1%)

Decreased consciousness 0 1 (<1%) SAM40040 NEUROLOGY continues ...

Page 2 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing NEUROLOGY Disturbances of sense of 0 1 (<1%) taste Hypnagogic effects 1 (<1%) 0 Memory effects 1 (<1%) 0 Neuralgia 1 (<1%) 0

LOWER RESPIRATORY CONFIDENTIAL Any event 108 (15%) 96 (14%) Lower respiratory 33 (5%) 34 (5%)

327 infections Viral respiratory 27 (4%) 29 (4%) infections Cough 25 (4%) 22 (3%) Bronchitis 17 (2%) 15 (2%) Breathing disorders 6 (<1%) 3 (<1%) Pneumonia 3 (<1%) 4 (<1%) Asthma 5 (<1%) 1 (<1%) Chest sounds 1 (<1%) 3 (<1%) Sputum abnormalities 2 (<1%) 2 (<1%) Airways constriction & 1 (<1%) 0 obstruction

Allergic lower respiratory 1 (<1%) 0 GM2004/00056/00 disorders Lower respiratory 0 1 (<1%) hemorrhage

LOWER RESPIRATORY continues ... SAM40040

Page 3 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing LOWER RESPIRATORY Lower respiratory signs & 1 (<1%) 0 symptoms Lung disorders 0 1 (<1%)

GASTROINTESTINAL Any event 102 (15%) 76 (11%)

Dental discomfort & pain 16 (2%) 12 (2%) CONFIDENTIAL Candidiasis mouth/throat 16 (2%) 10 (1%) Diarrhea 10 (1%) 15 (2%)

328 Abdominal discomfort & 11 (2%) 6 (<1%) pain Gastrointestinal 11 (2%) 4 (<1%) discomfort & pain Nausea & vomiting 12 (2%) 3 (<1%) Gastroenteritis 9 (1%) 5 (<1%) Dyspeptic symptoms 5 (<1%) 4 (<1%) Gastrointestinal 5 (<1%) 4 (<1%) infections Gastritis 6 (<1%) 2 (<1%) Hyposalivation 4 (<1%) 2 (<1%) Dental & gum inflammation 3 (<1%) 2 (<1%)

Oral ulcerations 1 (<1%) 4 (<1%) GM2004/00056/00 Viral gastrointestinal 3 (<1%) 2 (<1%) infections Swallowing disorders 3 (<1%) 1 (<1%)

Enteritis 2 (<1%) 1 (<1%) SAM40040 GASTROINTESTINAL continues ...

Page 4 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing GASTROINTESTINAL Regurgitation & reflux 1 (<1%) 2 (<1%) Bacterial gastrointestinal 0 2 (<1%) infections Gastric ulcers 1 (<1%) 1 (<1%) Gastrointestinal 1 (<1%) 1 (<1%) hemorrhage

Gastrointestinal herniae 1 (<1%) 1 (<1%) CONFIDENTIAL Gastrointestinal signs & 0 2 (<1%) symptoms

329 Inflammation of oral 2 (<1%) 0 mucosa Oral discomfort & pain 1 (<1%) 1 (<1%) Abdominal distention 1 (<1%) 0 Constipation 0 1 (<1%) Dental operations 1 (<1%) 0 Diverticulosis 1 (<1%) 0 Esophagitis 0 1 (<1%) Fungal gastrointestinal 1 (<1%) 0 infections Gastrointestinal lesions 1 (<1%) 0 Gastrointestinal spasms 0 1 (<1%)

Gum signs & symptoms 1 (<1%) 0 GM2004/00056/00 Oral hemorrhage 0 1 (<1%) Salivary gland 1 (<1%) 0 inflammation

SAM40040

Page 5 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

MUSCULOSKELETAL Any event 75 (11%) 72 (10%) Musculoskeletal pain 27 (4%) 40 (6%) Arthralgia & articular 16 (2%) 12 (2%) rheumatism Muscle pain 11 (2%) 6 (<1%) Muscle cramps & spasms 4 (<1%) 6 (<1%)

Musculoskeletal 6 (<1%) 3 (<1%) CONFIDENTIAL inflammation Bone & skeletal pain 4 (<1%) 4 (<1%)

330 Arthritis 3 (<1%) 3 (<1%) Degenerative arthritis 2 (<1%) 3 (<1%) Bone & cartilage disorders 1 (<1%) 1 (<1%) Musculoskeletal disorders 2 (<1%) 0 Spinal arthritis 1 (<1%) 1 (<1%) Acquired musculoskeletal 1 (<1%) 0 deformities Joint edema swelling & 0 1 (<1%) effusion Joint stiffness tightness 1 (<1%) 0 & rigidity Muscle atrophy weakness & 1 (<1%) 0

tiredness GM2004/00056/00 Muscle stiffness tightness 0 1 (<1%) & rigidity MUSCULOSKELETAL continues ...

SAM40040

Page 6 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing MUSCULOSKELETAL Osteitis osteomyelitis 1 (<1%) 0 osteochondritis & chondritis

NON-SITE SPECIFIC Any event 57 (8%) 47 (7%)

Viral infections 11 (2%) 10 (1%) CONFIDENTIAL Fever 10 (1%) 9 (1%) Chest symptoms 10 (1%) 8 (1%)

331 Candidiasis unspecified 6 (<1%) 7 (1%) site Allergies & allergic 8 (1%) 3 (<1%) reactions Malaise & fatigue 6 (<1%) 3 (<1%) Infections 2 (<1%) 3 (<1%) Edema & swelling 2 (<1%) 2 (<1%) Non-specific conditions 2 (<1%) 2 (<1%) Allergic reaction to 3 (<1%) 0 animals Cramps 2 (<1%) 1 (<1%) Pain 2 (<1%) 1 (<1%)

Allergic reaction to 1 (<1%) 0 GM2004/00056/00 non-drug products Fluid retention 0 1 (<1%) Fungal infections 0 1 (<1%)

Procedures 0 1 (<1%) SAM40040 NON-SITE SPECIFIC continues ...

Page 7 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing NON-SITE SPECIFIC Spirochete & actinomycete 1 (<1%) 0 infections Unusual taste 0 1 (<1%)

SKIN Any event 28 (4%) 23 (3%)

Skin rashes 7 (1%) 2 (<1%) CONFIDENTIAL Eczema 3 (<1%) 5 (<1%) Pruritus 2 (<1%) 6 (<1%)

332 Acne & folliculitis 1 (<1%) 3 (<1%) Fungal skin infections 2 (<1%) 2 (<1%) Urticaria 2 (<1%) 1 (<1%) Viral skin infections 3 (<1%) 0 Allergic skin reactions 1 (<1%) 1 (<1%) Bacterial skin infections 1 (<1%) 1 (<1%) Ectoparasite infestations 1 (<1%) 1 (<1%) Rubelliform & 1 (<1%) 1 (<1%) scarlatiniform rashes Skin infections 2 (<1%) 0 Erythematous skin 1 (<1%) 0 conditions

Erythematous skin rashes 1 (<1%) 0 GM2004/00056/00 Lichenoid disorders 0 1 (<1%) Nail disorders 0 1 (<1%) Skin cysts lumps & masses 1 (<1%) 0

Sweating 0 1 (<1%) SAM40040

Page 8 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

DRUG INTERACTION OVERDOSE & TRAUMA Any event 26 (4%) 21 (3%) Fractures 7 (1%) 6 (<1%) Contusions & hematomas 8 (1%) 2 (<1%) Muscle injuries 3 (<1%) 3 (<1%) Soft tissue injuries 2 (<1%) 4 (<1%)

Injuries 3 (<1%) 1 (<1%) CONFIDENTIAL Postoperative 0 3 (<1%) complications

333 Wound 2 (<1%) 1 (<1%) Craniocerebral injuries 2 (<1%) 0 Dislocations 0 2 (<1%)

CARDIOVASCULAR Any event 18 (3%) 25 (4%) Angina pectoris 8 (1%) 6 (<1%) Hypertension 1 (<1%) 10 (1%) Impaired peripheral 1 (<1%) 2 (<1%) circulation Hypotension 1 (<1%) 1 (<1%) Palpitations 1 (<1%) 1 (<1%)

Tachycardia 1 (<1%) 1 (<1%) GM2004/00056/00 Thrombophlebitis 1 (<1%) 1 (<1%) Coronary artery disorders 0 1 (<1%) Disturbances of 0 1 (<1%)

intracranial blood flow SAM40040 CARDIOVASCULAR continues ...

Page 9 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing CARDIOVASCULAR Flushing 1 (<1%) 0 Heart murmurs 0 1 (<1%) Ischemic heart disease 0 1 (<1%) Myocardial infarction 1 (<1%) 0 Myocarditis 0 1 (<1%) Syncope 1 (<1%) 0

Tachyarrhythmias 1 (<1%) 0 CONFIDENTIAL Thrombosis 0 1 (<1%) Varicosities 1 (<1%) 0

334 REPRODUCTION Any event 13 (2%) 18 (3%) Menstruation symptoms 7 (1%) 3 (<1%) Fungal reproductive 2 (<1%) 5 (<1%) infections Cysts lumps & masses of 0 2 (<1%) female reproductive tract Female reproductive tract 1 (<1%) 1 (<1%) bleeding & hemorrhage Bacterial reproductive 0 1 (<1%) infections

Breast discomfort 0 1 (<1%) GM2004/00056/00 Breast pain 0 1 (<1%) Cysts lumps & masses of 0 1 (<1%) breast

Genital disorders 1 (<1%) 0 SAM40040 REPRODUCTION continues ...

Page 10 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing REPRODUCTION Inflammation of fallopian 0 1 (<1%) tube Inflammation of scrotum 0 1 (<1%) Menopause & post 0 1 (<1%) menopausal state Polyps of female 0 1 (<1%)

reproductive tract CONFIDENTIAL Prostate disorders 1 (<1%) 0 Reproductive infections 1 (<1%) 0

335 Sexual function disorders 0 1 (<1%)

EYE Any event 12 (2%) 12 (2%) Keratitis & conjunctivitis 7 (1%) 3 (<1%) Allergic eye disorders 1 (<1%) 4 (<1%) Bacterial eye infections 2 (<1%) 0 Eye pain & discomfort 1 (<1%) 1 (<1%) Cataracts 1 (<1%) 0 Eye edema & swelling 0 1 (<1%) Eye redness 0 1 (<1%) Ocular pressure disorders 0 1 (<1%)

Pupillary function 0 1 (<1%) GM2004/00056/00 disorders

SAM40040

Page 11 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

PSYCHIATRY Any event 11 (2%) 13 (2%) Anxiety 5 (<1%) 5 (<1%) Depressive disorders 4 (<1%) 6 (<1%) Situational disorders 1 (<1%) 2 (<1%) Agitation 0 1 (<1%) Neurotic disorders 1 (<1%) 0

CONFIDENTIAL UROLOGY Any event 12 (2%) 12 (2%)

336 Urinary infections 11 (2%) 6 (<1%) Bladder inflammation 1 (<1%) 2 (<1%) Renal signs & symptoms 0 2 (<1%) Urinary calculi 1 (<1%) 0 Urinary frequency 0 1 (<1%) Urinary tract hemorrhage 0 1 (<1%)

ENDOCRINE & METABOLIC Any event 7 (1%) 7 (1%) Hypothyroidism 1 (<1%) 2 (<1%) Diabetes mellitus 2 (<1%) 0 Disorders of iron 1 (<1%) 1 (<1%)

metabolism GM2004/00056/00 Appetite disturbances 1 (<1%) 0 Disorders of lipid 0 1 (<1%) metabolism

ENDOCRINE & METABOLIC continues ... SAM40040

Page 12 of 13 Protocol: SAM40040 Population: Safety Table 15.4 Summary of All Adverse Events (Starting During Treatment)

... continuing ENDOCRINE & METABOLIC Disorders of thirst/fluid 0 1 (<1%) intake Endocrine disorders 1 (<1%) 0 Hyperglycemia 0 1 (<1%) Hyperthyroidism 0 1 (<1%) Vitamin disorders 1 (<1%) 0

CONFIDENTIAL HEPATOBILIARY TRACT & PANCREAS Any event 3 (<1%) 0

337 Cholecystitis 2 (<1%) 0 Biliary tract disorders 1 (<1%) 0 Pancreatitis 1 (<1%) 0

BLOOD & LYMPHATIC Any event 1 (<1%) 1 (<1%) Deficiency anemia 0 1 (<1%) Lymphatic obstructions 1 (<1%) 0

GM2004/00056/00

SAM40040

Page 13 of 13 Protocol: SAM40040 Population: Safety Table 15.5 Summary of All Adverse Events (Started Post-Treatment)

ANY EVENT 16 (2%) 14 (2%)

EAR NOSE & THROAT Any event 5 (<1%) 5 (<1%) Rhinitis 1 (<1%) 2 (<1%) Upper respiratory tract 2 (<1%) 1 (<1%) infection (URTI)

Hoarseness/dysphonia 1 (<1%) 1 (<1%) CONFIDENTIAL Ear,nose & throat 1 (<1%) 0 infections

338 Pharyngitis/throat 0 1 (<1%) infection Throat irritation 1 (<1%) 0

LOWER RESPIRATORY Any event 4 (<1%) 1 (<1%) Breathing disorders 2 (<1%) 0 Cough 0 1 (<1%) Lower respiratory 1 (<1%) 0 infections Viral respiratory 1 (<1%) 0 infections

GM2004/00056/00

SAM40040

Page 1 of 3 Protocol: SAM40040 Population: Safety Table 15.5 Summary of All Adverse Events (Started Post-Treatment)

GASTROINTESTINAL Any event 1 (<1%) 3 (<1%) Diarrhea 0 2 (<1%) Dental discomfort & pain 1 (<1%) 0 Oral ulcerations 0 1 (<1%)

MUSCULOSKELETAL

Any event 0 3 (<1%) CONFIDENTIAL Musculoskeletal pain 0 2 (<1%) Muscle pain 0 1 (<1%)

339 CARDIOVASCULAR Any event 2 (<1%) 0 Angina pectoris 1 (<1%) 0 Flushing 1 (<1%) 0

EYE Any event 1 (<1%) 1 (<1%) Eye & eyelid cysts lumps & 1 (<1%) 0 masses Retinopathies 0 1 (<1%)

SKIN GM2004/00056/00 Any event 2 (<1%) 0 Nail disorders 1 (<1%) 0 Skin rashes 1 (<1%) 0

SAM40040

Page 2 of 3 Protocol: SAM40040 Population: Safety Table 15.5 Summary of All Adverse Events (Started Post-Treatment)

HEPATOBILIARY TRACT & PANCREAS Any event 1 (<1%) 0 Cholecystitis 1 (<1%) 0

NON-SITE SPECIFIC Any event 0 1 (<1%) Viral infections 0 1 (<1%)

CONFIDENTIAL PREGNANCY Any event 1 (<1%) 0

340 Abortion & stillbirth 1 (<1%) 0

PSYCHIATRY Any event 0 1 (<1%) Anxiety 0 1 (<1%)

GM2004/00056/00

SAM40040

Page 3 of 3 Protocol: SAM40040 Population: Safety Table 15.6 Summary of Drug-Related Adverse Events

ANY EVENT 58 (8%) 61 (9%)

EAR NOSE & THROAT Any event 20 (3%) 19 (3%) Hoarseness/dysphonia 13 (2%) 13 (2%) Throat irritation 1 (<1%) 4 (<1%) Laryngitis 2 (<1%) 1 (<1%)

Pharyngitis/throat 3 (<1%) 0 CONFIDENTIAL infection Fungal infection mouth & 1 (<1%) 1 (<1%)

341 throat Ear signs & symptoms 1 (<1%) 0 Ear,nose & throat 1 (<1%) 0 infections Sinusitis/sinus infection 1 (<1%) 0 Upper respiratory tract 0 1 (<1%) infection (URTI) Vocal cord disorders 0 1 (<1%)

GASTROINTESTINAL Any event 22 (3%) 12 (2%) Candidiasis mouth/throat 12 (2%) 7 (1%)

Hyposalivation 3 (<1%) 2 (<1%) GM2004/00056/00 Inflammation of oral 2 (<1%) 0 mucosa Swallowing disorders 2 (<1%) 0

GASTROINTESTINAL continues ... SAM40040

Page 1 of 5 Protocol: SAM40040 Population: Safety Table 15.6 Summary of Drug-Related Adverse Events

... continuing GASTROINTESTINAL Abdominal discomfort & 0 1 (<1%) pain Dyspeptic symptoms 0 1 (<1%) Fungal gastrointestinal 1 (<1%) 0 infections Gastritis 1 (<1%) 0

Gastrointestinal 1 (<1%) 0 CONFIDENTIAL discomfort & pain Gastrointestinal spasms 0 1 (<1%)

342 Nausea & vomiting 1 (<1%) 0 Oral ulcerations 0 1 (<1%)

NEUROLOGY Any event 11 (2%) 21 (3%) Headaches 9 (1%) 12 (2%) Tremors 0 8 (1%) Dizziness 1 (<1%) 1 (<1%) Convulsions 0 1 (<1%) Disorders of equilibrium 1 (<1%) 0 Disturbances of sense of 0 1 (<1%) taste

Migraines 1 (<1%) 0 GM2004/00056/00 Sleep disorders 0 1 (<1%)

SAM40040

Page 2 of 5 Protocol: SAM40040 Population: Safety Table 15.6 Summary of Drug-Related Adverse Events

NON-SITE SPECIFIC Any event 6 (<1%) 8 (1%) Candidiasis unspecified 6 (<1%) 6 (<1%) site Cramps 0 1 (<1%) Unusual taste 0 1 (<1%)

MUSCULOSKELETAL CONFIDENTIAL Any event 3 (<1%) 4 (<1%) Muscle cramps & spasms 2 (<1%) 3 (<1%)

343 Musculoskeletal pain 1 (<1%) 1 (<1%)

SKIN Any event 3 (<1%) 3 (<1%) Pruritus 1 (<1%) 2 (<1%) Eczema 1 (<1%) 1 (<1%) Skin rashes 1 (<1%) 1 (<1%)

CARDIOVASCULAR Any event 3 (<1%) 1 (<1%) Palpitations 1 (<1%) 1 (<1%) Angina pectoris 1 (<1%) 0

Tachycardia 1 (<1%) 0 GM2004/00056/00

SAM40040

Page 3 of 5 Protocol: SAM40040 Population: Safety Table 15.6 Summary of Drug-Related Adverse Events

LOWER RESPIRATORY Any event 4 (<1%) 0 Lower respiratory 3 (<1%) 0 infections Cough 1 (<1%) 0

PSYCHIATRY

Any event 0 2 (<1%) CONFIDENTIAL Agitation 0 1 (<1%) Anxiety 0 1 (<1%)

344 REPRODUCTION Any event 0 2 (<1%) Fungal reproductive 0 2 (<1%) infections

DRUG INTERACTION OVERDOSE & TRAUMA Any event 1 (<1%) 0 Contusions & hematomas 1 (<1%) 0

ENDOCRINE & METABOLIC

Any event 1 (<1%) 0 GM2004/00056/00 Appetite disturbances 1 (<1%) 0

SAM40040

Page 4 of 5 Protocol: SAM40040 Population: Safety Table 15.6 Summary of Drug-Related Adverse Events

EYE Any event 0 1 (<1%) Allergic eye disorders 0 1 (<1%)

CONFIDENTIAL

345

GM2004/00056/00

SAM40040

Page 5 of 5 Protocol: SAM40040 Population: Safety Table 15.7 Summary of Serious Adverse Events

ANY EVENT 20 (3%) 12 (2%)

LOWER RESPIRATORY Any event 9 (1%) 1 (<1%) Asthma 6 (<1%) 1 (<1%) Pneumonia 2 (<1%) 1 (<1%) Breathing disorders 2 (<1%) 0

Airways constriction & 1 (<1%) 0 CONFIDENTIAL obstruction Cough 1 (<1%) 0

346 Lower respiratory 1 (<1%) 0 infections

DRUG INTERACTION OVERDOSE & TRAUMA Any event 2 (<1%) 2 (<1%) Fractures 1 (<1%) 2 (<1%) Craniocerebral injuries 2 (<1%) 0

CARDIOVASCULAR Any event 2 (<1%) 1 (<1%) Angina pectoris 0 1 (<1%)

Myocardial infarction 1 (<1%) 0 GM2004/00056/00 Tachyarrhythmias 1 (<1%) 0

SAM40040

Page 1 of 3 Protocol: SAM40040 Population: Safety Table 15.7 Summary of Serious Adverse Events

GASTROINTESTINAL Any event 2 (<1%) 1 (<1%) Abdominal discomfort & 2 (<1%) 0 pain Diverticulosis 1 (<1%) 0 Gastroenteritis 0 1 (<1%)

HEPATOBILIARY TRACT & PANCREAS CONFIDENTIAL Any event 2 (<1%) 1 (<1%) Cholecystitis 2 (<1%) 0

347 Cholangitis 0 1 (<1%)

NON-SITE SPECIFIC Any event 2 (<1%) 1 (<1%) Chest symptoms 2 (<1%) 1 (<1%)

EAR NOSE & THROAT Any event 0 2 (<1%) Hearing loss 0 1 (<1%) Hoarseness/dysphonia 0 1 (<1%)

UROLOGY

Any event 1 (<1%) 1 (<1%) GM2004/00056/00 Renal signs & symptoms 0 1 (<1%) Urinary infections 1 (<1%) 0

SAM40040

Page 2 of 3 Protocol: SAM40040 Population: Safety Table 15.7 Summary of Serious Adverse Events

MUSCULOSKELETAL Any event 0 1 (<1%) Degenerative arthritis 0 1 (<1%)

NEUROLOGY Any event 0 1 (<1%) Compressed nerve syndromes 0 1 (<1%)

CONFIDENTIAL PREGNANCY Any event 1 (<1%) 0

348 Abortion & stillbirth 1 (<1%) 0

SKIN Any event 1 (<1%) 0 Acne & folliculitis 1 (<1%) 0

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Page 3 of 3 Protocol: SAM40040 Population: Safety Table 15.8 Summary of Adverse Events Leading to Withdrawal

ANY EVENT 14 (2%) 10 (1%)

NEUROLOGY Any event 1 (<1%) 5 (<1%) Headaches 1 (<1%) 2 (<1%) Tremors 0 2 (<1%) Disturbances of sense of 0 1 (<1%)

taste CONFIDENTIAL

GASTROINTESTINAL

349 Any event 5 (<1%) 0 Gastroenteritis 2 (<1%) 0 Gastrointestinal 2 (<1%) 0 discomfort & pain Fungal gastrointestinal 1 (<1%) 0 infections Gastritis 1 (<1%) 0

LOWER RESPIRATORY Any event 5 (<1%) 0 Lower respiratory 3 (<1%) 0 infections

Asthma 1 (<1%) 0 GM2004/00056/00 Breathing disorders 1 (<1%) 0

SAM40040

Page 1 of 3 Protocol: SAM40040 Population: Safety Table 15.8 Summary of Adverse Events Leading to Withdrawal

SKIN Any event 1 (<1%) 2 (<1%) Skin rashes 1 (<1%) 1 (<1%) Pruritus 0 1 (<1%)

CARDIOVASCULAR Any event 2 (<1%) 0

Myocardial infarction 1 (<1%) 0 CONFIDENTIAL Tachycardia 1 (<1%) 0

350 EAR NOSE & THROAT Any event 0 2 (<1%) Hoarseness/dysphonia 0 1 (<1%) Throat irritation 0 1 (<1%)

DRUG INTERACTION OVERDOSE & TRAUMA Any event 1 (<1%) 0 Craniocerebral injuries 1 (<1%) 0 Fractures 1 (<1%) 0

ENDOCRINE & METABOLIC

Any event 1 (<1%) 0 GM2004/00056/00 Appetite disturbances 1 (<1%) 0

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MUSCULOSKELETAL Any event 0 1 (<1%) Muscle cramps & spasms 0 1 (<1%)

NON-SITE SPECIFIC Any event 1 (<1%) 0 Candidiasis unspecified 1 (<1%) 0

site CONFIDENTIAL

PSYCHIATRY

351 Any event 0 1 (<1%) Anxiety 0 1 (<1%)

UROLOGY Any event 1 (<1%) 0 Urinary infections 1 (<1%) 0

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Page 3 of 3 Protocol: SAM40040 Population: Safety Table 15.9 Summary of the Most Common Adverse Events During Treatment

SFC 50/250 FBC 4.5/160 Event (N=697) (N=700) ——————————————————————————————————————————————————————————————————————————————————————————

ANY EVENT 384 (55%) 377 (54%) Headaches 101 (14%) 95 (14%) Upper respiratory tract infection (URTI) 101 (14%) 94 (13%) Rhinitis 45 (6%) 34 (5%) Lower respiratory infections 33 (5%) 34 (5%) Musculoskeletal pain 27 (4%) 40 (6%) Viral respiratory infections 27 (4%) 29 (4%)

Throat irritation 32 (5%) 23 (3%) CONFIDENTIAL Cough 25 (4%) 22 (3%)

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ATTACHMENTS

Attachment 1 Asthma Control Questionnaire This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

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CONFIDENTIAL GM2001/00105/00 CONFIDENTIAL GM2001/00105/00 GlaxoGlaxo Wellcome,Wellcome, a a GlaxoSmithKline GlaxoSmithKline company company Study No. SAM40040

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SPONSOR INFORMATION PAGE

Title: A twenty-four week, randomised, double-dummy, double-blind, parallel group study to compare the occurrence of exacerbations between Seretide Diskus 50/250mcg 1 inhalation bd and Symbicort BADPI 4.5/160mcg 2 inhalations bd in subjects with moderate to severe asthma.

Study Number: SAM40040

Glaxo Wellcome plc Stockley Park West Uxbridge, Middlesex, UB11 1BT, UK Telephone:

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I agree:

• To assume responsibility for the proper conduct of the study at this site. • To conduct the study in compliance with this protocol, any future amendments, and with any other study conduct procedures provided by Glaxo Wellcome (GW). • Not to implement any deviations from or changes to the protocol without agreement from the sponsor and prior review and written approval from the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements). • That I am thoroughly familiar with the appropriate use of the investigational medication(s), as described in this protocol, and any other information provided by the sponsor including, but not limited to the following: the current Clinical Investigator’s Brochure (CIB) or equivalent document, CIB supplement (if applicable), and approved product label (if the product is marketed in this country and the label is not already provided as an equivalent to a CIB). • That I am aware of, and will comply with, “good clinical practices” (GCP) and all applicable regulatory requirements. • To ensure that all persons assisting me with the study are adequately informed about the investigational medication(s) and of their study- related duties and functions as described in the protocol.

Investigator Name: ______

Investigator Signature Date

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TABLE OF CONTENTS

Page ABBREVIATIONS ...... ~xr1i 8 PROTOCOL SUMMARY ...... ~xr2i 9 1. INTRODUCTION ...... ~xr3i15 1.1. Background ...... ~xr4i15 1.2. Study Rationale...... ~xr5i15 2. STUDY OBJECTIVE(S) AND ENDPOINT(S)...... ~xr6i16 2.1. Study Objective(s)...... ~xr7i16 2.1.1. Primary objective (s) ...... ~xr8i16 2.1.2. Secondary objective (s) ...... ~xr9i16 2.1.3. Other objective(s)...... ~xr10i16 2.1.4. Safety ...... ~xr11i16 2.2. Study Endpoint(s)...... ~xr12i16 2.2.1. Primary endpoint (s)...... ~xr13i16 2.2.2. Secondary endpoint (s)...... ~xr14i16 2.2.3. Other endpoint(s) ...... ~xr15i17 2.2.4. Safety ...... ~xr16i17 3. INVESTIGATIONAL PLAN ...... ~xr17i17 3.1. Study Design...... ~xr18i17 3.2. Study Population ...... ~xr19i18 3.2.1. Inclusion Criteria ...... ~xr20i18 3.2.2. Exclusion Criteria ...... ~xr21i19 3.2.3. Other Study Eligibility Criteria Considerations ...... ~xr22i20 3.3. Treatment During Study...... ~xr23i21 3.3.1. Study medications and Dosages ...... ~xr24i21 3.3.2. Study Treatment Assignment...... ~xr25i23 3.3.3. Concurrent Medications and Non-Medication Therapies...... ~xr26i25 3.3.4. Medication permitted for other disorders ...... ~xr27i26 4. STUDY MEDICATION MANAGEMENT ...... ~xr28i26 4.1. Study medication Packaging and Labeling...... ~xr29i26 4.2. Study Medication Handling ...... ~xr30i27 4.3. Study Medication Accountability Procedures...... ~xr31i27 5. MEASUREMENTS AND EVALUATIONS ...... ~xr32i28 5.1. Time and Events Schedule ...... ~xr33i28 5.2. Demographic and Baseline Characteristics...... ~xr34i28 5.3. Efficacy...... ~xr35i29 5.3.1. Lung function and reversibility ...... ~xr36i29 5.3.2. Occurrence of Asthma Exacerbations ...... ~xr37i30 5.3.3. Use of Relief Medication and Other Medication ...... ~xr38i31 5.3.4. Asthma Control Questionnaire (ACQ)...... ~xr39i31 5.3.5. Resource Utilization ...... ~xr40i32 5.3.6. Well-controlled Asthma ...... ~xr41i33 5.3.7. Oropharangeal Examination ...... ~xr42i33 5.4. Study Medications...... ~xr43i33

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Page 5.5. Endpoints ...... ~xr44i34 5.5.1. Lung Function ...... ~xr45i34 5.5.2. Occurrence of Asthma Exacerbations ...... ~xr46i34 5.5.3. Use of Relief Medication and Other Medications...... ~xr47i34 5.5.4. Asthma Control Questionnaire (ACQ)...... ~xr48i34 5.5.5. Resource Utilisation ...... ~xr49i35 5.5.6. Well-controlled Asthma ...... ~xr50i35 5.5.7. Oropharangeal Examination ...... ~xr51i35 5.6. Safety ...... ~xr52i35 5.6.1. Adverse events (AEs) ...... ~xr53i35 5.6.2. Pregnancy ...... ~xr54i35 5.7. Premature Discontinuation...... ~xr55i36 5.7.1. Premature Discontinuation from the Study ...... ~xr56i36 5.7.2. Premature Discontinuation of the Study medication...... ~xr57i37 6. DATA ANALYSIS METHODS ...... ~xr58i37 6.1. Sample Size Determination...... ~xr59i37 6.2. General Considerations ...... ~xr60i37 6.2.1. Analysis Populations...... ~xr61i37 6.2.2. Interim Analysis...... ~xr62i38 6.2.3. Other Issues...... ~xr63i38 6.3. Efficacy...... ~xr64i39 6.3.1. Primary Efficacy Measure(s)...... ~xr65i39 6.3.2. Secondary Efficacy Measure(s) ...... ~xr66i40 6.3.3. Other Endpoint (s)...... ~xr67i40 6.4. Health Outcomes ...... ~xr68i43 6.5. Safety ...... ~xr69i44 6.5.1. Adverse Events ...... ~xr70i44 6.5.2. Oropharyngeal Examination ...... ~xr71i44 7. AES AND SAES...... ~xr72i44 7.1. Definition of an AE ...... ~xr73i44 7.2. Definition of a SAE...... ~xr74i45 7.2.1. Events or Outcomes Not Qualifying as SAEs...... ~xr75i46 7.3. Lack of Efficacy as an AE or SAE...... ~xr76i46 7.4. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs...... ~xr77i47 7.5. Method, Frequency, and Time Period for Detecting AEs and SAEs ...... ~xr78i47 7.6. Documenting AEs and SAEs ...... ~xr79i47 7.7. Follow-up of AEs and SAEs...... ~xr80i48 7.8. Prompt Reporting of SAEs to GW...... ~xr81i48 7.8.1. Timeframes for Submitting SAE Reports to GW...... ~xr82i49 7.8.2. Transmission of the SAE Reports...... ~xr83i49 7.9. Regulatory Reporting Requirements For SAEs ...... ~xr84i49 7.10. Post-study AEs and SAEs...... ~xr85i49 7.11. SAEs Related to Study Participation...... ~xr86i50 7.12. SAEs Involving a Non-GW Product ...... ~xr87i50 8. STUDY ADMINISTRATION ...... ~xr88i50 8.1. Data Management...... ~xr89i50

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Page 8.1.1. Subject Tracking ...... ~xr90i50 8.1.2. Data Collection and Retrieval ...... ~xr91i50 8.1.3. Database Processing...... ~xr92i50 8.2. Regulatory and Ethical Considerations...... ~xr93i51 8.2.1. Regulatory Authority Approval ...... ~xr94i51 8.2.2. Ethical Conduct of the Study and Ethics Approval ...... ~xr95i51 8.2.3. Subject Informed Consent ...... ~xr96i51 8.2.4. Investigator Reporting Requirements ...... ~xr97i52 8.3. Study Monitoring ...... ~xr98i52 8.4. Quality Assurance ...... ~xr99i53 8.5. Study and Site Closure ...... ~xr100i53 8.6. Records Retention ...... ~xr101i54 8.7. Investigator Access to Data and Provision of Study Results...... ~xr102i54 8.8. Information Disclosure and Inventions...... ~xr103i54 9. REFERENCES ...... ~xr104i56 10. TABLES ...... ~xr105i57 10.1. Table 1.Time and Events Schedule ...... ~xr106i57 11. FIGURES...... ~xr107i58 11.1. Figure 1.Study Schedule...... ~xr108i58 12. APPENDICES ...... ~xr109i59 12.1. Appendix 1:Country Specific Appendices...... ~xr110i59 12.2. Appendix 3:Asthma Control Questionnaire...... ~xr111i61

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ABBREVIATIONS

ACQ Asthma Control Questionnaire AE Adverse Event BADPI Breath-actuated Dry Powder Inhaler BD Twice Daily BDP Beclomethasone Dipropionate BUD Budesonide CIB Clinical Investigator’s Brochure CRF Case Report Form DAP Data Analysis Plan DAR Medication Accountability Record DCF Data Clarification Form DRC Daily Record Card ECCS European Community Coal and Steel Guidelines ECG Electrocardiogram FDA US Food and Medication Administration FEV1 Forced Expiratory Volume in one second FP Fluticasone Propionate GCP Good Clinical Practice GSK GlaxoSmithKline GW Glaxo Welcome, A GlaxoSmithKline Company HPA Hypothalamic-pituitary-adrenal ICF Informed Consent Form ICS Inhaled Corticosteroid IEC Independent Ethics Committee ITT Intention-to-Treat IUD Intrauterine Device IVRS Interactive Voice Response System LABA Long-acting β2 agonist MCG Microgram MDA Medical Devices Agency MDI/pMDI Metered Dose Inhaler/Pressurised Metered Dose Inhaler MIDAS/MEDRA Medical Conditions, Indications, Diagnoses, Adverse Events, and Symptoms Dictionary Database PEF Peak Expiratory Flow PP Per Protocol PRN For use as required SABA Short-acting β2 agonist SAE Serious Adverse Event SCAD System for Central Allocation of Medications SDV Source Document Verification WPSP Worldwide Product Safety and Pharmacovigilance UK United Kingdom

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PROTOCOL SUMMARY

Study Rationale

Greening et al. in 1994 (1) shows that adding a long acting beta agonist (LABA) to an inhaled corticosteroid (ICS) is superior to doubling the dose of ICS in treating patients with asthma. Further studies on poorly controlled patients treated with ICS, show that the addition of LABAs improves lung function and reduces symptoms in moderate to severe asthma ( 2, 3, 4 & 5). The evidence supporting these findings has now made the co- prescribing of these two categories of medication the treatment of choice (6, 7), further supported by incorporation into international asthma treatment guidelines (8).

New combination products, Seretide and Symbicort have been developed containing an ICS and a LABA in the same inhaler device. Seretide has been marketed since 1999, and contains the LABA salmeterol xinafoate 50mcg and the ICS fluticasone propionate at one of 3 doses, 100, 250 or 500mcg in a single Diskus inhaler. Symbicort containing the LABA formoterol 4.5mcg (delivered dose), and the ICS, budesonide at one of 2 doses, 80 and 160mcg (delivered dose) in a single Turbuhaler device, received regulatory approval in Europe in 2001.

A recent comparison study of Seretide 50/250mcg bd with formoterol 12mcg bd and budesonide 800mcg bd shows that Seretide is significantly better at preventing exacerbations, nights without awakenings and nocturnal symptoms. However, there is little information on the efficacy of Symbicort compared to its component products, and a small amount of published data comparing Symbicort with Seretide. Symbicort has been shown to have a faster onset of bronchodilation than Seretide during the first 30 minutes after the first dose of medication.

The primary objective of this study is to assess the occurrence of exacerbations between the two combination products, Seretide Diskus 50/250mcg 1 inhalation bd and Symbicort BADPI 4.5/160mcg (delivered dose) 2 inhalations bd.

Further to this, the study will compare the efficacy of Seretide Diskus 50/250mcg bd and Symbicort BADPI 4.5/160mcg 2 inhalations bd in treating subjects with moderate to severe asthma by comparing the severity of asthma exacerbations, lung function parameters, symptoms, the need for relief medication and asthma control.

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Study Objective(s)

Primary objective (s)

To compare the efficacy of the two treatment groups in preventing the occurrence of asthma exacerbations in moderate to severe asthma.

Secondary objective (s)

To compare the efficacy of two treatment groups in treating moderate to severe asthma with respect to the following parameters:

• severity of exacerbations

Other objective(s)

• lung function (Peak Expiratory Flow (PEF), Forced Expiratory Volume in one second (FEV1)) • symptoms • need for relief medication • ‘well-controlled’ asthma

Safety

To compare the two treatment groups with respect to the incidence of adverse events.

Study Endpoint(s)

Primary endpoint (s)

To evaluate efficacy relative to the measurement of the number of asthma exacerbations experienced by the subject as expressed as a rate over the 24-week treatment period

(Standardised definitions for asthma exacerbations are detailed in the Measurements and Evaluations, Section 5.3.2)

Secondary endpoint (s)

To evaluate efficacy relative to the measurement of the following parameters:

• Severity of exacerbations • Number of exacerbations • Time to first exacerbation

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Other endpoint(s)

To evaluate efficacy relative to the measurement of the following parameters:

• morning PEF • evening PEF

• Clinic FEV1 • days with no symptoms • nights with no symptoms • days with no need for relief medication • nights with no need for relief medication • number of subjects who achieve ‘well-controlled’ asthma • asthma control score as measured by the Asthma Control Questionnaire (ACQ)

Safety

To measure the incidence of adverse events.

Study Design

This study is a multi-national, multi-centre, double-blind, double-dummy, randomised, twenty-four week study to compare the occurrence of exacerbations between Seretide Diskus 50/250mcg bd and Symbicort BADPI 4.5/160mcg 2 inhalations bd in subjects with asthma. Randomisation is 1:1 for the two treatment groups.

Subjects meeting the Visit 1 (Week-2) inclusion criteria are entered into a 2-week run-in period to collect baseline data on a daily record card. During the run-in period, subjects continue to take their pre-study inhaled corticosteroid (ICS) at the pre-study dose; 1000- 2000mcg/day beclomethasone dipropionate (BDP) or equivalent [800-1600mcg/day budesonide (BUD), 500-1000mcg/day fluticasone propionate (FP) or QVAR]. All disallowed medication must be stopped at Visit 1. At the end of this 2-week period, subjects complying with inclusion/exclusion criteria attend for randomisation at Visit 2 (Week 0) to either; Seretide Diskus 50/250mcg bd or Symbicort BADPI 4.5/160mcg 2 inhalations bd for twenty-four weeks. Subjects who fail the entry criteria at the end of the run-in period (Visit 2) are allowed to repeat the run-in once and attend for randomisation at Visit 2a. Subsequent scheduled visits occur as follows: Week 4 (Visit 3), Week 8 (Visit 4), Week 16 (Visit 5) and Week 24 (Visit 6). Throughout the study, subjects complete a paper daily record card (DRC) recording their morning PEF, evening PEF, daytime and night-time asthma symptoms, use of relief medication, any other concomitant medications, and details of asthma exacerbations and other AEs. The final visit is performed at Visit 6 (Week 24) or earlier in the event of subject withdrawal from the study. A post-study safety assessment is performed by telephone approximately 7 days after the end of treatment. The total duration of the study is 27 weeks, but may be extended to 29 weeks if the run-in period is repeated.

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Planned Sample Size

The total sample size for this study was determined on the basis of anticipated differences between treatments in average asthma exacerbation rate over a twenty-four week treatment period. Based on the data from EDICT study (SAS40002) and the FACET paper (9), the average exacerbation rate for Symbicort BADPI is estimated to be 1 per subject per six months. Therefore, in order to detect a reduction of 20% in the relative risk of exacerbations with Seretide Diskus, at a two-sided α=0.05 significance level with 90% power using Poisson regression techniques, 525 subjects per group will be required.

Therefore, incorporating a 20% overage to account for invalidity and withdrawals, 656 subjects per group should be randomised, 1312 in total.

Study Population

Male and female subjects of 18 years of age or greater, currently suffering from symptomatic moderate to severe asthma and receiving treatment with 1000-2000mcg/day BDP or equivalent [800-1600mcg/day BUD, 500-1000mcg/day FP or QVAR] for at least four weeks prior to Visit 1.

Subjects participating in the study are selected from primary or secondary care environment and treated on an out-patient basis. Subjects must comply with the inclusion/exclusion criteria detailed in section 3.2 of this protocol.

Study Medications and Dosages

GSK will supply the following double-dummy, double-blind medication for this study:

Seretide Diskus 50mcg salmeterol xinafoate 250mcg fluticasone propionate Seretide Diskus placebo placebo Symbicort BADPI 4.5mcg formoterol 160mcg budesonide Symbicort BADPI placebo placebo

Medication sourced locally:

Relief medication, Ventolin.

Oral corticosteroids: Prednisolone

Dosing instructions: Each subject is dispensed 3 Diskus devices and 3 BADPI devices (enough for 12 weeks treatment) for each 8 week study treatment period. Study medication will be dispensed at Randomisation Visit 2/2a, Visit 4 and Visit 5. Subjects are instructed to take one dose (one inhalation from the Diskus and 2 inhalations from the BADPI) each morning and evening for the duration of the twenty-four week study treatment period (Visit 2/2a to Visit 6).

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Measurements and Evaluations

Baseline and anthropological measurements

History of asthma including duration of asthma prior to Visit 1

History of asthma exacerbation(s) in the 12 months prior to Visit 1

Use of corticosteroids (inhaled or oral) and bronchodilators for asthma in the 12 months prior to Visit 1

Classification of asthma according to National Institutes of Health, National Heart, Blood and Lung Institute criteria for asthma diagnosis (8) at Visit 1

Lung function measurements

FEV1 performed to show reversibility completed at any time up to 2 years before Visit 2/2a.

Subjects must have ≥12% (and ≥200ml) in FEV1 reversibility. Subjects who have no record of reversibility of ≥12% in FEV1 within the last 2 years, must have their reversibility assessed before randomisation.

Clinic measurements of FEV1 will be taken before and 15 minutes after inhalation of 200- 400mcg of Ventolin.

Percent reversibility will be calculated as follows:

Post-bronchodilator FEV1 –pre-bronchodilator FEV1 X 100 pre-bronchodilator FEV1

FEV1 at each of the following visits: V2, V3, V4, V5 and V6

Symptom measurements at visits

ACQ at V2, V3, V4, V5 and Visit 6

Daily record card

Throughout the study the daily record card will record the following:

Morning PEF

Evening PEF

Symptom scores – day (0-5) and night (0-4) (See section 12.2 Appendix 2)

Use of relief medication

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Use of ‘other’ concurrent medications

Evaluations

Definition of asthma exacerbation(s)

Each exacerbation is characterised based on one or more of the following defining characteristics (taking the worst to determine the applicable severity):

Mild

morning PEF >20% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or;

more than 3 additional reliever occasions/24 hour period with respect to baseline for > 2 consecutive days, or;

awakening at night due to asthma for > 2 consecutive nights

Moderate

A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a morning PEF >30% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or; b a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Individual courses of oral corticosteriods are classified as separate exacerbations only if they are administered >1 week apart. Any course started within one week of finishing the previous course is considered part of the previous exacerbation.

Severe

deterioration in asthma which requires hospital admission.

Time/date of resolution

Time/date at which the exacerbation had resolved, in the opinion of the investigator and/or subject

Data Collection

• Data recorded by the investigator will be collected on NCR paper Case Report Forms (CRFs) • Data generated directly by the subject will be collected on paper daily record cards and questionnaires.

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1. INTRODUCTION

1.1. Background

1.2. Study Rationale

The primary objective of this study is to compare the occurrence of exacerbations between the two combination products, Seretide Diskus 50/250mcg 1 inhalation bd and Symbicort BADPI 4.5/160mcg (delivered dose) 2 inhalations bd.

Further to this, the study will assess the efficacy of Seretide Diskus 50/250mcg bd and Symbicort BADPI 4.5/160mcg 2 inhalations in treating subjects with moderate to severe asthma by comparing the severity of asthma exacerbations, lung function parameters, symptoms, the need for relief medication and asthma control.

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2. STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1. Study Objective(s)

2.1.1. Primary objective (s)

To compare the efficacy of the two treatment groups in preventing the occurrence of asthma exacerbations in moderate to severe asthma.

2.1.2. Secondary objective (s)

To compare the efficacy of two treatment groups in treating moderate to severe asthma with respect to the following parameters:

• severity of exacerbations

2.1.3. Other objective(s)

• lung function (Peak Expiratory Flow (PEF), Forced Expiratory Volume in one second (FEV1)) • symptoms • need for relief medication • ‘well-controlled’ asthma

2.1.4. Safety

To compare the two treatment groups with respect to the incidence of adverse events.

2.2. Study Endpoint(s)

2.2.1. Primary endpoint (s)

To evaluate efficacy relative to the measurement of the number of asthma exacerbations experienced by the subject as expressed as a rate over the 24-week treatment period

(Standardised definitions for asthma exacerbations are detailed in the Measurements and Evaluations Section 5.3.2.)

2.2.2. Secondary endpoint (s)

To evaluate efficacy relative to the measurement of the following parameters:

• severity of exacernation • number of exacerbations

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• time to first exacerbation

2.2.3. Other endpoint(s)

To evaluate efficacy relative to the measurement of the following parameters:

• morning PEF • evening PEF

• clinic FEV1 • days with no symptoms • nights with no symptoms • days with no need for relief medication • nights with no need for relief medication • number of subjects who achieve ‘well-controlled’ asthma • asthma control score as measured by the Asthma Control Questionnaire (ACQ)

2.2.4. Safety

To measure the incidence of adverse events.

3. INVESTIGATIONAL PLAN

3.1. Study Design

Subjects meeting the Visit 1 (Week-2) inclusion criteria are entered into a 2-week run-in period to collect baseline data on a daily record card. During the run-in period, subjects continue to take their pre-study inhaled corticosteroid (ICS) at the prestudy dose; 1000- 2000mcg/day beclomethasone dipropionate (BDP) or equivalent [800-1600mcg/day budesonide (BUD), 500-1000mcg/day fluticasone propionate (FP) or QVAR]. All disallowed medication must be stopped at Visit 1. At the end of this 2-week period, subjects complying with inclusion/exclusion criteria attend for randomisation at Visit 2 (Week 0) to either; Seretide Diskus 50/250mcg bd or Symbicort BADPI 4.5/160mcg 2 inhalations bd for twenty-four weeks. Subjects who fail the entry criteria at the end of the run-in (Visit 2) are allowed to repeat the run-in once and attend for randomisation at Visit 2a. Subsequent scheduled visits occur as follows: Week 4 (Visit 3), Week 8 (Visit 4), Week 16 (Visit 5) and Week 24 (Visit 6). Throughout the study, subjects complete a paper daily record card recording their morning PEF, evening PEF, daytime and night- time asthma symptoms, use of relief medication, any other concomitant medications, and details of asthma exacerbations and other AEs. The final visit is performed at Visit 6

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(Week 24) or earlier in the event of subject withdrawal from the study. A post-study safety assessment is performed by telephone approximately 7 days after the end of treatment. The total duration of the study is 27 weeks, but may be extended to 29 weeks if the run-in is repeated.

The protocol time and events schedule is shown in Section 11.1 Table 1 and the Study Schedule in Section 12.1 Figure 1.

3.2. Study Population

3.2.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

3.2.1.1. Inclusion criteria for entry into the run-in period at Visit 1

1. Male or female out patients A female is eligible to enter and participate in the study if she is of:

a Non childbearing potential (i.e. physiologically incapable of becoming pregnant), including any female who is post-menopausal. For the purposes of this study, post menopausal is defined as one year without menses; or b Child-bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the acceptable contraceptive methods when used consistently and correctly (i.e. in accordance with the approved product label and the instructions of a physician for the duration of the study – Screening visit to Follow-up contact). • Complete abstinence from intercourse from two weeks prior to the study medication administration, throughout the 24-week treatment phase, and for one week following study completion; or • Sterilisation of male partner; or • Implants of levonorgestrel inserted for at least one month prior to the study medication administration but not beyond the third successive year following insertion; or • Injectable progestogen administered for at least one month prior to the study medication administration and administered for one month following study completion; or • Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or • An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or

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• Any other methods with published data showing that the highest expected failure rate is less than 1% per year. 2. At least 18 years of age at the time of Visit 1 (Screening Visit). 3. Documented clinical history of asthma for at least 6 months prior to Visit 1 4. No change in regular medication or use of oral/parenteral steroids in the 4 weeks before Visit 1 5. Currently receiving 1000-2000mcg/day BDP or equivalent, such as 800- 1600mcg/day budesonide, 500-1000mcg/day fluticasone propionate or QVAR, for at least 4 weeks prior to Visit 1 6. A signed and dated written informed consent is obtained from the subject prior to study participation 7. Able to comply with therapy and to complete daily record cards and subject- completed questionnaires correctly.

3.2.1.2. Inclusion criteria at Visit 2/2a

At the end of the run-in period (Visit 2/2a), patients must still comply with the inclusion criteria for entry into the run-in period and in addition, must also meet the following:

1. At Visit 1 or 2/2a, a demonstrable reversible increase in FEV1 of at least 12% (and ≥200mls), 15 minutes after inhaling 200-400mcg of Ventolin or; At any time in the last 2 years documentary evidence of a reversible increase in FEV1, of at least 12% (and ≥200mls), 15 mins after inhaling a short-acting bronchodilator 2. During the 2-week run-in period (10 to 18 days), subjects must have an asthma symptom score (day and night combined) of a least 2 (see Appendix 2, Section 12.2) recorded in their daily record card on at least 4 of the last 7 evaluable days 3. During the 2-week run-in period, subjects must complete daily record cards on at least 10 days (run-in window is 10-18 days). Subjects who fail to meet this criteria are permitted to repeat the run-in once, at the investigators discretion.

3.2.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

3.2.2.1. Exclusion criteria

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4. Previous participation in a clinical study in which the subject was exposed to an investigational or non-investigational medication or device within 30 days prior to Visit 1 5. Concurrently participating in another clinical study in which the subject is or will be exposed to an investigational or a non-investigational medication or device 6. Any evidence of or treatment of malignancy (other than localised basal cell, squamous cell skin cancer or localised cancer in situ that has been resected) within the previous five years 7. A pregnant woman or any woman intending to become pregnant 8. A woman breastfeeding an infant(s) 9. Inability or unwillingness to take study medication (non-compliance), follow directions or unable to complete a written paper daily record card and self-rating questionnaires 10. Previous allergic reaction to study medications or any excipients of the formulations

11. Subjects receiving any of the following medications: long-acting inhaled β2-agonists, oral β2-agonists or slow-release bronchodilators, combination therapy (containing β2- agonist and/or inhaled corticosteroids for asthma), sodium cromoglycate or nedocromil sodium, ketotifen, leukotriene-receptor antagonists, anticholinergics, short-acting inhaled β2-agonists (other than Ventolin provided at Visit 1), theophyllines, these medications must be stopped at Visit 1. (During the run-in, subjects continue on their pre-study dose of inhaled corticosteroids, which are stopped at Visit 2/2a). 12. Use of oral/parenteral corticosteroids for 4 weeks prior to Visit 1 13. Use of depot corticosteroids for 12 weeks prior to Visit 1 14. History of alcohol or medication abuse

15. Pre-bronchodilator FEV1 of <50% of predictive normal values using ECCS standard ranges (10) (bronchodilators must be withheld for 6 hours previously) 16. Use of any concurrent prohibited medications (subjects must not take prohibited medications during the run-in and must remain off these medications for the duration of the study as listed in Section 3.3.3.1. of the protocol)

3.2.3. Other Study Eligibility Criteria Considerations

In order to assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the study medication(s) being used in this study: the CIB; CIB supplement and approved product labels.

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3.3. Treatment During Study

3.3.1. Study medications and Dosages

3.3.1.1. Study medications and devices

The Clinical Trials Supplies Department at GlaxoSmithKline Research and Development will supply the following study medications and devices.

• Seretide 50/250mcg strength Diskus inhaler containing 50mcg salmeterol xinafoate /250mcg fluticasone propionate per inhalation • Placebo Diskus inhaler to match the active study medication • Symbicort 4.5/160mcg strength Breath-Actuated Dry Powder Inhaler (BADPI) containing 4.5mcg formoterol and 160mcg budesonide, delivered dose • Placebo BADPI to match the active Symbicort study medication Each Diskus will contain 60 doses of study medication or placebo, each BADPI will contain 120 doses of study medication or placebo.

Following randomisation at Visits 2/2a, Visits 4 and 5, each subject will receive a Treatment Pack containing 6 devices; 3 Diskus and 3 BADPIs according to their randomisation schedule. Subjects take the same study treatment for the duration of the 24-week study.

Subjects will be randomised in equal numbers to receive:

EITHER

Seretide Diskus 50/250mcg 1 inhalation bd and Symbicort BADPI placebo, 2 inhalations bd

Seretide Diskus placebo 1 inhalation bd and Symbicort BADPI 4.5/160mcg, 2 inhalations bd.

Subjects will be asked to take one inhalation from the Diskus inhaler and two inhalations from the BADPI every morning and every evening for 24 weeks (Visit 2/2a to Visit 6).

Inhaled relief medication (Ventolin via the Diskus inhaler or pressurised CFC or non-CFC MDI) will be provided by the GSK operating company. These will be provided locally as bulk supplies to each centre, to be dispensed as required both during the run-in and the treatment periods.

Oral prednisolone for the treatment of moderate or severe asthma exacerbation will be provided locally by the GSK operating company.

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All study medications should be stored by the investigator separately from any other medication and in accordance with the manufacturer’s instructions. All investigational products should be stored safely and properly. The study medication should be stored at 2 to 25°C.

The local GSK operating company will provide each centre with supplies of standard mini-Wright peak flow meters, and dipstick urine pregnancy tests.

3.3.1.2. Dose rationale

Several studies have shown adding an inhaled long-acting β2-agonist to inhaled steroid treatment is more effective than doubling the steroid dose. Delivery of inhaled medications to the desired site of action allows use of smaller doses than the oral or parenteral routes.

Subjects with moderate to severe asthma as diagnosed by their physician are screened (V1) and continue their pre-study dose of ICS during the run-in. Following randomisation, they are given either Seretide 50/250mcg 1 inhalation bd or Symbicort 4.5/160mcg 2 inhalations bd, which are the recommended doses and available formulation of the two products.

3.3.1.3. Dosages and dosing

• Up to the start of study medication treatment (Visit 2/2a), subjects should continue on their current ICS plus allowed short-acting bronchodilators (Section 3.3.3). • At Visit 2/2a (start of study treatment) subjects are randomised to one of the treatment groups and issued with their first Treatment Pack of study medication (containing either 3 active Diskus and 3 placebo BADPIs or 3 placebo Diskus and 3 active BADPIs). After 28 days the subject should return for Visit 3 bringing their study medication to the visit. Study medication will be dispensed at Visits 2/2a, 4 and 5. • Twelve weeks of study treatment is supplied in each Treatment Pack for each 8 week period between dispensing visits (V2/2a, 4 and 5). This is to ensure that all subjects have adequate overage. All six devices must be returned at dispensing visits. Study medication must not be redispensed. Study medication must not be collected at Visit 3. Subjects use the treatment dispensed at Visit 2/2a until Visit 4. • Each morning (immediately after waking) and each evening (shortly before going to bed) the subject takes one inhalation from the Diskus, two from the BADPI. Each inhaler must be used within two minutes of the previous one and the Diskus must be used first. Missed doses should not be taken later with the next scheduled dose. • Reliever medication should be taken as required. Salbutamol (Ventolin) will be issued at Visit 1 and afterwards as required. Subjects who stop taking their treatment due to adverse reactions or who must have their treatment changed must be withdrawn from the study and reasons for their withdrawal documented in the CRF.

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3.3.1.4. Overdose and toxicity management

There are no data available from clinical trials on overdose with Seretide or Symbicort, however data on overdose with both salmeterol, fluticasone propionate, formoterol and budesonide are given below:

Fluticasone propionate Inhalation of fluticasone in doses in excess of those recommended may lead to temporary suppression of hypothalamic-pituitary adrenal (HPA function). This does not necessitate emergency action being taken. In these subjects, treatment with fluticasone propionate or other steroids by inhalation should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol.

Salmeterol Xinafoate The symptoms and signs of salmeterol overdose are tremor, headache, tachycardia and fall in diastolic pressure. The preferred antidote for overdose with salmeterol is a cardio- selective beta-blocking medication which should be used with caution in subjects with a medical history of bronchspasm. Additionally, hypokalemia can occur, in this event potassium replacement therapy should be considered. Any change in medication must be recorded in the CRF.

Budesonide Inhalation of large amounts of budesonide over a short period will cause suppression of the hypothalamic-pituitary (HPA function). No special emergency action needs to be taken. Treatment should be continued at the specified dose and any change recorded in the concurrent medication section.

Formoterol There is no clinical experience on the management of formoterol overdose but the symptoms and signs are likely to be tremor, headache, palpitations and tachycardia. Hypotension, metabolic acidosis, hypokalaemia and hyperglycaemia may also occur. Supportive and symptomatic treatment is indicated. Use of cardio-selective beta-blockers may be considered, but only subject to extreme caution since the use of β-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored. Any change in medication must be recorded in the CRF.

Section 5.7 details the procedures to be followed for subjects withdrawn from study medication.

3.3.2. Study Treatment Assignment

Each subject eligible at screening (Visit 1) to enter the run-in phase will be assigned a unique subject number. At the screening visit (Visit 1), the subject will be assigned the lowest number in the subject block assigned to the site. This subject number is to be recorded on the subject’s signed Informed Consent Form, the Case Report Form (CRF) and the Medication Accountability Record (DAR). Once a subject number has been assigned, it may not be assigned to another study subject.

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Once the run-in period has been completed successfully, at Visit 2/2a (randomisation to study medication), eligible subjects will be assigned to study treatment in accordance with the randomisation schedule from the Interactive Voice Recognition System (IVRS) which is part of the System for the Central Allocation of Medication (SCAD). The randomisation schedule will be given to the automated system administrator prior the start of the study. Treatment number assigned will be recorded on the CRF.

Each subject will be assigned a Treatment Pack at the Visit 2/2a (randomisation visit), Visit 4 and Visit 5 of the study treatment phase. The principal investigator or designee must contact the IVRS system at each of these scheduled visits to obtain the Pack number. Each treatment Pack number will be recorded on the DAR.

Treatment Packs will be supplied in sealed 8 week cartons which are identical in appearance. The investigator or designee will dispense the study treatment pack to the subject as directed and document this information in the DAR. The investigator and the subject will remain blind to treatment.

Procedures for breaking the randomisation code.

Only in the case of an emergency, when knowledge of the study medication is essential for the clinical management or welfare of the subject, the investigator may unblind a subject’s treatment assignment. If the blind is broken for any reason, the investigator must notify GW immediately of the unblinding incident without revealing the subject’s study treatment assignment. In addition, the investigator will record the date and reason for revealing the blinded treatment assignment for that subject on the “Status of Treatment Blind” CRF. The investigator must not reveal the blind to the study monitor.

The automated 24-hour IVRS will give the option to either notify the system of the withdrawal of the subject or after a series of questions, break the randomisation code for this subject. If the blind is broken for any reason, the investigator must notify the appropriate GW representative immediately. Notification that a subject's randomisation code has been broken will be sent immediately to GW and designee.

If a serious adverse event (SAE; as defined in Section 7.2.,“Definition of an SAE”) is reported to Glaxo Wellcome (GW), Worldwide Product Safety & Pharmacovigilance (WPSP)/Global Clinical Safety and Pharmacovigilance (GCSP) staff will unblind the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies is required, the report will identify the subject’s treatment assignment. When applicable, a copy of the regulatory report may be sent to investigators in accordance with relevant regulations, GW policy, or both.

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3.3.3. Concurrent Medications and Non-Medication Therapies

3.3.3.1. Non-permitted asthma medication

The following asthma medication is not permitted during the study:

• Oral, parenteral or depot corticosteroids other than a short course required to treat an exacerbation of asthma during the treatment period. (See Section 5.3.2. – Procedure in case of Asthma Exacerbation)

• Long-acting inhaled β2-agonists (e.g. salmeterol)

• Oral β2-agonists (e.g. bambuterol) • Slow release bronchodilators

• Combination medication (containing any β2-agonist or corticosteroid) for asthma other than the study medication provided during the treatment period • Anticholinergics • Theophyllines • Sodium Cromoglycate • Nedocromil Sodium • Ketotifen

• Short-acting inhaled β2-agonists other than the salbutamol (Ventolin) provided • Anti-Leukotrienes including suppressers of leukotriene production and antagonists The following asthma medication is not permitted during the treatment period and must be discontinued at Visit 2/2A:

• Inhaled steroids other than the study medication during the treatment period (except for treatment of exacerbations - see Section 3.3.4). Full details of all concurrent asthma medication and concurrent medication for other disorders must be recorded in the CRF.

3.3.3.2. Permitted asthma medications

During the run-in period, subjects continue to take their pre-study ICS medication. This treatment is stopped at Visit 2/2a. Where indicated, individual courses of oral prednisolone may be prescribed (see Section 5.3.2.).

The sponsor will provide the following reliever medication from local commercial stock: salbutamol sulphate Diskus or pMDI designed to deliver 100µg salbutamol actuated dose.

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3.3.4. Medication permitted for other disorders

All medications for other disorders may be continued providing the dose remains constant and their use would not be expected to affect lung function. However, no systemic corticosteroids for other conditions will be permitted. Intranasal steroids (e.g. Beconase or Flixonase) may be used for rhinitis. An attempt should be made to keep the dose constant throughout the study. However, it may be necessary during the course of the study to vary the dose. If necessary, this is permitted within the recommended dose range. Short courses of intranasal steroids may also be taken for seasonal rhinitis. The usage should be documented in the concurrent medication section of the CRF.

If the subject develops oropharyngeal candidiasis, antifungal lozenges may be taken. An adverse event form should be completed and the medication recorded in the concurrent medication page of the CRF.

Full details of all concurrent asthma medication and concurrent medication for other disorders must be recorded in the CRF.

4. STUDY MEDICATION MANAGEMENT

4.1. Study medication Packaging and Labeling

Blinded Study medication

Blinded study medication will be supplied in Treatment Packs as described below.

Issued at Clinic Visit Period Inhalers

Visit 2/2A Weeks 1-8 3 x Diskus inhaler and 3 x BADPI

Visit 4 Weeks 9-16 3 x Diskus inhaler and 3 x BADPI

Visit 5 Weeks 17-24 3 x Diskus inhaler and 3 x BADPI

Each subject will receive three Diskus devices and three BADPIs for each eight week treatment period according to the randomisation schedule. Subjects will be instructed to take one inhalation from the Diskus and two inhalations from the BADPI, every morning and every evening.

The contents of the label will be in accordance with all applicable regulatory requirements.

Blinded study medication will be packaged and labelled by GSK. Each Treatment Pack will contain sufficient supplies to last until the next dispensing visit. Each device will provide sufficient treatment for 30 days/4 weeks. Three devices of each type are provided, thus 12 weeks of treatment are provided for each 8 week period. Each

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CONFIDENTIAL GM2001/00105/00 CONFIDENTIAL GM2001/00105/00 SAM40040 Study No. SAM40040 treatment pack will be labelled with the protocol number, container contents and quantity, storage information and the dosing instructions. The study medication devices should be stored between 2 to 25°.

Relief Medication: Ventolin

Commercial packs of branded Ventolin for symptomatic relief (via the Diskus device or pressurised CFC or non CFC MDI) will be provided by the GSK local operating company and therefore, will be labelled in accordance with local requirements.

4.2. Study Medication Handling

Study medication will be dispatched to a site only after receipt of required documents in accordance with all applicable regulatory requirements and GW procedures.

• Signed and dated copy of Regulatory approval letter (where applicable) • Signed and dated protocol and any amendments • Signed and dated letter of Ethics Committee approval • Signed and dated copy of the investigator financial agreement(s) • Up to date Principal Investigators’ curriculum vitae Study medication must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive study medication, in accordance with all applicable regulatory requirements. Only authorized site personnel may supply or administer study medication. All study medications must be stored in a secure area with access limited to the investigator and authorized study site personnel and under physical conditions that are consistent with study medication-specific requirements.

4.3. Study Medication Accountability Procedures

The investigator is responsible for study medication accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designated study site personnel must maintain study medication accountability records throughout the course of the study. This person(s) will document the amount of study medication received from GW, the amount supplied and/or administered to and returned by subjects, if applicable.

A medication dispensing and accountability log will be provided and the investigator or designee must record the number of inhalers dispensed to and returned by each subject. The subject must return all used and unused study inhalers and the investigator or designee must reconcile or resolve any discrepancies.

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5. MEASUREMENTS AND EVALUATIONS

5.1. Time and Events Schedule

The time and events schedule is summarised in Section 11.1 Table 1.

Study visits will be performed at the required intervals relative to the Randomisation Visit, Visit 2/2a. The following windows are acceptable:

Visit 1 (Screening visit) Week –2 (or Week –4 ±4 days if run-in repeated ±8 days

Visit 2/2a (Randomisation visit) Day 0

Visit 3 Week 4 Day 28 ±7 days

Visit 4 Week 8 Day 56 ±7 days

Visit 5 Week 16 Day 112 ±7 days

Visit 6 Week 24 Day 168 ±7 days

Early withdrawal/Visit 6 may occur at any time after randomisation.

The follow-up telephone contact is relative to the Week 24 visit

Follow-up contact Week 24 +7 days ±2 days

5.2. Demographic and Baseline Characteristics

The following will be recorded in the CRF at Visit 1:

Demographic information including gender, ethnic origin, date of birth, height, weight

History of asthma including duration of asthma

History of asthma exacerbations in the 12 months prior to Visit 1

Concurrent medical conditions and concurrent medication (both asthma and non-asthma). All concurrent medications must be entered in the Concurrent Medications Section of the CRF throughout the study, beginning at Visit 1.

Use of corticosteroids for asthma in the 12 months prior to Visit 1, and duration of inhaled corticosteroid treatment.

The following must be recorded at Visit 1, 2 or 2a:

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Calculated percent of predicted FEV1.

FEV1 airway reversibility assessment of at least ≥12% (and ≥200mls) at Visits 1, 2/2a or during the run-in period, if documentary evidence of reversibility in the previous 2 years is not available.

The following will be recorded at Visit 2 or 2a:

Confirm that an asthma symptom score of 2 (day and night combined) on at least 4 of the last 7 evaluable days of the run-in period has been achieved.

5.3. Efficacy

5.3.1. Lung function and reversibility

Subjects should refrain from using short-acting bronchodilators for at least 6 hours prior to performing FEV1 measurements.

5.3.1.1. Calculation of percent predicted FEV1 (Clinic)

Subjects predicted FEV1 will be calculated based on the European Community for Coal and Steel [ECCS] “Standardisation of Lung Function Tests” (10) for 18 years and older.

5.3.1.2. Assessment of Airway Reversibility by FEV1 (Clinic)

The highest of three technically acceptable measurements of FEV1 will be taken before and 15 minutes after inhalation of 200-400mcg short-acting bronchodilator. Percent reversibility will be calculated as follows:

Post-bronchodilator FEV1 –pre-bronchodilator FEV1 X 100 pre-bronchodilator FEV1

The time of short-acting bronchodilator administration and the time and result of the FEV1 measurement will be recorded on the “Pulmonary Function Testing” page in the CRF.

5.3.1.3. PEF procedures

• At Visit 1, the subject will be given a Peak Flow Meter and taught how to measure their PEF. At each visit the subject’s ability to measure their PEF will be checked and, if the investigator has any concerns, the subject will be retrained. The instructions for use will be provided with each Peak Flow Meter. PEF should be measured while subject is in the sitting position. • Where possible, peak flow measurements should be performed at the same time of day, when first rising in the morning prior to study medication or relief salbutamol/albuterol use, using the same Peak Flow Meter.

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The local GSK operating company will provide each centre with a supply of standard mini-Wright peak flow meters.

5.3.2. Occurrence of Asthma Exacerbations

Subjects who experience worsening of symptoms should:

• increase relief medication usage for relief of symptoms • contact the investigator or primary physician immediately and report to the clinic as soon as possible (ideally within 24-hours) • record their symptoms, PEF and relief medication usage in their DRC as previously instructed • if intervention therapy is required during a treatment period, subjects may receive oral corticosteroids (40-60mg prednisolone daily, or equivalent, for 10 days), over and above their study medication. Exacerbations will be assessed by the physician at each scheduled visit by reviewing the DRC entries, as well as specific questioning on AEs.

Exacerbations will be defined based on one or more of the following characteristics:

Definition of asthma exacerbation(s)

Each exacerbation is characterised based on one or more of the following defining characteristics (taking the worst to determine the applicable severity):

Mild

morning PEF >20% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or;

more than 3 additional reliever occasions/24-hour period with respect to baseline for > 2 consecutive days, or;

awakening at night due to asthma for > 2 consecutive nights

Moderate

A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a morning PEF >30% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or; b a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

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Severe

deterioration in asthma which requires hospital admission.

Time/date of resolution

Time/date at which the exacerbation had resolved, in the opinion of the investigator and/or subject

Details of exacerbations will be collected in the “Asthma Exacerbations” page of the CRF and diary card as follows:

An exacerbation resulting in hospitalisation will be recorded as a serious adverse event (SAE) in the “Serious Adverse Event” pages of the CRF. However, it is not only these exacerbations resulting in hospitalisation which require collection as SAEs, but those that meet any of the definitions of Seriousness, listed in Section 7.2.

5.3.3. Use of Relief Medication and Other Medication

Each time the subject uses relief medication for relief of symptoms (not for prophylactic use), details will be recorded on the DRC. Information for the previous 24 hours will be recorded each morning.

Subjects will be asked to record any medical problems and changes in medication on the DRC and to inform the investigator. Medical problems and changes in study medications will be assessed by the investigator for adverse events.

5.3.4. Asthma Control Questionnaire (ACQ)

The Asthma Control Questionnaire (ACQ) is a seven item questionnaire which has been developed as a measure of patients’ asthma control that can be quickly and easily completed in clinical practice (Section 12.3, Appendix 3).

The first six questions are designed to be self-completed by the patient, with the seventh requiring completion by clinic staff. The six subject-completed questions enquire about the frequency and/or severity of symptoms (nocturnal awakening, asthma symptoms on waking in the morning, activity limitation, shortness of breath, wheeze) and use of short- acting bronchodilator, over the previous week. The response options for all these questions consist of a zero (no impairment/limitation) to six (total impairment/limitation) scale. The final item on the questionnaire should be completed by a member of clinic

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CONFIDENTIAL GM2001/00105/00 CONFIDENTIAL GM2001/00105/00 SAM40040 Study No. SAM40040 staff, who records the patient’s FEV1 % predicted, again using a seven point response option anchored between zero (>95% predicted) and six (<50% predicted).

At all visits (from V2 to V6), the investigator will provide each subject with the ACQ. The subject should be given a quiet area in which to complete the questionnaire ands should be instructed to answer the first six questions only. Upon completion of these questions, the subject should return the ACQ to the investigator who will complete question 7. It is important that subjects are allowed to complete questions 1 to 6 prior to the investigator completing question 7 as the answer could influence how subjects respond to the questions. In addition, questions 1 to 6 must be completed prior to the physician consultation or any discussion over clinical test results.

Any deviation from the questionnaire schedule must be clearly noted. The investigator will ask the subject to complete the question as accurately as possible. If the subject should request help or clarification with any of the questions, he or she should be asked to reread the instructions and give the answer that best reflects how he/she has felt over the previous week. The subject should be reassured that there are no right or wrong answers. The investigator will not provide the subject with any answers or attempt to interpret any portion of these questions in behalf of the subject.

It is recommended that the ACQ be administered at the same time during each visit. To avoid biasing responses, the subjects should not be told the results of diagnostic tests prior to completing the questionnaire.

Adequate time should be allowed to complete all items on the ACQ. No stated or implied time for completing the ACQ will be given, though the survey typically takes under 5 minutes to complete. Upon completion, the questionnaire should be returned to the subject’s CRF.

5.3.5. Resource Utilization

5.3.5.1. Unscheduled Asthma-Related Resource Utilisation

Information on unscheduled, asthma-related healthcare resource utilisation associated with the subject’s condition will be collected during both phases of the study. Scheduled, protocol-driven utilisation such as physician visits and study medication will not be collected.

Following the collection and review of DRCs and AEs at each scheduled visit, the investigator should ask the subject if they have had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit. If the answer is yes, the following information will be recorded on the Unscheduled Asthma Related Healthcare Contacts form in the CRF: date of contact; number of visits/calls (in the case of primary care contacts); number of visits to outpatient clinics; number of visits to hospital Accident and Emergency departments; number of days hospitalised; and whether it was related to an asthma exacerbation.

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The investigator should prompt the subject to give answers that are as complete as possible. If the subject cannot recall an exact figure, an estimate is acceptable. The investigator can refer to his/her records to verify or supplement information given by the subject, if necessary.

5.3.6. Well-controlled Asthma

Subjects will have their asthma control assessed weekly for the duration of the study based on symptoms, use of relief medication and peak flow measurements.

A week of ‘well-controlled’ asthma is defined as meeting the following criteria assessed over 7 consecutive days:

1. two or more of the following 3 criteria:

AND

2. all of the following criteria:

• no night-time awakenings due to asthma • no exacerbations • no emergency visits • no treatment related adverse effects enforcing a change in asthma therapy

5.3.7. Oropharangeal Examination

Oropharangeal examination will be performed to assess the existence of candidiasis. An oral swab will be taken if there is visible signs of infection. Oral swabs for testing will be sent to a local laboratory for analysis.

5.4. Study Medications

At Visit 2/2a all subjects will be able to use a demonstration (placebo) Diskus and a demonstration (placebo) BADPI to familiarise themselves with the devices and to practice inhaler technique. Inhaler technique will be checked at these and subsequent visits as required.

At screening, all subjects will be provided with inhaled Ventolin for use as PRN relief medication throughout the study. This should be entered in the “Asthma Concurrent Medication” page in the CRF.

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The following study medication information must be recorded in the CRF.

Start and stop dates of study treatment and any reason for premature discontinuation of study medication and/or non-compliance or any reasons for breaking treatment blind (to be entered in ‘Trial Medication’, ‘End of Study Record’ and ‘Status of Treatment Blind’ page(s) in the CRF)

Number of remaining doses from each study treatment inhaler prescribed is to be entered in the Compliance section of the CRF.

5.5. Endpoints

5.5.1. Lung Function

5.5.1.1. FEV1 (Clinic)

FEV1 will be measured at each visit and the percent predicted value will be calculated using ECCS normal ranges. If the calculated value at Visit 1 is <50% then this can be calculated again at Visit 2/2a.

5.5.1.2. Airway reversibility FEV1 assessment

Must be performed at Visit 1, 2 or 2a, if documented evidence not available from previous 2 years.

5.5.1.3. Daily morning and evening PEF

Daily morning and evening PEF are recorded on the daily record card both morning and evening on each day throughout the study (Visit 1 to Visit 6).

5.5.2. Occurrence of Asthma Exacerbations

Asthma exacerbations must be recorded on the Asthma exacerbations page of the CRF at the Visit immediately following the exacerbation. Severe asthma exacerbations must be recorded as SAEs at the time of reporting (see Section 7).

5.5.3. Use of Relief Medication and Other Medications

Data from the daily record card will be reviewed at each visit and where appropriate documented in the CRF.

5.5.4. Asthma Control Questionnaire (ACQ)

Must be completed by the subject at each visit following randomisation (Visit 2/2a, 3, 4, 5 and 6).

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5.5.5. Resource Utilisation

Information relating to unscheduled asthma related healthcare resource utilisation will be recorded in the CRF when received during the study period.

5.5.6. Well-controlled Asthma

‘Well-controlled’ asthma will be assessed weekly from the DRC data following entry on the database.

5.5.7. Oropharangeal Examination

An oropharyngeal examination will be performed at each Visit (V1, 2/2a, 3, 4, 5 and 6)

5.6. Safety

Any events ongoing at the end of the study will be followed until their resolution (Section 7.7).

Safety will be assessed on the following parameters.

5.6.1. Adverse events (AEs)

Full AE monitoring procedures must be adhered to (see Section 7). AE monitoring will be conducted throughout the study, from entry to final completion or discontinuation.

5.6.2. Pregnancy

There is insufficient experience of the use of these medications in pregnancy and lactation to properly assess their effects. Extensive clinical experience has revealed no evidence of any relevant effects at therapeutic doses, but as with all medicines, administration during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. Data sheets on Ventolin and Seretide/ Advair/ Viani (salmeterol/FP combination) Symbicort should be referred to for further guidance.

Female subjects already known to be pregnant will not be eligible for entry into this study. Local legal restrictions on use of these medications in female subjects of childbearing potential must be observed. If a subject becomes pregnant during the study, the subject will be withdrawn.

5.6.2.1. Pregnancy testing

A urine dipstick pregnancy test should be performed at Visit 1 and at Visit 6.

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5.6.2.2. Time period for collecting pregnancy information

Information on whether a pregnancy has occurred must be collected from the Screening Visit (Visit 1) to final completion or discontinuation.

5.6.2.3. Occurrence of pregnancy

Any female subject who becomes pregnant while participating in this study will be followed to determine the outcome of the pregnancy. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. The investigator, or his or her designee, will collect pregnancy information on the appropriate GW form and submit it to GW within 2 weeks of learning of the subject’s pregnancy.

While pregnancy itself is not considered to be an adverse event (AE) or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or a SAE, as described in Section 7.6, “Documenting AEs and SAEs” and will be followed-up as described in Section 7.7, “Follow-up of AEs and SAEs.” Furthermore, any SAE occurring as a result of a post-study pregnancy and which is reasonably related to the study medication will be reported to GW as described in Section 7.10, “Post-study AEs and SAEs,” if the investigator learns of this SAE through spontaneous reporting.

5.7. Premature Discontinuation

5.7.1. Premature Discontinuation from the Study

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from participating in this study at any time.

A subject will be considered to have completed the study if they have participated fully in the treatment period of the study for 27 weeks.

Subjects who fail the entry criteria or fail to maintain their DRCs and have incomplete data during the run-in should be discontinued from the study. Subjects with insufficient data to assess asthma control during the period between two visits should be withdrawn from study medication since it is not possible to evaluate the subject’s treatment.

If a subject is prematurely discontinued for any reason, the investigator must make every effort to perform the following evaluations: collect used/unused study medication; check for adverse events, changes in concurrent medication, exacerbations, administer ACQ, record FEV1, unscheduled asthma-related healthcare contacts, record date and reason for discontinuation, and collect subject DRC. These data should be recorded, as they comprise an essential evaluation that should be done prior to discharging any subject from the study.

In the event that a subject is prematurely discontinued from the study at any time due to an AE (as defined in Section 7.1, “Definition of an AE”) or SAE (as defined in

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Section 7.2, “Definition of an SAE”), the procedures stated in Section 7, (“AEs and SAEs”) must be followed.

Every effort should be made to follow subjects who withdraw from the study due to an adverse event.

5.7.2. Premature Discontinuation of the Study medication

If the subject discontinues the study medication at any time, it is up to the discretion of the investigator whether the subject should continue or be withdrawn. If the subject is withdrawn reasons for his/her discontinuation should be recorded in the “End of Study Record” page of the CRF.

6. DATA ANALYSIS METHODS

6.1. Sample Size Determination

The total sample size for this study was determined on the basis of anticipated differences between treatments in average asthma exacerbation rate over a twenty-four week treatment period. Based on data from the EDICT study (SAS40002) and the FACET paper (9), the average exacerbation rate for Symbicort Turbuhaler is estimated to be 1 per subject per six months. Therefore, in order to detect a reduction of 20% in the relative risk of exacerbations with Seretide Diskus, at a two-sided α=0.05 significance level with 90% power using Poisson regression techniques, 525 subjects per group will be required.

Therefore, incorporating a 20% overage to account for invalidity and withdrawals, 656 subjects per group should be randomised, 1312 in total.

6.2. General Considerations

6.2.1. Analysis Populations

Four populations will be considered for analysis:

Total Population

The total population will consist of all subjects who entered the study. This population will be used for tabulating and listing reasons for withdrawal before randomisation and listing adverse events for these subjects.

Intent-to-Treat Population

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CONFIDENTIAL GM2001/00105/00 CONFIDENTIAL GM2001/00105/00 SAM40040 Study No. SAM40040 which they were randomised. The ITT population will be used for all tables and analyses (except those specified for the Total, Safety or Per Protocol Populations) and will be the primary population for all efficacy endpoints and for all safety endpoints (provided all subjects receive the treatment to which they were randomised).

Safety Population

If any subjects do not receive study treatment as randomised, they will be analysed for safety according to the treatment they actually received. If this occurs, the patient population for the tables and listings of safety data will be labelled as the Safety Population. If all subjects receive the treatment to which they were randomised, all safety tabulations will be produced using the ITT population.

Per Protocol Population

This population will consist of all subjects in the ITT population who do not have any protocol violations which could impact treatment effect. These violations will be defined explicitly in the Data Analysis Plan and the decision to exclude a subject from the Per Protocol population will be made prior to breaking the study blind. For the Per Protocol population, subjects will be analysed according to the treatment received, providing the same treatment was taken for the duration of the study. If study medication was changed then the subject will be considered a partial protocol violator (i.e. from the point of change onwards). This population will only be used for confirmatory analysis of the primary endpoint if one or more of these violations are observed in >20% of subjects.

6.2.2. Interim Analysis

There is no interim analysis planned for this study.

6.2.3. Other Issues

The analysis methodology for this study is described in the sections below. If at any time after protocol finalisation, a change to the planned analyses is considered necessary, this will be documented and justified in the DAP (if the change is made prior to database authorisation). Similarly, if a change is made after the final statistical analysis has been performed, this will be documented and justified in the Final Study Report.

All confidence intervals calculated in the study analyses will be symmetric and of size 95% and all hypothesis tests will be 2-sided and conducted using a 5% significance level unless otherwise stated.

It is planned that study subjects will be enrolled in approximately 315 centres with a maximum of 20 countries. Since it is likely that a high proportion of centres will recruit a small number of subjects, centres will be amalgamated within country with the aim of obtaining a minimum of 60 subjects within each country. Countries with fewer than 60 randomised subjects may be combined with the country of nearest geographical location or ethnic origin. Details of country amalgamations will be decided prior to unblinding and will be specified in the DAP.

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Missing data will be imputed for the purposes of efficacy analyses if subjects withdraw from the study due to lack of efficacy or adverse events related to lack of efficacy. Such subjects will be assumed to conform to a ‘worst case’ scenario for all efficacy endpoints e.g. values for lung function measurements and symptom scores will be calculated using a last observation carried forward approach, subjects will be assumed to have no further symptom free days or nights etc. No imputation of missing data will be performed for subjects withdrawing prematurely for other reasons or for any other occurrences of missing data.

For exacerbations, if a subject withdraws from the study before 24 weeks of treatment, the number of exacerbations will be imputed in order to give the number of exacerbations in 24 weeks, as follows:

No. of exacerbations per 24 weeks = 6 x no. of exacerbations / no. of 4 week periods, where number of 4 week periods equals the number of weeks on treatment divided by 4, rounded up. This imputation is only for the purposes of summarising the data, as the analysis will not use the imputed data.

Further details of handling of missing data or imputation will be given in the DAP.

No formal statistical comparisons between treatments will be performed for baseline and demographic characteristics – these data will be summarised by treatment group and assessed informally for evidence of imbalance.

Since there is a single primary endpoint with a single primary analysis, supported by several secondary analyses, the nominal levels of significance are not impacted by multiple comparisons and no adjustments will be made.

6.3. Efficacy

For the purposes of all diary card efficacy analyses, baseline is defined as the mean of the daily values over the last seven days of the two-week run-in. For clinic visit efficacy endpoints, baseline is defined as the pre-Ventolin visit 2/2a assessment.

6.3.1. Primary Efficacy Measure(s)

The primary efficacy endpoint is the number of asthma exacerbations experienced by the subject, expressed as a rate over the treatment period, based on the ITT population. This will be analysed using maximum likelihood based analysis, assuming the Poisson distribution, with time on treatment as an offset variable. The model will include adjustment for effects of sex, country and age.

The adjusted mean rates per 24-week treatment period, treatment ratio and associated p- values and confidence intervals will be presented.

Interactions of treatment with sex, country and age will be tested in separate analysis models for statistical significance at the 10% level. If an interaction is considered

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The analysis will be repeated for the Per-Protocol population, if used.

6.3.2. Secondary Efficacy Measure(s)

Tests for interactions will not be performed for any of the secondary endpoints. Also, analysis of the Per-Protocol population will not be performed, unless different results were obtained from the two populations for the primary endpoint.

6.3.2.1. Number of Exacerbations

The number of exacerbations per subject will be assigned to one of the following four categories:- 0, 1, 2, >2. The percentage of subjects in each category will be presented by treatment group, and treatment groups compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country and treatment. This model will be used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

The number of subjects with at least one exacerbation will be analysed using the Cochran-Mantel-Haenszel test, stratified by country. Percentages, differences in percentages between treatments, 95% confidence intervals and p-values will be presented.

6.3.2.2. Severity of Exacerbations

The number and percentage of subjects with mild, moderate and severe exacerbations will be presented by treatment group.

Each subject will be assigned to a ‘severity’ category based on the maximum severity of any of their exacerbations. The percentage of subjects in each category will be presented by treatment group, and treatment groups will be compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country and treatment. This model will be used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

6.3.2.3. Time to First Exacerbation

Time to first exacerbation will be summarised using survival analysis. A Cox’s proportional hazard model will be used to compare treatment groups. Age, sex and country will be used as covariates in the model. If the assumption of proportionality of hazards is clearly not met, then a Wilcoxon test will be used.

6.3.3. Other Endpoint (s)

Lung function endpoints and ACQ total core will be analysed using analysis of covariance, allowing for effects due to baseline value, country, sex, age and treatment. If

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CONFIDENTIAL GM2001/00105/00 CONFIDENTIAL GM2001/00105/00 SAM40040 Study No. SAM40040 assumptions underlying the analysis model are not met for these or other efficacy endpoints, the data will be log transformed. If assumptions are still not met for a specific endpoint, it will be analysed non-parametrically using the Van Elteren extension to the Wilcoxon Rank Sum test.

Tests for interactions will not be performed for any of the other endpoints. Also, analysis of the Per-Protocol population will not be performed, unless different results were obtained from the two populations for the primary endpoint.

6.3.3.1. Mean Daily Morning PEF Measurements (Weeks 1-24).

The mean daily morning PEF will be derived from the DRC over the 24-week treatment period. Individual subject means will be compared between treatment groups using analysis of covariance, allowing for effects specified in Section 1.3.2. This model will be used to estimate the treatment group difference and p-value, and calculate the 95% confidence interval for this difference.

Summary statistics for the raw and adjusted values of the mean and mean change from baseline will also be presented.

6.3.3.2. Mean Daily Morning PEF Measurements (Weeks 1-8, 9-16,17-24).

This will be derived from the DRC data for the time intervals above, using time windows specified in the DAP, and will be analysed using analysis of covariance as above. A summary table will also be prepared.

6.3.3.3. Mean Daily Evening PEF Measurements (Weeks 1-24).

This will be derived, analysed and summarised in the same way as for morning PEF.

6.3.3.4. Mean % Predicted Morning PEF (Weeks 1-24)

This will be calculated using the ECCS standards for predicted values, according to the following formula:

(Morning PEF/Predicted PEF) x 100

Mean values over the 24-week treatment period will be analysed using analysis of covariance and summarised by treatment group.

6.3.3.5. Mean % Predicted Evening PEF (Weeks 1-24)

This will be calculated using the ECCS standards according to the following formula:

(Evening PEF/Predicted PEF) x 100

Mean values will be analysed and summarised in the same way as % predicted morning PEF.

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6.3.3.6. Mean Circadian Variation in Peak Flow (Weeks 1-24)

Circadian variation will be calculated according to the following formula:

(PEFpm-PEFam| ÷ mean(PEFam,PEFpm)) x 100 where the PEFpm is the evening PEF from the DRC and PEFam is the PEF from the following morning.

Mean values will be summarised by treatment group. No formal analysis will be performed.

6.3.3.7. Clinic FEV1

Summary statistics will be tabulated by treatment group at all clinic visits. Assessment windows for the clinic visits will be defined in the DAP. Values recorded at Visit 6 (week 24), will also be analysed using analysis of covariance in the same way as diary card PEF values. The visit 2/2a (day 0) value will be used as baseline.

6.3.3.8. Daytime Symptom Scores (Weeks 1-24).

Provided parametric model assumptions hold, mean symptom scores (recorded in the daytime) on the DRC will be calculated for each subject and analysed using analysis of covariance in the same way as for the lung function endpoints. A tabulation of summary statistics by treatment group will also be produced.

6.3.3.9. Night-time Symptom Scores (Weeks 1-24).

These will be calculated using the symptom score recorded on the DRC in the evening and analysed in the same way as daytime symptom scores.

6.3.3.10. Percentage of Symptom Free Days (Weeks 1-24)

The percentage of days with a symptom score of zero will be calculated for each subject and assigned to one of the following four categories:- 0% to 25%, >25% to 50%, >50% to 75%, >75%. The numbers of subjects in each of the treatment groups will be compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country and treatment. This model will be used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

6.3.3.11. Percentage of Symptom Free Nights (Weeks 1-24)

The percentage of nights with a symptom score of zero will be calculated for each subject, categorised as for % symptom free days and compared between treatments using logistic regression as described above.

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6.3.3.12. Percentage of Days with No Relief Medication (Weeks 1-24)

The percentage of days on which no relief Ventolin was taken will be calculated for each subject and analysed in the same way as % symptom free days and nights.

6.3.3.13. Percentage of Nights with No Relief Medication (Weeks 1-24)

The percentage of nights on which no relief Ventolin was taken will be calculated for each subject and analysed in the same way as % symptom free days and nights.

6.3.3.14. Withdrawals Due to Lack of Efficacy

The number and percentage of subjects withdrawing during the treatment period due to lack of efficacy will be tabulated by treatment group. A 95% confidence interval for the difference in the proportion of these withdrawals will also be presented.

6.3.3.15. ‘Well-controlled’ Asthma

The difference between treatments in the proportion of patients who achieve ‘Well- controlled’ asthma at anytime during the treatment period be assessed using a 2-sided Fisher's Exact test, and presented with the associated 95% confidence interval.

6.3.3.16. Asthma Control Questionnaire

The ACQ total score will be calculated for each subject at each visit from the 7 questions of the ACQ (as detailed in Sections 5.3.4. and Section 12.3, Appendix 3) and analysed as using analysis of covariance as described for mean daily PEF.

6.4. Health Outcomes

6.4.1.1. Resource Utilisation

Direct healthcare resource use data collected on the Asthma-related Unscheduled Healthcare Contacts form will be summarised. Estimates of healthcare resource use will be made based on resources used by subjects during the treatment phase of the study. The total number of units consumed for each type of healthcare contact will be summarised independently. For healthcare contacts involving hospitalisation, the total number of hospitalisations will be summarised as well as the total number of inpatient days. Primary care (general practice) contacts (surgery visits and house calls) will be summarised separately.

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6.5. Safety

6.5.1. Adverse Events

Adverse events will be coded using the GW MIDAS/MEDRA dictionary, and grouped by body system. Within each treatment group, adverse events will be summarised by frequency and proportion of total subjects, by event type and by category of body system. Separate summaries will be given for all AEs, for drug-related events, for SAEs, and for AEs leading to withdrawal. Where appropriate, each phase of the study (pre-treatment, treatment and follow-up) will be tabulated separately.

The proportion of subjects reporting at least one AE, at least one drug-related AE, at least one SAE, and at least one AE leading to withdrawal will also be calculated for each treatment group.

6.5.2. Oropharyngeal Examination

The number and percentage of patients with clinical evidence of candidiasis and the number and percentage with a positive swab result will be tabulated at each time point by treatment group. Allowable time windows for each assessment will be defined in the DAP.

7. AEs AND SAEs

The investigator is responsible for the detection and documentation of events meeting the definition of an AE or SAE as provided in this protocol. During each treatment period, when there is a safety evaluation, the investigator or study site personnel will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol. In order to fulfill international safety reporting obligations, the investigator will include in his or her assessment any SAEs resulting from study participation (e.g., complications resulting from the taking of a blood sample).

7.1. Definition of an AE

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

An AE can therefore be any unfavorable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

An AE does include a/an:

• exacerbation of a pre-existing illness (excluding asthma or exacerbations of asthma unless they meet a definition of SAE)

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• increase in frequency or intensity of a pre-existing episodic event or condition. • condition detected or diagnosed after study medication administration even though it may have been present prior to the start of the study. • continuous persistent disease or symptoms present at baseline that worsen following the start of the study. An AE does not include a/an:

• medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); the condition that leads to the procedure is an AE. • pre-existing disease or conditions present or detected at the start of the study that do not worsen. • situations where an untoward medical occurrence has not occurred (e.g., hospitalizations for cosmetic elective surgery, social and/or convenience admissions). • the disease or disorder being studied or sign or symptom associated with the disease or disorder unless more severe than expected for the subject’s condition. • overdose of either study medication or concurrent medication without any signs or symptoms. For GW clinical trials, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen).

Information on managing an overdose, including medication and non-medication therapies, is described in Section 3.3.1.4., “Overdose and Toxicity Management”.

7.2. Definition of a SAE

An SAE is any adverse event occurring at any dose that results in any of the following outcomes: a Death b A life-threatening adverse event c Inpatient hospitalization or prolongation of existing hospitalization d A disability/incapacity e A congenital anomaly in the offspring of a subject who received medication f Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or

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convulsions that do not result in inpatient hospitalization, or the development of medication dependency or medication abuse. Clarifications:

• “Occurring at any dose” does not imply that the subject is receiving study medication. • Life-threatening means that the subject was, in the view of the investigator, at immediate risk of death from the event as it occurred. This definition does not include an event that, had it occurred in a more severe form, might have caused death. • Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not considered an AE. • Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization, the event is an SAE. • “Inpatient” hospitalization means the subject has been formally admitted to a hospital for medical reasons. This may or may not be overnight. It does not include presentation at a casualty or emergency room. • With regard to criteria “f” above, medical and scientific judgment should be used in deciding whether prompt reporting is appropriate in this situation.

7.2.1. Events or Outcomes Not Qualifying as SAEs

The events or outcomes identified as asthma exacerbations will be recorded in the “asthma exacerbations” page of the case report form (CRF) page if they occur. However, these individual events or outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these events or outcomes, are not reported to GW as SAEs even though such event or outcome may meet the definition of SAE, unless the following conditions apply:

• the investigator determines that the event or outcome qualifies as an SAE under part “f” of the SAE definition (see Section 7.2., “Definition of a SAE”), or • the event or outcome is in the investigator’s opinion of greater intensity, frequency or duration than expected for the individual subject, or • death occurring for any reason during a study, including death due to a disease-related event, will always be reported promptly.

7.3. Lack of Efficacy as an AE or SAE

“Lack of efficacy” per se will not be reported as an AE. The signs and symptoms or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including clarifications).

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7.4. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs

Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other abnormal assessments (e.g. ECGs, X-rays, vital signs) that are judged by the investigator as clinically significant must be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 7.1., (“Definition of an AE”), or SAE, as defined in Section 7.2., (“Definition of a SAE”). Clinically significant abnormal laboratory findings or other abnormal assessments that are detected after study medication administration or that are present at baseline and worsen following the start of the study are included as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that are present or detected at the start of the study that do not worsen, are not included as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgement in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.

7.5. Method, Frequency, and Time Period for Detecting AEs and SAEs

The investigators should ask subjects at each visit, whether or not they have had any medical problems since their last visit and record the results on the “Adverse events” page of the CRF.

In addition, AEs from the DRCs and from any other source of information the investigator has about subjects, should also be recorded.

Run-in Period

Those events meeting the definition of “serious” adverse events will be recorded in the subject’s notes and the CRF. A serious adverse event report will be completed and faxed to the appropriate study personnel. Non-serious adverse events with the exception of asthma exacerbations which will be recorded in the CRF, will be captured in the subject’s notes, in accordance with the investigators normal practice, but no captured in the CRFs.

Treatment and Follow-up Periods

During the 24 weeks treatment and one week follow-up phases, those events meeting the definitions of adverse events and serious adverse events will be recorded in the CRF. These events will also be documented in the subject’s notes.

7.6. Documenting AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostic reports) relative

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AEs and subject-completed questionnaires are independent components of the study. Responses to each question in the questionnaires will be treated in accordance with standard scoring and statistical procedures detailed by the scale’s developer. The use of a single question from a multidimensional health survey to designate a cause-effect relationship to an AE is inappropriate.

7.7. Follow-up of AEs and SAEs

All AEs and SAEs must be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or the subject is lost to follow-up. The investigator is responsible to ensure that follow-up includes any supplemental investigations as may be indicated to elucidate as completely as practical the nature and/or causality of the AE or SAE. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.

GW may request that the investigator perform or arrange for the conduct of supplemental measurements and/or evaluations. If a subject dies during participation in the study or during a recognized follow-up period, GW will be provided with a copy of any post-mortem findings, including histopathology.

New or updated information will be recorded on the originally completed “SAE” CRF with all changes signed and dated by the investigator.

7.8. Prompt Reporting of SAEs to GW

SAEs must be reported promptly to GW as described in the following table once the investigator determines that the event meets the protocol definition of an SAE.

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7.8.1. Timeframes for Submitting SAE Reports to GW

Initial SAE Reports Additional Information on a Previously Reported SAE Type of SAE Time Frame Documents Time Frame Documents Death or Life- 24/48 hrsa “SAE” CRF 48 hrs Updated “SAE” Threatening pages CRF pages Event Other SAEs 48 hrs “SAE” CRF 48 hrs Updated “SAE” pages CRF pages a Initial notification should be sent to GW within 24 hours of the investigator learning of the death or life- threatening event. Fully completed documents (“SAE” CRF pages) should be sent to GW within 48 hours.

7.8.2. Transmission of the SAE Reports

Facsimile transmission of the “SAE” CRF is the preferred method to transmit this information to the project contact for SAE receipt. In the absence of facsimile equipment, notification by telephone is acceptable for deaths and life-threatening events, with a copy of the “SAE” CRF sent by overnight mail. For SAEs that are not deaths or life-threatening events, telephone notification, in the absence of facsimile equipment, is not acceptable. Instead, a copy of the “SAE” CRF will be sent by overnight mail. GW will provide separately a list of project contacts for SAE receipt, fax numbers, and mailing addresses.

7.9. Regulatory Reporting Requirements For SAEs

The investigator must promptly report all SAEs to GW in accordance with the procedures detailed in Section 7.8., “Prompt Reporting of SAEs to GW”. GW has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a medication under clinical investigation. Prompt notification of SAEs by the investigator to the appropriate project contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, must comply with the applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).

7.10. Post-study AEs and SAEs

Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE at any time after a subject has been discharged from the study, and such event(s) is(are) reasonably related to the study medication, the investigator will promptly notify GW.

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7.11. SAEs Related to Study Participation

An SAE considered related to study participation (e.g., procedures, invasive tests), even if it occurs during the pre- or post-treatment period, will be reported promptly to GW (see Section 7.8., “Prompt Reporting of SAEs to GW”).

7.12. SAEs Involving a Non-GW Product

In those instances where an SAE has occurred in a subject receiving a non-GW product as a comparator or concurrent medication, the report must be sent to the appropriate project contact for SAE receipt in the same time frames as if it were a GW product (see Section 7.8., “Prompt Reporting of SAEs to GW”).

8. STUDY ADMINISTRATION

8.1. Data Management

Data Management will be performed in accordance with all applicable GW standards and procedures.

8.1.1. Subject Tracking

8.1.2. Data Collection and Retrieval

Subject data will be collected on CRFs provided to the investigator by GW. In addition, subject generated data will be collected on daily record cards and subject completed questionnaires.

The investigator or designee must record all required subject data using the previously specified data collection method defined by GW. An explanation must be documented for any missing data. The investigator must sign and date a declaration on the CRF attesting to his/her responsibility for the quality of all data recorded and that the data represents a complete and accurate record of each subject’s participation in the study.

The site will send original completed CRF data to GW for processing and will retain a copy.

8.1.3. Database Processing

The clinic visit and diary data will be collected using valid data collection tools. The study subjects will complete the Asthma Control Questionnaires (ACQs). All subjects will record daily diary data on a daily record card (DRC).

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Data management will be performed in accordance with ICH GCP and Standard Operating Procedures. The data will be entered into a database by the GW data management designee who will also validate it according to predefined validation checks, either at the point of entry and/or at a later stage in processing. Any inconsistencies or anomalies will be queried with the investigator or their designees, and the database will be updated accordingly, until all data are deemed “clean” or authorised. Quality control procedures will be applied to ensure that the quality of the data in the final database meets the expected standards.

8.2. Regulatory and Ethical Considerations

8.2.1. Regulatory Authority Approval

GW will obtain approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulations prior to a site initiating the study in that country.

8.2.2. Ethical Conduct of the Study and Ethics Approval

The study will be conducted in accordance with “good clinical practice” (GCP) and all applicable regulations, including, where applicable, the Declaration of Helsinki 1996.

It is the investigator’s responsibility to ensure that this protocol, the site’s informed consent form, and any other information (e.g., advertisements or information that supports or supplements the informed consent) is reviewed and approved by the appropriate IEC or IRB. GW must receive copies of the IEC or IRB approval and the approved informed consent materials before shipment of study medication.

If, during the study, it is necessary to amend either the protocol or the informed consent form, the investigator will be responsible for ensuring the IEC or IRB reviews and approves these amended documents. IEC or IRB approval of the amended informed consent form must be obtained before new subjects consent to take part in the study using this version of the form. Copies of the IEC or IRB approval of the amended informed consent form and the approved amended informed consent form must be forwarded to GW as soon as available.

8.2.3. Subject Informed Consent

Informed consent will be obtained before the subject can participate in the study. The contents and process of obtaining informed consent will be in accordance with all applicable regulatory requirements.

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If the informed consent form is amended during the study, the investigator must follow all applicable regulatory requirements pertaining to approval of the amended informed consent form by the IEC or IRB and use of the amended form.

8.2.4. Investigator Reporting Requirements

In accordance with applicable local regulatory requirements, the investigator may be obligated to provide periodic safety updates on the conduct of the study at his or her site and notification of study closure to the IRB or IEC. Such periodic safety updates and notifications are the responsibility of the investigator and not of Glaxo Wellcome.

8.3. Study Monitoring

In accordance with applicable regulations, GCP, and GW procedures, monitors will periodically contact the site, including conducting on-site visits. The extent, nature and frequency of on-site visits will be based on such considerations as the study objective and/or endpoints, the purpose of the study, study design complexity, and enrollment rate.

During these contacts, the monitor will:

• check and assess the progress of the study • review study data collected • conduct Source Document Verification • identify any issues and address their resolution This will be done in order to verify that the:

• data are authentic, accurate, and complete • safety and rights of subjects are being protected • study is conducted in accordance with the currently approved protocol (and any amendments), GCP, and all applicable regulatory requirements. The investigator agrees to allow the monitor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the monitor to discuss findings and any relevant issues.

In addition to contacts during the study, the monitor will also contact the site prior to the start of the study to discuss the protocol and data collection procedures with site personnel.

At study closure, monitors will also conduct all activities as indicated in Section 8.5, “Study and Site Closure”.

The monitor is also responsible for reviewing subject-completed health outcome questionnaires. The monitor will review the subject-completed health outcome questionnaires for extraneous written comments that could indicate possible AEs. Information collected in the CRF and in the subject-completed health outcome

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8.4. Quality Assurance

At its discretion, GW may conduct a quality assurance audit of this study. If such an audit occurs, the investigator agrees to allow the auditor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor to discuss findings and any relevant issues.

In addition, regulatory agencies may conduct a regulatory inspection of this study. If such an inspection occurs, the investigator agrees to allow the inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the inspector to discuss findings and any relevant issues.

8.5. Study and Site Closure

Upon completion of the study, the monitor will conduct the following activities in conjunction with the investigator, as appropriate: insert relevant activities, including but not limited to the following, if they are applicable to the study:

• Return of all study data to Glaxo Wellcome. • Data clarifications and/or resolutions. • Accountability, reconciliation, and arrangements for unused study medications. • Review of site study records for completeness. • Return of treatment codes to Glaxo Wellcome. In addition, GW reserves the right to temporarily suspend or prematurely discontinue this study either at a single site or at all sites at any time and for reasons including, but are not limited to, safety or ethical issues or severe non-compliance. If such action is taken, GW will discuss this with the Investigator (including the reasons for taking such action) at that time. GW will promptly inform all other investigators and/or institutions conducting the study if the study is suspended or terminated for safety reasons, and will also inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator must inform the IRB or IEC promptly and provide the reason for the suspension or termination.

If the study is prematurely discontinued, all study data must be returned to GW. In addition, arrangements will be made for all unused study medications in accordance with GW procedures for the study.

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Financial compensation to investigators and/or institutions will be in accordance with the agreement established between the investigator and GW.

8.6. Records Retention

In accordance with applicable regulatory requirements, following closure of the study, the investigator will maintain a copy of all site study records in a safe and secure location. GW will inform the investigator of the time period for retaining these records in order to comply with applicable regulatory requirements.

8.7. Investigator Access to Data and Provision of Study Results

GW will provide the investigator with a copy of the CRF data collected from the site. When a clinical study report is completed, GW will provide the major findings of the study to the investigator.

In addition, details of the study treatment assignment will be provided to the investigator to enable him/her to review the data to determine the outcome of the study for his/her subject.

8.8. Information Disclosure and Inventions

Ownership:

All data and records provided by GW or generated during the study (other than a subject’s medical records) and all inventions discovered in the course of conducting the study are the property of GW. If a written contract for the conduct of the study which includes ownership provisions inconsistent with this statement is executed, that contract’s ownership provisions shall apply rather than this statement.

Confidentiality:

The investigator and other study site personnel will keep confidential any information provided by GW (including this protocol) related to this study and all data and records generated in the course of conducting the study, and will not use the information, data, or records for any purpose other than conducting the study. These restrictions do not apply to: (1) information which becomes publicly available through no fault of the investigator or study site personnel; (2) information which it is necessary to disclose in confidence to an IEC or IRB solely for the evaluation of the study; (3) information which it is necessary to disclose in order to provide appropriate medical care to a study subject, or (4) study results which may be published as described in the next paragraph. If a written contract for the conduct of the study which includes confidentiality provisions inconsistent with this statement is executed, that contract’s confidentiality provisions shall apply rather than this statement.

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Publication:

For multi-center studies, the first publication or disclosure shall be a complete, joint multi-center publication or disclosure that GW will coordinate. Thereafter, any secondary publications will reference the original publication(s).

The investigator shall inform GW of any publication plans. Prior to submitting for publication, presenting, using for instructional purposes or otherwise disclosing the results of the study, the investigator shall allow GW a period of at least thirty (30) days [or, for abstracts, at least five (5) working days] to review the proposed publication or disclosure prior to its submission for publication or other disclosure. Publications or disclosures of study results shall not include other, confidential information of Glaxo Wellcome’s. If the proposed publication/disclosure risks GW’s ability to patent any invention related to the study, the publication or disclosure will be modified or delayed, at the investigator’s option, a sufficient time to allow GW to seek patent protection of the invention. This statement does not give GW any editorial rights over the content of a publication or disclosure, other than to restrict the disclosure of GW’s confidential information. If a written contract for the conduct of the study, which includes publication provisions inconsistent with this statement is executed, that contract’s publication provisions shall apply rather than this statement.

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9. REFERENCES

1. Greening, AP; Ind, PW; Northfield, M and Shaw, G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219-24. 2. Woolcock, A; Lundback, B; Ringdal, N and Jacques, LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153: 1481-88. 3. van Noord JA, Schreurs AJ, Mol SJ, Mulder PG. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 1999; 54:207-212. 4. Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky P, Woodring A, Prillaman B, Shah T. Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma. Ann Allergy Asthma Immunol 1999; 82(3): 257-65. 5. Condemi JJ, Goldstein S, Kalberg C, Yancey S, Emmett A, Rickard K. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group. Ann Allergy Asthma Immunol 1999;82:383-389. 6. Global Initiative for Asthma. National Institute of Health, National Heart, Lung and Blood Institute. Publication number 95-3659. 1995; Chapter 7:70-117. 7. British Thoracic Society. The British guidelines on asthma management. Thorax 1997; 52 suppl 1:S1-S21. 8. Guidelines for the Diagnosis and Management of Asthma National Institute of Health, National Heart Lung and Blood Institute: Clinical Practice Guidelines NIH Publication Number 97-4051. 9. Pauwels TA, Lofdahl C-G, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-1411. 10. Standardisation of lung function as contained in the report of the working party of the European Community for Coal and Steel. Bull Eur Physiopath Resp 1983;19 (Suppl 5).

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10. TABLES

10.1. Table 1. Time and Events Schedule

Timeline: Visit 1 Visit 2/2a Visit 3 Visit 4 Visit 5 Visit 6 Optional -2w ±±± 4d (Day 0) 4w ±±± 1w 8w ±±± 1w 16w ±±± 1w 24 ±±± 1w follow-up Period Run-in Treatment Follow-up Treatments Usual Seretide Diskus (50mcg salmeterol xinafoate + 250mcg Appropriate inhaled fluticasone propionate, actuated dose) 1 inhalation bd asthma steroids OR medication Symbicort BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose) 2 inhalations bd Relief Ventolin Relief Ventolin Visit 1 2/2A 3 4 5 6 7 Informed Consent X Demography X Reversibilityª XX Inclusion/Exclusion XX Criteria Medical History X Oropharangeal exam X X X X X X X b Lung Function (FEV1)XXXXXXX b Issue Daily Record Cards X X X X X Issue Study Medication X XX ACQ c XXXXX Collect Daily Record XXXXX Cards Collect Study Medication XXX X b Adverse Event XXXXX X b Concurrent Medication X X X X X X X a. at only one of the Visits 1, 2/2a or up to 2 years before Visit 2/2a b. if follow-up visit required these procedures may be performed c. ACQ should be completed by the subject prior to the visit with the investigator/study team

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11. FIGURES

11.1. Figure 1. Study Schedule

Run-in Study treatment Follow-up

Seretide Diskus (50mcg salmeterol xinafoate + 250mcg fluticasone propionate, actuated dose), 1 inhalation bd

BDP (1000-2000 mcg/d same as pre-study dose)

or equivalent

Symbicort BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose), 2 inhalations bd

Weeks -2 0 4 8 16 24 25

Visits V1 V2 V3 V4 V5 V6 Follow-up contact

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12. APPENDICES

12.1. Appendix 1:Country Specific Appendices

Country-Specific Requirements

Austria

Canada

Denmark

France

Germany

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Appendix 2: Asthma Symptom Scores

Asthma Symptom scores during the day and at night

The following will be recorded daily before taking any relief and study medication:

Daytime Symptom Score:

0 = No symptoms during the day

1 = Symptoms for one short period during the day

2 = Symptoms for two or more short periods during the day

3 = Symptoms for most of the day which did not affect my daily activities

4 = Symptoms for most of the day which did affect my normal daily activities

5 = Symptoms so severe that I could not go to work or perform normal daily activities.

Night-time Symptom Score:

0 = No symptoms during the night

1 = Symptoms causing me to wake once or wake early

2 = Symptoms causing me to wake twice or more (including waking early)

3 = Symptoms causing me to be awake for most of the night

4 = Symptoms so severe that I did not sleep at all

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12.2. Appendix 3: Asthma Control Questionnaire This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

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INVESTIGATOR PROTOCOL AMENDMENT AGREEMENT PAGE

I agree:

• to conduct the study in compliance with this protocol amendment. • not to implement this protocol amendment without agreement from the sponsor and prior submission to and written approval from (where required) the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except when necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements).

Investigator Name: ______

Investigator Signature Date

Physician Name Date

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ABBREVIATIONS

ACQ Asthma Control Questionnaire AE Adverse Event BADPI Breath-actuated Dry Powder Inhaler BD Twice Daily BDP Beclomethasone Dipropionate BUD Budesonide CIB Clinical Investigator’s Brochure CRF Case Report Form DAP Data Analysis Plan DAR Drug Accountability Record DCF Data Clarification Form DRC Daily Record Card ECCS European Community Coal and Steel Guidelines ECG Electrocardiogram FDA US Food and Medication Administration FEV1 Forced Expiratory Volume in one second FP Fluticasone Propionate GCP Good Clinical Practice GSK GlaxoSmithKline GW Glaxo Welcome, A GlaxoSmithKline Company HPA Hypothalamic-pituitary-adrenal ICF Informed Consent Form ICS Inhaled Corticosteroid IEC Independent Ethics Committee ITT Intention-to-Treat IUD Intrauterine Device IVRS Interactive Voice Response System LABA Long-acting β2 agonist MCG Microgram MDA Medical Devices Agency MDI/pMDI Metered Dose Inhaler/Pressurised Metered Dose Inhaler MIDAS/MEDRA Medical Conditions, Indications, Diagnoses, Adverse Events, and Symptoms Dictionary Database PEF Peak Expiratory Flow PP Per Protocol PRN For use as required SABA Short-acting β2 agonist SAE Serious Adverse Event SCAD System for Central Allocation of Medications SDV Source Document Verification WPSP Worldwide Product Safety and Pharmacovigilance UK United Kingdom

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1. STATEMENT OF INTENT

This protocol amendment number 1 applies to all study sites in all participating countries.

2. RATIONALE

In order to comply with trademark laws it is necessary to correct the name of the comparator combination product to formoterol/budesonide breath-actuated dry powder inhaler in the study protocol. Other trademarks mentioned in the protocol, are registered trademarks owned by the GlaxoSmithKline group of companies.

Clarification of Inclusion Criterion Number 4 for entry to Run-in period

Inconsistencies exist in the finalised protocol (Version dated 30th July 2001). This amendment will correct and/or clarify any identified inconsistencies, errors and omissions. Typographical errors will not be specifically listed in this amendment unless correction of the error is significant to the implementation of the protocol.

3. LOCATION OF THE CHANGES

3.1. Reference to Symbicort™

3.1.1. Front Page, Page 1Signature page and Page 3 Sponsor information page – Protocol title

Original text

A twenty-four week, randomised, double-dummy, double-blind, parallel group study to compare the occurrence of exacerbations between Seretide Diskus 50/250mcg 1 inhalation bd and Symbicort BADPI 4.5/160mcg 2 inhalations bd in subjects with moderate to severe asthma.

Amended text

A twenty-four week, randomised, double-dummy, parallel group study to compare the occurrence of exacerbations between Seretide™Diskus™ 50/250mcg 1 inhalation bd and formoterol/budesonide Breath Activated Dry Powder Inhaler 4.5/160mcg 2 inhalations bd in subjects with moderate to severe asthma.

Foot note: Seretideä and Diskusä are trade marks owned by Glaxo Wellcome, a GlaxoSmithKline company.

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3.1.2. Text changes throughout the protocol

All pages

The term ‘Symbicort™’ or ‘Symbicort’ will be removed and the following (generic names of the drugs) will be inserted ‘formoterol/budesonide'.

3.2. Text changes throughout the protocol

Page 8 Abbreviations

Original text

DAR Medication Accountibility Record

Amended text

DAR Drug Accountability Record

Page 9 Protocol Summary

Original text

Symbicort containing the LABA formoterol 4.5mcg (delivered dose), and the ICS, budesonide at one of 2 doses, 80 and 160mcg (delivered dose) in a single Turbuhaler device, received regulatory approval in Europe in 2001.

Amended text

The formoterol/budesonide combination product containing the LABA formoterol 4.5mcg (delivered dose), and the ICS, budesonide at one of 2 doses, 80 and 160mcg (delivered dose) in a single device, received regulatory approval in Europe in 2001.

Page 12 Study medication and dosages

Original text

Medication sourced locally:

Relief medication, Ventolin.

Amended text

Medication sourced locally:

Relief medication, Ventolinä

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Footnote: VentolinTM is a trade mark owned by Glaxo Wellcome, a GlaxoSmithKline company.

Page 13 Summary - Baseline and Anthropological measurements.

Original text

Use of corticosteroids (inhaled or oral) and bronchodilators for asthma in the 12 months prior to Visit 1.

Amended text

All previous medication for asthma in the 12 months prior to visit 1.

Additional sentence to be added

Smoking history and current status.

Page 15 1.1. Background, third paragraph

Original text

Amended text

Page 19 Section 3.2.1.1. Inclusion criterion Number 4 for entry into the run-in period.

Original text

No change in regular medication or use of oral/parenteral steroids in the 4 weeks before Visit 1.

Amended text

No change in regular asthma medication dose or use of oral/ parenteral steroids in the 4 weeks before visit 1.

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Page 19 Section 3.2.1.2. Inclusion criteria at visit 2/2a. First sentence.

Original text

At the end of the run-in period (Visit 2/2a), patients must still comply with the inclusion criteria for entry into the run-in period and in addition, must also meet the following:

Amended text

At the end of the run-in period (Visit 2/2a), subjects must still comply with the inclusion criteria for entry into the run-in period and in addition, must also meet the following:

Page 19 Section 3.2.1.2. Inclusion criterion Number 3 at visit 2/2a.

Original text

During the 2-week run-in period, subjects must complete daily record cards on at least 10 days (run-in window is 10-18 days). Subjects who fail to meet this criteria are permitted to repeat the run-in once, at the investigators discretion.

Amended text

During the 2 week run-in period, subjects must complete daily record cards on at least 10 days (run in window 10-18 days) of which 4 days of complete data must be within the last 7 days of the run-in. Subjects who fail to meet this criterion are permitted to repeat the run-in once at the investigators discretion.

Page 20 Section 3.2.3. Other eligibility criteria considerations

Original text

Amended text

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Page 25 Section 3.3.3.1. Non-Permitted asthma medication. Last sentence.

Original text

Full details of all concurrent asthma medication and concurrent medication for other disorders must be recorded in the CRF.

Amended text

Full details of the concurrent asthma medications (except Ventolin used as relief medication in this protocol but including all other short acting bronchodilators) must be recorded in the CRF.

Page 26 Section 3.3.4. Medications permitted for other disorders. Last sentence.

Original text

Full details of all concurrent asthma medication and concurrent medication for other disorders must be recorded in the CRF.

Amended text

Full details of concurrent asthma medication (other than Ventolin provided as relief medication for the study) and all concurrent medication for other disorders must be recorded in the CRF.

Page 28 Section 5.2. Demographic and Baseline Characteristics. The following information will be recorded in the CRF at Visit 1:

Original text

Demographic information including gender, ethnic origin, date of birth, height, weight

History of asthma including duration of asthma

History of asthma exacerbation in the 12 months prior to Visit 1.

Use of corticosteroids for asthma in the 12 months prior to Visit 1, duration of inhaled corticosteroid treatment.

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Amended text

Demographic information including gender, ethnic origin, date of birth, height, weight

History of asthma including duration of asthma

History of asthma exacerbation in the 12 months prior to Visit 1.

Smoking history and current status

All previous medication for asthma in the 12 months prior to Visit 1

Classification of asthma according to National Institute of Health, National Heart, Blood and Lung Institute criteria for asthma diagnosis (8) at Visit 1.

Page 29 Section 5.2. Demographic and Baseline Characteristics. The following information will be recorded in the CRF at Visit 1, 2 or 2a:

Original text

Calculated percent predicted FEV1

Amended text

Calculated percent predicted FEV1

Page 30 Section 5.3.2. Occurrence of exacerbations, fourth bullet.

Original text

• if intervention therapy is required during a treatment period, subjects may receive oral corticosteroids (40-60mg prednisolone daily, or equivalent, for 10 days), over and above their study medication.

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Amended text

• if intervention therapy is required during a treatment period, subjects may receive oral corticosteroids (40-60mg prednisolone daily, for 7 to 10 days), over and above their study medication.

Page 29. Section 5.3.1.2. Assessment of Airway Reversibility by FEV1(Clinic) .

Addition of new text at beginning of section

FEV1 will be measured using a spirometer. Measurements will be made using the methodology in the manufacturers’ instruction booklet and in accordance with the American Thoracic Society (ATS) Standardization of Spirometry (11).

Page 31. Section 5.3.4. Asthma Control Questionnaire (ACQ). Paragraph 3.

Original text

At all visits (from V2 to V6), the investigator will provide each subject with the ACQ. The subject should be given a quiet area in which to complete the questionnaire and should be instructed to answer the first six questions only. Upon completion of these questions, the subject should return the ACQ to the investigator who will complete question 7. It is important that subjects are allowed to complete questions 1 to 6 prior to the investigator completing question 7 as the answer could influence how subjects respond to the questions. In addition, questions 1 to 6 must be completed prior to the physician consultation or any discussion over clinical test results.

Amended text

At all visits (from V2 to V6), the investigator will provide each subject with the ACQ (where translations are available). The subject should be given a quiet area in which to complete the questionnaire and should be instructed to answer the first six questions only. Upon completion of these questions, the subject should return the ACQ to the investigator. Questions 1 to 6 must be completed by the subjects prior to the physician consultation or any discussion over clinical test results. ()

Page 33. Section 5.3. Efficacy. Additional section to be added after Section 5.3.7

Amended text

5.3.8 Productivity

Details of management of the exacerbation (e.g. clinic or emergency room visit, self- managed, hospital admission etc.); duration of in-subject care (if applicable) and total

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CONFIDENTIAL GM2001/00105/01 SAM40040 time off from school, work, or usual activities; restriction/prevention from continuing usual activities will be collected.

Page 33. Section 5.3.7. Oropharangeal Examination

Original text

Oropharangeal

Amended text

Oropharyngeal

Page 33. Section 5.4. Study Medications. Second paragraph. Last sentence

Original text

This should be entered in the “Asthma Concurrent Medication” page in the CRF.

Amended text

This should not be entered in the “Asthma Concurrent Medication” page of the CRF. Use of any other short acting bronchodilator (other than ventolin provided with the study) should be recorded in the “Asthma Concurrent Medication” page of the CRF.

Page 35. Section 5.5.7 Oropharangeal Examination.

Original text

An oropharangeal examinatoin will be performed at each Visit (V1, 2/2a, 3, 4, 5 and 6)

Ameneded Text

An oropharyngal examinatoin will be performed at each Visit (V1, 2/2a, 3, 4, 5 and 6)

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Page 41. Section 6.3.3.1. Mean Daily Morning PEF Measurements (Weeks 1- 24. 1st paragraph. second sentence

Original text

Individual subject means will be compared between treatment groups using analysis of covariance, allowing for effects specified in Section 1.3.2.

Amended text

Individual subject means will be compared between treatment groups using analysis of covariance, allowing for effects specified in Section 6.3.3.

Page 42. Section 6.3.3.6. Mean Circadian Variation in Peak Flow (Weeks 1-24).

Original text

(PEFpm-PEFam| ÷ mean(PEFam,PEFpm)) x 100

Amended text

(|PEFpm-PEFam|÷mean(PEFam,PEFpm)) x 100

Page 42. Section 6.3.3.8. Daytime Symptom Scores (Weeks 1-24)

Original text

Amended text

Provided parametric model assumptions hold, mean symptom scores (recorded in the evening) on the DRC will be calculated for each subject and analysed using analysis of covariance in the same way as for the lung function endpoints. A tabulation of summary statistics by treatment group will also be produced.

Page 42. Section 6.3.3.9. Night-time Symptom Scores (Weeks 1-24)

Original text

These will be calculated using the symtpom score recorded in the DRC in the evening and analysed in the same way as daytime symptom scores.

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Amended text

These will be calculated using the symtpom score recorded in the DRC in the morning and analysed in the same way as daytime symptom scores.

Page 46. Section 7.2.1. Events or Outcomes Not Qualifying as SAEs

Original text

Amended text

Remove section entirely

Page 47. Section 7.5. Methodology, frequency and time period for detailing AEs and SAEs, third paragraph, third sentence

Original text

Non-serious adverse events with the exception of asthma exacerbations, which will be recorded in the CRF, will be captured in the subjects’ notes, in accordance with the investigators normal practice, but no capture in the CRF’s.

Amended text

Non-serious adverse events including asthma exacerbations, will be recorded in the CRF.

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Page 49 Section 7.8.1. Timeframes for submitting SAE reports to GW

Original text

7.8.1. Timeframes for Submitting SAE Reports to GSK

Revised text

7.8.1. Timeframes for Submitting SAE Reports to GSK

Initial SAE Reports Follow-up Information on a Previously Reported SAE

Type of SAE Time Frame Documents Time Frame Documents

All SAEs 24 hrs "SAE" CRF 24 hrs Updated "SAE" pages CRF pages

Page 50. Section 8.1. Data Management, subsection headings

Original text for subheadings

8.1 Data Management

8.1.1. Subject Tracking

8.1.2. Data Collection and Retrieval

8.1.3. Database Processing

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Amended text for subheadings

8.1 Data Management

8.1.1. Data Collection and Retrieval

8.1.2. Database Processing

Foot note: All retained text is unchanged.

Page 56. Section 9. References

Addition of reference

1. Standardization of Spirometry – 1987 update. American review of Respiratory Disease 1987; 136: 1285-1298.

Page 57 Section 10.1. Tables 1, Time and Events Schedule

Original text

Timeline: Visit 1 Visit 2/2a Visit 3 Visit 4 Visit 5 Visit 6 Optional -2w ±±± 4d (Day 0) 4w ±±± 1w 8w ±±± 1w 16w ±±± 1w 24 ±±± 1w follow-up Period Run-in Treatment Follow-up Treatments Usual Seretide Diskus (50mcg salmeterol xinafoate + 250mcg Appropriate inhaled fluticasone propionate, actuated dose) 1 inhalation bd asthma steroids OR medication Symbicort BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose) 2 inhalations bd Relief Ventolin Relief Ventolin Visit 1 2/2A 3 4 5 6 7 Informed Consent X Demography X Reversibilityª XX Inclusion/Exclusion Criteria X X Medical History X Oropharangeal exam XXXXXX X b Lung Function (FEV1)XXXXXXX b Issue Daily Record Cards X X X X X Issue Study Medication X XX ACQ c XXXXX Collect Daily Record Cards XXXXX Collect Study Medication XXX X b Adverse Event XXXXX X b Concurrent Medication X X X X X X X ª at only one of the Visits 1, 2/2a or up to 2 years before Visit 2/2a b if follow-up visit required these procedures may be performed c ACQ should be completed by the subject prior to the visit with the investigator/study team

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Revised text

Timeline: Visit 1 Visit 2/2a Visit 3 Visit 4 Visit 5 Visit 6 Follow-up -2w ±±± 4d (Day 0) 4w ±±± 1w 8w ±±± 1w 16w ±±± 1w (or contact premature discontinu ation) 24 ±±± 1w Period Run-in Treatment Follow-up Treatments Usual Seretide Diskus (50mcg salmeterol xinafoate + 250mcg Appropriate inhaled fluticasone propionate, actuated dose) 1 inhalation bd asthma steroids OR medication Formoterol/budesonide BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose) 2 inhalations bd Relief Ventolin Relief Ventolin Visit 1 2/2A 3 4 5 6 7 Informed Consent X Demography X Pregnancy test X XXb Reversibilityª XX Inclusion/Exclusion Criteria X X Medical History X Oropharangeal exam XXXXXX X b Lung Function (FEV1)XXXXXXX b Health care contacts XXXXX b Issue Daily Record Cards X X X X X Issue Study Medication X XX ACQ c XXXX X Collect Daily Record Cards XXXXX Collect Study Medication XXX X b Adverse Event X d XXXX X X b Concurrent Medication X X X X X X X b ª at only one of the Visits 1, 2/2a, if not performed in the 2 years before Visit 2/2a b if follow-up visit required these procedures may be performed c ACQ should be completed by the subject before the interview with the investigator/study team d study participation events only

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Page 58. Section 11. Figures, Figure 1

Original text

Run-in Study treatment Follow-up

Seretide Diskus (50mcg salmeterol xinafoate + 250mcg fluticasone propionate, actuated dose), 1 inhalation bd

BDP (1000-2000 mcg/d same as pre-study dose)

or equivalent

Symbicort BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose), 2 inhalations bd

Weeks -2 0 4 8 16 24 25

Visits V1 V2 V3 V4 V5 V6 Follow-up contact

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Revised text

Run-in Study treatment Follow-up

Seretide Diskus (50mcg salmeterol xinafoate + 250mcg fluticasone propionate, actuated dose), 1 inhalation bd

BDP (1000-2000 mcg/d same as pre-study dose)

or equivalent

formoterol/budesonide BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose), 2 inhalations bd

Weeks -2 0 4 8 16 24 25

Visits V1 V2 V3 V4 V5 V6 Follow-up contact

Page 60. Appendix 2 Asthma symptom scores. Daytime symptom score

Original text

3 = Symptoms for most of the day which did not affect my daily activities.

Revised text

3 = Symptoms for most of the day which did not affect my normal daily activities.

18 CONFIDENTIAL YM2002/00030/00 The GlaxoSmithKline group of companies SAM40040

Division: New Product Document Number: YM2002/00030/00 Development Document Type: Reporting and Analysis Study Identifier: SAM40040 Plan Site of Issue: Greenford Classification: Level 2 Issue Date: 3rd December 2002

Title: Reporting and Analysis Plan for SAM40040. A twenty-four week, randomised, double- dummy, double-blind, parallel group study to compare the occurrence of exacerbations between salmeterol xinafoate/fluticasone propionate Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide breath-actuated dry powder inhaler 4.5/160mcg 2 inhalations bd in subjects with moderate to severe asthma.

Abstract: (For Internal Use Only)

Authors:

Compound Numbers/Keywords (if applicable):

FINAL 03-Dec-02 CONFIDENTIAL YM2002/00030/00 The GlaxoSmithKline group of companies SAM40040

Distribution: *denotes summary only, **denotes partial copy only Respiratory Clinical Development & Medical Affairs, UK Respiratory Clinical Development & Medical Affairs, UK Respiratory Clinical Development & Medical Affairs, UK Respiratory Clinical Development & Medical Affairs, UK Respiratory Clinical Development & Medical Affairs, UK Biomedical Data Sciences, Respiratory Biomedical Data Sciences, Respiratory Biomedical Data Sciences, Respiratory Global Health Outcomes, UK Global Clinical Safety and Pharmacovigilance

For all documents originating from North America and South America: US Internal Databases, RTP 17.2136J (1 copy, unbound, plain paper, single-sided).

For all clinical documents originating from the UK or Rest of World: UK INDI Team, Bldg. 20E, Greenford (2 copies, unbound, plain paper, single-sided).

FINAL 03-Dec-02 CONFIDENTIAL YM2002/00030/00 SAM40040

Title:

Reporting and Analysis Plan for SAM40040. A twenty-four week, randomised, double- dummy, double-blind, parallel group study to compare the occurrence of exacerbations between salmeterol xinafoate/fluticasone propionate Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide breath-actuated dry powder inhaler 4.5/160mcg 2 inhalations bd in subjects with moderate to severe asthma.

YM2002/00030/00 Study No.: SAM40040 Document Type: Reporting and Analysis Plan Document Date: 3rd December 2002

Author(s):

Department: BDS Respiratory Stats & Programming

RAP Version Number: Final Version

Date of version: 3rd December 2002

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Approval Page

Study Identifier: SAM40040

Study Title: A twenty-four week, randomised, double-dummy, double-blind, parallel group study to compare the occurrence of exacerbations between salmeterol xinafoate/fluticasone propionate Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide breath-actuated dry powder inhaler 4.5/160mcg 2 inhalations bd in subjects with moderate to severe asthma.

YM2002/00030/00 Document Type: Reporting and Analysis Plan Document Date: 3rd December 2002

Approver(s): Signature: Date:

Biostatistics & Programming Manager Biomedical Data Sciences

Statistician Biomedical Data Sciences

Clinical Research Scientist Respiratory Clinical Development & Medical Affairs, UK

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TABLE OF CONTENTS

PAGE

1. INTRODUCTION ...... 6

2. STUDY OBJECTIVE(S) AND ENDPOINT(S) ...... 6 2.1. Study Objective(s) ...... 6 2.2. Study Endpoint(s) ...... 7 2.3. Statistical Hypotheses...... 7

3. STUDY DESIGN ...... 8

4. PLANNED ANALYSES ...... 8 4.1. Interim Analyses ...... 8

5. SAMPLE SIZE CONSIDERATIONS ...... 8

6. ANALYSIS POPULATIONS ...... 9

7. TREATMENT COMPARISONS ...... 10

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES ...... 10 8.1. Multicentre Studies ...... 10 8.2. Other Strata and Covariates ...... 10 8.3. Examination of Subgroups ...... 10 8.4. Multiple Comparisons and Multiplicity ...... 10

9. DATA HANDLING CONVENTIONS ...... 11 9.1. Premature Withdrawal and Missing Data ...... 11 9.2. Derived and Transformed Data ...... 11 9.3. Assessment Windows ...... 13 9.4. Values of Clinical Concern ...... 14

10. STUDY POPULATION ...... 14 10.1. Disposition of Subjects ...... 14 10.2. Protocol Deviations ...... 15 Subjects whose visits fall outside of the windows defined in Section 0 ...... 18 10.3. Demographic and Baseline Characteristics ...... 19 10.4. Treatment Compliance ...... 20

11. EFFICACY ANALYSES ...... 20 11.1. Primary Efficacy Analysis(es) ...... 21 11.1.1. Exacerbations to be included in analyses ...... 21 11.1.2. Exacerbations During the run-in Period ...... 21 11.2. Secondary Efficacy Analysis(es) ...... 22 11.2.1. Number of Exacerbations ...... 22 11.2.2. Severity of Exacerbations ...... 22 11.2.3. Time to First Exacerbation ...... 22 11.3. Other Efficacy Analysis(es) ...... 23 11.3.1. Mean Daily Morning PEF Measurements (Weeks 1-24)...... 23

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11.3.2. Mean Daily Morning PEF Measurements (Weeks 1-8, 9- 16,17-24)...... 23 11.3.3. Mean Daily Evening PEF Measurements (Weeks 1-24)...... 23 11.3.4. Mean % Predicted Morning PEF (Weeks 1-24) ...... 23 11.3.5. Mean % Predicted Evening PEF (Weeks 1-24) ...... 23 11.3.6. Mean Circadian Variation in Peak Flow (Weeks 1-24) ...... 24 11.3.7. Clinic FEV1...... 24 11.3.8. Daytime Symptom Scores (Weeks 1-24)...... 24 11.3.9. Night-time Symptom Scores (Weeks 1-24)...... 24 11.3.10. Percentage of Symptom Free Days (Weeks 1-24) ...... 24 11.3.11. Percentage of Symptom Free Nights (Weeks 1-24) ...... 24 11.3.12. Percentage of Days with No Relief Medication (Weeks 1- 24) ...... 25 11.3.13. Percentage of Nights with No Relief Medication (Weeks 1- 24) ...... 25 11.3.14. Withdrawals Due to Lack of Efficacy ...... 25 11.3.15. ‘Well-controlled’ Asthma ...... 25 11.3.16. Asthma Control Questionnaire ...... 25 11.3.17. Exploratory Sensitivity Analysis of Exacerbation Rates ...... 25

12. SAFETY ANALYSES ...... 26 12.1. Extent of Exposure ...... 26 12.2. Adverse Events...... 26 12.3. Deaths and Serious Adverse Events ...... 26 12.4. Device Incidents and Near Incidents ...... 26 12.5. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events...... 26 12.6. Pregnancies (as applicable) ...... 27 12.7. Clinical Laboratory Evaluations ...... 27 12.8. Other Safety Measures ...... 27 12.8.1. Oropharyngeal Candidiasis ...... 27 12.8.2. Unscheduled/Emergency Visits ...... 27

13. HEALTH OUTCOMES ANALYSES ...... 27 13.1. Humanistic Measures ...... 27 13.2. Resource Utilisation Measures ...... 27

14. CLINICAL PHARMACOLOGY DATA ANALYSES ...... 28

15. BIOMARKER DATA ANALYSIS ...... 28

16. PHARMACOGENETIC DATA ANALYSES ...... 28

17. VIRAL GENOTYPING/PHENOTYPING ...... 28

18. REFERENCES ...... 29

19. ATTACHMENTS ...... 30 19.1. Table of Contents for Data Display Specifications ...... 30 19.2. Data Display Specifications ...... 34

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List of Abbreviations

ACQ Asthma Control Questionnaire AE Adverse Event BADPI Breath-actuated Dry Powder Inhaler bd Twice Daily BDP Beclomethasone Dipropionate BDS Biomedical Data Sciences CDMA Clinical Development and Medical Affairs CI Confidence Interval CPMP Committee for Proprietary Medicinal Products DRC Diary Record Card FBC formoterol/budesonide combination ICH International Conference on Harmonisation ITT Intent-to-Treat IUD Inter-uterine Device

FEV1 Forced Expiratory Volume in one second GCSP Global Clinical Safety and Pharmacovigilance GSK GlaxoSmithKline GW GlaxoWellcome mcg micrograms MIDAS/MEDRA Medical Conditions, Indications, Diagnoses, Adverse Events, and Symptoms Dictionary Database mls millilitres PEF Peak Expiratory Flow PP Per-protocol Population RAP Reporting and Analysis Plan SAE Serious Adverse Event SFC salmeterol xinafoate/fluticasone propionate combination

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1. INTRODUCTION

This Reporting and Analysis Plan (RAP) is written to describe intended analyses for SAM40040 – a salmeterol xinafoate/fluticasone propionate combination Phase IV protocol (document number GM2001/00105/01). Results from efficacy analyses of this study will be used for publication and marketing purposes. All study results will be included in a Clinical Study Report.

In this RAP references are made to the following study document:

The European Agency for the Evaluation of Medicinal Products, Note for Guidance on Statistical Principles for Clinical Trials, ICH Topic E9, (CPMP/ICH/363/96), 18 March 1998.

This RAP conforms to GSK Document Standard DS-NPD-400 v01 – Reporting and Analysis Plan.

The audience for this document are any members of the Seretide BDS and CDMA groups involved in the conduct of study SAM40040.

2. STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1. Study Objective(s)

Primary

To compare the efficacy of salmeterol xinafoate/fluticasone propionate combination Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide combination BADPI 4.5/160mcg 2 inhalations bd in preventing the occurrence of asthma exacerbations in moderate to severe asthma.

Secondary

To compare the efficacy of two treatment groups in treating moderate to severe asthma with respect to severity of exacerbations

Other Objectives

To compare the efficacy of two treatment groups in treating moderate to severe asthma with respect to lung function To compare the efficacy of two treatment groups in treating moderate to severe asthma with respect to the incidence of adverse events

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2.2. Study Endpoint(s)

Primary

To evaluate efficacy relative to the measurement of the rate of asthma exacerbations experienced by subjects as expressed as a rate over the 24-week treatment period

Secondary

Severity of exacerbations Number of exacerbations Time to first exacerbation

Other

To evaluate efficacy relative to the measurement of the following parameters:

morning PEF evening PEF

Clinic FEV1 days with no symptoms nights with no symptoms change in symptom scores days with no need for relief medication nights with no need for relief medication number of subjects who achieve ‘well-controlled’ asthma asthma control score as measured by the Asthma Control Questionnaire (ACQ) time missed from work or usual activities resource utilisation incidence of adverse events

2.3. Statistical Hypotheses

Null Hypothesis

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Salmeterol xinafoate/fluticasone propionate combination Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide combination BADPI 4.5/160mcg 2 inhalations bd have equal effect in preventing the occurrence of asthma exacerbations in moderate to severe asthma:

H0: μ1 – μ2= 0

Alternative Hypothesis Salmeterol xinafoate/fluticasone propionate combination Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide combination BADPI 4.5/160mcg 2 inhalations bd have different effects in preventing the occurrence of asthma exacerbations in moderate to severe asthma:

H1: μ1 μ2

Where μ1 and μ2 are the mean exacerbation rates in the salmeterol xinafoate/fluticasone propionate combination and formoterol/budesonide combination groups respectively. All tests will use a two-sided significance level of α=0.05, unless otherwise specified (see Section 11.1.2). P-values of 0.05 will be considered statistically significant.

3. STUDY DESIGN

A randomised, double-dummy, double-blind, parallel group study comparing salmeterol xinafoate/fluticasone propionate combination Diskus 50/250mcg 1 inhalation bd and formoterol/budesonide combination BADPI 4.5/160mcg 2 inhalations bd.

4. PLANNED ANALYSES

4.1. Interim Analyses

No formal unblinded interim statistical analyses is planned.

5. SAMPLE SIZE CONSIDERATIONS

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20% in the relative risk of exacerbations with salmeterol xinafoate/fluticasone propionate combination, at a two-sided =0.05 significance level with 90% power using Poisson regression techniques, 525 subjects per group will be required.

Therefore, incorporating a 20% overage to account for invalidity and withdrawals, 656 subjects per group should be randomised, 1312 in total.

6. ANALYSIS POPULATIONS

Three populations will be considered for analysis:

Total Population

Intent-to-Treat Population

The intent-to-treat (ITT) population represents all subjects randomised to treatment who have taken at least one dose of study medication and have at least one post-randomisation diary assessment. Randomised subjects will only be excluded if there is clear evidence of failure to take any study medication or if there is no on-treatment DRC data. Subjects in the ITT population will be analysed for efficacy according to the treatment group to which they were randomised. The ITT population will be used for all tables and analyses (except those specified for the Total, Safety or Per Protocol Populations) and will be the primary population for all efficacy endpoints and for all safety endpoints (provided all subjects receive the treatment to which they were randomised).

Safety Population

The safety population represents all subjects who have been randomised to treatment and have taken at least one dose of study medication. If any subjects do not receive study treatment as randomised, they will be analysed for safety according to the treatment they actually received. If this occurs, the patient population for the tables and listings of safety data will be labelled as the Safety Population.

Per Protocol Population

This population will consist of all subjects in the ITT population who do not have any protocol violations which could impact treatment effect. These violations will be defined explicitly in the RAP and the decision to exclude a subject from the Per Protocol population will be made prior to breaking the study blind. For the Per Protocol population, subjects will be analysed according to the treatment received, providing the same treatment was taken for the duration of the study. If study medication was changed then the subject will be considered a partial protocol violator (i.e. from the point of

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7. TREATMENT COMPARISONS

The primary comparison of interest will be the treatment comparison of salmeterol xinafoate/fluticasone propionate combination to formoterol/budesonide combination.

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES

8.1. Multicentre Studies

8.2. Other Strata and Covariates

Covariates expected to have an influence on efficacy are baseline value, country cluster, sex and age. All of these variables will be included in all efficacy analyses, where appropriate, as explanatory covariates.

8.3. Examination of Subgroups

Interactions of treatment with sex, country and age will be tested in separate analysis models for statistical significance at the 10% level. If an interaction is considered meaningful, the effects of treatment will also be presented separately for each subgroup factor level.

8.4. Multiple Comparisons and Multiplicity

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9. DATA HANDLING CONVENTIONS

9.1. Premature Withdrawal and Missing Data

Length of time (days) on the study is defined as :

(treatment stop date – treatment start date) + 1

For any subject who withdraws from the study prematurely, all available data up to the time of discontinuation will be included in the analysis. In addition, missing data will be imputed for the purposes of efficacy analyses if subjects withdraw from the study due to lack of efficacy or adverse event due to lack of efficacy. For lung function measurements and symptom scores, values will be calculated using a last observation carried forward approach.

The actual number of days with non-missing values will be used as the denominator in the derivation of ‘percentage’ endpoints, e.g. % symptom-free days/nights, rather than the total number of days in the assessment period.

No. of exacerbations per 24 weeks = 6 x no. of exacerbations / no. of 4 week periods, where number of 4 week periods equals the number of weeks on treatment divided by 4, rounded up. This imputation is only for the purposes of summarising the data, as the statistical analysis will not use the imputed data.

9.2. Derived and Transformed Data

Percent reversibility

Post-bronchodilator FEV1 –pre-bronchodilator FEV1 x 100 pre-bronchodilator FEV1

Definition of asthma exacerbation(s)

Each exacerbation is characterised based on one or more of the following defining characteristics (taking the worst to determine the applicable severity):

Mild

morning PEF >20% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or;

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more than 3 additional reliever occasions/24-hour period with respect to baseline for > 2 consecutive days, or;

awakening at night due to asthma for > 2 consecutive nights

Moderate

A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for > 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Severe

deterioration in asthma which requires hospital admission.

Mean % Predicted Morning or Evening PEF

This will be calculated using the guidelines of the working party of the European Community for Coal and Steel according to the following formula: (AM PEF/Predicted PEF) x 100

(PM PEF/Predicted PEF) x 100

The ECCS formula calculates predicted PEF using the following equations, according to the sex of the subject, where height is measured to the nearest cm and age is in whole years attained:

Predicted PEF = [(6.14 x Height (cm) / 100) – (0.043 x Age (yrs)) + 0.15] x 60 (for males)

Predicted PEF = [(5.50 x Height (cm) / 100) – (0.030 x Age (yrs)) – 1.11] x 60 (for females)

Mean Circadian Variation in Peak Flow

Circadian variation will be calculated according to the following formula: (|PEFpm-PEFam| mean(PEFam,PEFpm)) x 100

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CONFIDENTIAL YM2002/00030/00 SAM40040 where the PEFpm is the evening PEF from the DRC and PEFam is the PEF from the following morning.

Definition of Well Controlled Asthma

Subjects will have their asthma control assessed weekly for the duration of the study based on symptoms, use of relief medication and peak flow measurements.

A week of ‘well-controlled’ asthma is defined as meeting the following criteria assessed over 7 consecutive days:

1. two or more of the following 3 criteria:

a symptom score of greater than 1 on no more than two days

no more than 2 days of rescue salbutamol/albuterol use, up to a maximum of 4 occasions per week

80% predicted AM PEF every day

AND

2. all of the following criteria:

no night-time awakenings due to asthma

no exacerbations

no emergency visits

no treatment related adverse effects enforcing a change in asthma therapy

Definition of Baseline for Efficacy Analyses

For the purposes of all diary card efficacy analyses, baseline is defined as the mean of the daily values over the last seven days (prior to treatment start date) of the two-week run- in. For clinic visit efficacy endpoints, baseline is defined as the pre-Ventolin visit 2/2a assessment.

9.3. Assessment Windows

Study visits will be performed at the required intervals relative to the Randomisation Visit, Visit 2/2a. The following windows are acceptable:

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Visit 1 (Screening visit) Week –2 (or Week –4 4 days if run-in repeated 8 days

Visit 2/2a (Randomisation visit) Day 0

Visit 3 Week 4 Day 28 7 days

Visit 4 Week 8 Day 56 7 days

Visit 5 Week 16 Day 112 7 days

Visit 6 Week 24 Day 168 7 days

Early withdrawal/Visit 6 may occur at any time after randomisation.

The follow-up telephone contact is relative to the Week 24 visit

Follow-up contact Week 24 +7 days 2 days

9.4. Values of Clinical Concern

No laboratory data are being collected.

10. STUDY POPULATION

Tabulations of the study populations will be produced using the ITT Population and the Per Protocol Population, when specified.

10.1. Disposition of Subjects

A data display using the Total Population will be produced to account for all subjects involved in the study, including the number of subjects randomised.

Individual subject listings will also be prepared showing treatment allocation, country of recruitment and investigator. Information regarding the number of patients screened by investigator and country allocation will be tabulated. Summaries of the number of patients randomised for both the ITT and PP populations will also be tabulated.

Overall percentages of withdrawal from the study will be tabulated by treatment group, as will be the reasons for withdrawal. Tables and listings of withdrawals will be split into those that occurred prior to randomisation, using the Total Population and those that occurred post-randomisation, using the Intent-To-Treat Population. Withdrawals after randomisation by time in study will also be tabulated.

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A listing of subjects who did not satisfy the entry criteria will be given and the number in each treatment group tabulated.

For all patients in the ITT population, a tabulation of the number of patients attending each scheduled clinic visit will be given.

10.2. Protocol Deviations

Subject data will be examined for evidence of protocol violations in order to assess how well the protocol was followed. Where possible, inclusion and exclusion criteria will be assessed. If any of the data are not available, a written confirmation from the investigator will be given on the compliance of all subjects to these criteria.

Violators of these criteria will be shown in a listing. They will not be excluded from any ITT Population analyses. However, major protocol violators will be excluded from the Per Protocol Population. Minor protocol violators will not be excluded from the Per Protocol Population. Subjects can be either full or partial protocol violators. A full protocol violator is completely excluded from the Per Protocol Population. A partial protocol violator is excluded from the Per Protocol population from the point that they violated the protocol. For subjects who violated the protocol during the treatment period due to non-permitted changes in medication or non-permitted concurrent medication, the analysis will only use data recorded prior to the violation. Where lung functions measurements have been affected by the use of rescue medication, data will be excluded at the particular assessment it occurred.

Major Protocol Violations

The major protocol violations are detailed below. A subject is a major protocol violator if they are reported in the CRF or subsequently found to have failed to meet one or more of the inclusion criteria shown below and/or met one or more of the exclusion criteria shown below.

Inclusion criteria for entry into the run-in period at Visit 1

1. Male or female out patients A female is eligible to enter and participate in the study if she is of:

a) Non childbearing potential (i.e. physiologically incapable of becoming pregnant), including any female who is post-menopausal. For the purposes of this study, post menopausal is defined as one year without menses; or

b) Child-bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the acceptable contraceptive methods when used consistently and correctly (i.e. in accordance with the approved product

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label and the instructions of a physician for the duration of the study – Screening visit to Follow-up contact).

Complete abstinence from intercourse from two weeks prior to the study medication administration, throughout the 24-week treatment phase, and for one week following study completion; or

Sterilisation of male partner; or

Implants of levonorgestrel inserted for at least one month prior to the study medication administration but not beyond the third successive year following insertion; or

Injectable progestogen administered for at least one month prior to the study medication administration and administered for one month following study completion; or

Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or

An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or

Any other methods with published data showing that the highest expected failure rate is less than 1% per year.

2. At least 18 years of age at the time of Visit 1 (Screening Visit).

3. Documented clinical history of asthma for at least 6 months prior to Visit 1

4. No change in regular medication or use of oral/parenteral steroids in the 4 weeks before Visit 1

5. Currently receiving 1000-2000mcg/day BDP or equivalent, such as 800-1600mcg/day budesonide, 500-1000mcg/day fluticasone propionate or QVAR, for at least 4 weeks prior to Visit 1

6. A signed and dated written informed consent is obtained from the subject prior to study participation

7. Able to comply with therapy and to complete daily record cards and subject- completed questionnaires correctly.

Inclusion criteria at Visit 2/2a

At the end of the run-in period (Visit 2/2a), patients must still comply with the inclusion criteria for entry into the run-in period and in addition, must also meet the following:

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1. At Visit 1 or 2/2a, a demonstrable reversible increase in FEV1 of at least 12% (and 200mls), 15 minutes after inhaling 200-400mcg of Ventolin or; At any time in the last 2 years documentary evidence of a reversible increase in FEV1, of at least 12% (and 200mls), 15 mins after inhaling a short-acting bronchodilator

2. During the 2-week run-in period (10 to 18 days), subjects must have an asthma symptom score (day and night combined) of a least 2 (see Appendix 2, Section 12.2) recorded in their daily record card on at least 4 of the last 7 evaluable days

Exclusion Criteria

1. History of upper or lower respiratory tract infection, middle ear or sinus infection within 4 weeks prior to Visit 1 2. An acute asthma exacerbation requiring emergency hospital/clinic treatment and/or hospitalisation within 4 weeks prior to Visit 1 3. A smoking history of 10 pack years, or likely to change smoking habits during the study, or having given up smoking within 4 weeks of Visit 1 4. Previous participation in a clinical study in which the subject was exposed to an investigational or non-investigational medication or device within 30 days prior to Visit 1 5. Concurrently participating in another clinical study in which the subject is or will be exposed to an investigational or a non-investigational medication or device 6. Any evidence of or treatment of malignancy (other than localised basal cell, squamous cell skin cancer or localised cancer in situ that has been resected) within the previous five years 7. A pregnant woman or any woman intending to become pregnant 8. A woman breastfeeding an infant(s) 9. Inability or unwillingness to take study medication (non-compliance), follow directions or unable to complete a written paper daily record card and self-rating questionnaires 10. Previous allergic reaction to study medications or any excipients of the formulations

11. Subjects receiving any of the following medications: long-acting inhaled 2-agonists, oral 2-agonists or slow-release bronchodilators, combination therapy (containing 2- agonist and/or inhaled corticosteroids for asthma), sodium cromoglycate or nedocromil sodium, ketotifen, leukotriene-receptor antagonists, anticholinergics, short-acting inhaled 2-agonists (other than Ventolin provided at Visit 1), theophyllines, these medications must be stopped at Visit 1. (During the run-in, subjects continue on their pre-study dose of inhaled corticosteroids, which are stopped at Visit 2/2a).

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12. Use of oral/parenteral corticosteroids for 4 weeks prior to Visit 1 13. Use of depot corticosteroids for 12 weeks prior to Visit 1 14. History of alcohol or medication abuse

DRC Data Violations

Violators of the following criterion are partial violators and data will only be excluded at the particular assessment it occurred.

1. Subjects who had lung functions measurements affected by the use of rescue medication, i.e. subjects have taken relief medication within 6 hours of measuring PEF in the DRC.

Other Violations

1. For subjects not withdrawing early from the study, subjects who fail to take a total of at least 80% study drug, as reported in the drug accountability records for the Diskus and BADPI.

2. Unblinding of the treatment allocation for subjects (except for emergency treatment or care of the subject) will result in partial violators and subjects’ data will be excluded from the analysis from the time at which the unblinding occurred.

Minor Protocol Violations

The following violation will not be used to exclude subjects, nor exclude subject data, from the Per Protocol analysis but will be identified in a data listing:

Subjects whose visits fall outside of the windows defined in Section 0

Assessment Windows (except Visit 6 when this occurs as an Early Withdrawal Visit).

For subjects with less than 8 weeks of diary data: those who fail to record a total of at least 70% of the required PEF diary data during the treatment period. For those with greater than 8 weeks of diary data, at least 30% of the PEF data for the number of days in the treatment period before withdrawal needs to be recorded.

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10.3. Demographic and Baseline Characteristics

Data collected at Visit 1 pertaining to demography i.e. age, sex, ethnic origin, height, and weight will be tabulated by treatment group using both Intent-To-Treat and Per Protocol Populations and listed for the Intent-To-Treat population. Summaries for the childbearing status and pregnancy test results of female subjects and smoking status will also be provided.

Baseline data, i.e. current medical conditions and medications taken will only be reported using the Intent-To-Treat Population. A unique terms report showing the relationship between medications’ verbatim, preferred and grouped terms will be given.

Summaries of asthma medications will be split between any medication that started prior to treatment start, i.e. randomisation (regardless of when it ceased) and any medication that was present during the treatment period (regardless of when it commenced). Non- asthma medications that were present during the treatment period only, will be reported. Asthma and non-asthma medications will be listed separately. The following tabular All medication verbatim text will be coded using the THERAPY dictionary to obtain the appropriate therapy group and preferred term.

Disease history will be summarised by treatment group, including:-

Duration of asthma symptoms

Duration of inhaled corticosteroid use

The number of asthma exacerbations in the previous 12 months that required oral corticosteroids and/or antibiotics treatment or hospitalisation will be summarised by treatment group. The initial assessment and diagnosis of asthma will be listed only.

No formal statistical comparisons between treatments will be performed for baseline and demographic characteristics.

Baseline Clinic Lung function data recorded at Visits 1 and 2/2A (both pre-Ventolin and post-Ventolin assessments will be considered) will be summarised by treatment group using both Intent-to-Treat and Per Protocol Populations, including:-

Clinic Pre-Ventolin FEV1

Clinic Post-Ventolin FEV1

Predicted Normal FEV1 and % Predicted Normal FEV1

% Reversibility

In addition, the mean values of the DRC data recorded over the last seven days of the run-in period will be summarised by treatment group using both Intent-to-Treat and Per- Protocol Populations, including:-

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Mean morning PEF

Mean evening PEF

Mean circadian variation in PEF

Mean % predicted morning PEF

Mean % predicted evening PEF

Mean daytime symptom scores

Mean night-time symptom scores

% symptom-free days

% symptom-free nights

% Ventolin–free days

% Ventolin-free nights

10.4. Treatment Compliance

Compliance will be assessed by:

Compliance = number of doses used /number of doses expected to be used x 100% and both tabulated by treatment group and listed.

Assuming that treatment started on the date of the randomisation visit, and that only one dose is taken that day, while 2 are taken every other day the number of doses expected to be used is:

Expected no. of doses used = [ 2 x (treatment stop date – randomisation date + 1)] – 1

The doses used will be calculated as the sum of the doses used over all Diskus inhalers given, including reserve inhalers. Each Diskus contains 60 doses therefore, for each Diskus, the doses used will be calculated as:

60 - number of doses remaining

If for some reason the data is missing (e.g. the Diskus is not returned), worst case will be assumed, i.e. that zero doses were taken.

11. EFFICACY ANALYSES

The analysis methodology for this study is described in the sections below. If at any time after protocol finalisation, a change to the planned analyses is considered necessary, this

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11.1. Primary Efficacy Analysis(es)

The primary efficacy endpoint is the number of asthma exacerbations experienced by the subject, expressed as a rate over the period of treatment, based on the ITT population. This will be analysed using maximum likelihood based analysis, assuming the Poisson distribution, with time on treatment as an offset variable.

The model will include adjustment for effects of sex, country (grouping) and age. The adjusted mean rates per 24-week treatment period, treatment ratio and associated p-values and confidence intervals will be presented.

Interactions of treatment with sex, country (grouping) and age will be tested in separate analysis models for statistical significance at the 10% level. If an interaction is considered meaningful, the effects of treatment will also be presented separately for each subgroup factor level.

Any potential over-dispersion will be accounted for by using ‘SCALE=DEVIANCE’ in the model. A sensitivity analysis will be conducted with out adjusting for any overdispersion.

The analysis will be repeated for the Per-Protocol population, if used. The exacerbation data for each patient in the Intent-to-Treat population will be listed.

11.1.1. Exacerbations to be included in analyses

For the purposes of all primary and secondary analyses, any exacerbation regardless of severity, that begins pre-treatment will not be included. Only exacerbations that are treatment emergent (i.e. exacerbation onset date >= treatment start date) will be included in the analyses.

11.1.2. Exacerbations During the run-in Period

The number of exacerbations commencing during the run-in period, including those that continue into the treatment period, will be summarised by severity and treatment group for the Intent-to-Treat population, but no formal statistical tests will be performed.

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11.2. Secondary Efficacy Analysis(es)

11.2.1. Number of Exacerbations

The number of exacerbations per subject will be assigned to one of the following four categories:- 0, 1, 2, 3, >3. The percentage of subjects in each category will be presented by treatment group, and treatment groups compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country (grouping) and treatment. This model will be used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

The number of subjects with at least one exacerbation will be analysed using the Cochran-Mantel-Haenszel test, stratified by country (grouping). Percentages, differences in percentages between treatments, 95% confidence intervals and p-values will be presented.

11.2.2. Severity of Exacerbations

The number and percentage of subjects with mild, moderate and severe exacerbations will be presented by treatment.

Each subject will be assigned to a ‘severity’ category based on the maximum severity of any of their exacerbations. The percentage of subjects in each category will be presented by treatment group, and treatment groups will be compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country (grouping) and treatment. This model will be used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

11.2.3. Time to First Exacerbation

Time to first exacerbation will be summarised using survival analysis. Subjects not experiencing any exacerbations and patients who withdraw from the study early, will be censored at their last assessment date. A Cox’s proportional hazard model will be used to compare treatment groups. Age, sex and country (grouping) will be used as covariates in the model. If the assumption of proportionality of hazards is clearly not met, ascertained by examination of plots of the log(log[survival curve]) versus time, then a Wilcoxon test will be used with treatment as a single covariate.

A Kaplan Meier estimate of the survival curve will be produced for this endpoint.

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11.3. Other Efficacy Analysis(es)

Lung function endpoints and ACQ total score will be analysed using analysis of covariance, allowing for effects due to baseline value (see Section 9.2 for definition, unless specified otherwise), country (grouping), sex, age and treatment. If assumptions underlying the analysis model are not met for these or other efficacy endpoints, the data will be log transformed. If assumptions are still not met for a specific endpoint, it will be analysed non-parametrically using the Van Elteren extension to the Wilcoxon Rank Sum test with treatment as a single covariate.

Tests for interactions will not be performed on these endpoints. Also, analysis of the Per- Protocol population will not be performed, unless different results were obtained from the two populations for the primary endpoint.

Data for the endpoints derived from DRC data will be listed.

11.3.1. Mean Daily Morning PEF Measurements (Weeks 1-24).

The mean daily morning PEF will be derived from the DRC over the 24-week treatment period. Individual subject means will be compared between treatment groups using analysis of covariance, allowing for effects specified in Section 11.3. This model will be used to estimate the treatment group difference and p-value, and calculate the 95% confidence interval for this difference.

Summary statistics for the raw and adjusted values of the mean and mean change from baseline will also be presented.

11.3.2. Mean Daily Morning PEF Measurements (Weeks 1-8, 9-16,17-24).

This will be derived from the DRC data for the time intervals above, using time windows specified in Section 0, and will be analysed using analysis of covariance as above . A summary table will also be prepared.

11.3.3. Mean Daily Evening PEF Measurements (Weeks 1-24).

This will be derived, analysed and summarised in the same way as for morning PEF (Section 11.3.1).

11.3.4. Mean % Predicted Morning PEF (Weeks 1-24)

Mean values over the 24-week treatment period will be analysed using analysis of covariance and summarised by treatment group.

11.3.5. Mean % Predicted Evening PEF (Weeks 1-24)

Mean values will be analysed and summarised in the same way as % predicted morning PEF (Section 11.3.4).

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11.3.6. Mean Circadian Variation in Peak Flow (Weeks 1-24)

Mean values will be summarised by treatment group. No formal analysis will be performed.

11.3.7. Clinic FEV1

Summary statistics will be tabulated by treatment group at all clinic visits. Assessment windows for the clinic visits are as defined in Section 0. Values recorded at Visit 6 (week 24), will also be analysed using analysis of covariance in the same way as diary card PEF values. The visit 2/2a (day 0) value will be used as baseline. Clinic FEV1 data for each patient will be listed.

11.3.8. Daytime Symptom Scores (Weeks 1-24).

Provided parametric model assumptions hold, mean symptom scores on the DRC will be calculated for each subject and analysed using analysis of covariance in the same way as for the lung function endpoints. A tabulation of summary statistics by treatment group will also be produced.

11.3.9. Night-time Symptom Scores (Weeks 1-24).

These will be calculated using the symptom score recorded on the DRC in the evening and analysed in the same way as daytime symptom scores.

11.3.10. Percentage of Symptom Free Days (Weeks 1-24)

The percentage of days with a symptom score of zero will be calculated for each subject and assigned to one of the following four categories:- 0% to 25%, >25% to 50%, >50% to 75%, >75%. The numbers of subjects in each of the treatment groups will be compared using logistic (proportional odds) regression, adjusting for covariates of age, sex, country (grouping) and treatment. This model will be used to estimate the treatment difference (expressed as an odds ratio), the corresponding 95% confidence interval and p-value.

Missing data will not be imputed for this endpoint.

11.3.11. Percentage of Symptom Free Nights (Weeks 1-24)

Missing data will not be imputed for this endpoint.

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11.3.12. Percentage of Days with No Relief Medication (Weeks 1-24)

The percentage of days on which no relief Ventolin was taken will be calculated for each subject and analysed in the same way as % symptom free days and nights.

Missing data will not be imputed for this endpoint.

11.3.13. Percentage of Nights with No Relief Medication (Weeks 1-24)

The percentage of nights on which no relief Ventolin was taken will be calculated for each subject and analysed in the same way as % symptom free days and nights.

Missing data will not be imputed for this endpoint.

11.3.14. Withdrawals Due to Lack of Efficacy

11.3.15. ‘Well-controlled’ Asthma

The number of weeks with ‘Well-controlled’ asthma will be analysed non-parametrically using the Wilcoxon Rank Sum test with treatment as a single covariate.

A number of exploratory analyses will also be conducted to allow for comparisons to be made with results from other studies that also collected data on asthma control, this will include an assessment of longitudinal asthma control over weeks 5-12 and 18-26, using the rules set out in the RAP for the GOAL study (YM2002/00017/00). Summary information will be provided but no formal statistical analysis is planned.

11.3.16. Asthma Control Questionnaire

The ACQ total score will be calculated for each subject at each visit from the 7 questions of the ACQ (as detailed in Sections 5.3.4. and Section 12.3, Appendix 3 of the protocol) and analysed as using analysis of covariance as described for mean daily PEF for each time point (Weeks, 4, 8, 16 and 24). Scores at Baseline, each visit and change from Baseline will be presented. Individual scores for each subject will be listed.

11.3.17. Exploratory Sensitivity Analysis of Exacerbation Rates

An exploratory sensitivity analysis of the number of asthma exacerbations experienced by the subject, expressed as a rate over the exacerbation-free days during the period of treatment will be performed. This will be analysed using maximum likelihood based

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12. SAFETY ANALYSES

12.1. Extent of Exposure

The extent of exposure, calculated as the number of days between start of treatment and end of treatment (i.e., treatment stop date minus treatment start date+1) will be summarised by treatment group and listed.

12.2. Adverse Events

Adverse events (AEs) will be coded using the GW MIDAS/MEDRA dictionary, and grouped by body system. Within each treatment group, adverse events will be summarised by frequency and proportion of total subjects, by event type and by category of body system. Separate summaries will be given for all AEs, most common AEs occurring on treatment, for drug-related AEs, for SAEs, and for AEs leading to withdrawal. Where appropriate, each phase of the study (pre-treatment, treatment and follow-up) will be tabulated separately.

The proportion of subjects reporting at least one AE, at least one drug-related AE, at least one SAE, and at least one AE leading to withdrawal will also be calculated for each treatment group.

The relationship between verbatim and dictionary terms (body system and group term) will be given in Listing 21.

12.3. Deaths and Serious Adverse Events

Deaths will be listed only, SAEs will be tabulated separately.

12.4. Device Incidents and Near Incidents

Any device incidents or near incidents reported during this study will be summarised in case narratives written by GSK GCSP personnel.

12.5. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events

See section 12.2.

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12.6. Pregnancies (as applicable)

Pregnancy data will be listed as adverse events.

12.7. Clinical Laboratory Evaluations

No laboratory data is collected in this study.

12.8. Other Safety Measures

12.8.1. Oropharyngeal Candidiasis

The number and percentage of patients with clinical evidence of candidiasis and the number and percentage with a positive swab result will be tabulated at each time point by treatment group. Individual subject data will be listed. Allowable time windows for each assessment are defined in Section 0.

12.8.2. Unscheduled/Emergency Visits

Individual subject data on unscheduled or emergency visits to the clinic during the trial will be listed.

13. HEALTH OUTCOMES ANALYSES

13.1. Humanistic Measures

No humanistic measures are collected in this study.

13.2. Resource Utilisation Measures

Unscheduled Asthma-related Healthcare Contacts

Direct healthcare resource use data collected on the Unscheduled Asthma-related Healthcare Contacts form will be summarised. Estimates of healthcare resource use will be made based on resources used by subjects during the treatment phase of the study. The total number of units consumed for each type of healthcare contact will be summarised independently. For healthcare contacts involving hospitalisation, the total number of hospitalisations will be summarised as well as the total number of inpatient days. Hospitalisations involving both ICU and general ward visits will be counted as single visits. Primary care (general practice) contacts (surgery visits and house calls) will be summarised separately. Data for each subject will be listed.

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Time Missed From Work Or Usual Activities

Time off work, as collected in the DRC, will be summarised by treatment group in the following way: The number of days missed from work and the percentage of days with no time off work will be summarised using descriptive statistics. In addition, the following categories will be summarised: Number of days with no time off work, Number of half days lost, Number of complete days lost and the total number of days lost. These categories will also present the number of subjects who fall within each category.

14. CLINICAL PHARMACOLOGY DATA ANALYSES

This Section is not applicable.

15. BIOMARKER DATA ANALYSIS

This Section is not applicable.

16. PHARMACOGENETIC DATA ANALYSES

This Section is not applicable.

17. VIRAL GENOTYPING/PHENOTYPING

This Section is not applicable.

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18. REFERENCES

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19. ATTACHMENTS

19.1. Table of Contents for Data Display Specifications

Listings

1. Randomisation Code 2. Inclusion/Exclusion Criteria 3. Subjects Who Did Not Satisfy Inclusion/Exclusion Criteria Either for Entry into the Screening Period or for Entry into the Treatment Period 4. Withdrawals Prior To Randomisation 5. Childbearing Potential and Pregnancy Test Results 6. Subject Accountability: End of Study Record 7. Subjects for Whom the Treatment Blind was Broken During The Study 8. Protocol Violators 9. Demographic Details 10. Baseline Asthma Related Characteristics 11. Current Medical Conditions 12. Relationship Between Concurrent Medication Class, Preferred Terms and Verbatim Text 13. Asthma Medication Taken 14. Non-asthma Medication Taken 15. Initial Assessment and Diagnosis of Asthma 16. Asthma Exacerbation Data 17. Clinic FEV1 (mL) Data 18. Efficacy Measurements derived from the Daily Record Card 19. ACQ: Overall and Individual Summaries 20. Resource Utilisation 21. Trial Medication and Duration of Exposure 22. Relationship of Adverse Event Body Systems, Group Terms and Verbatim Text 23. All Adverse Events 24. Subject Numbers for Individual Adverse Events 25. Serious Adverse Events 26. Deaths 27. Assessment of Oropharyngeal Candidiasis

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28. Trial Medication Compliance 29. Unscheduled/Emergency Visits

Tables D1 Summary of Population Screened – Total Population D2 Summary of Screened Subjects By Investigator – Intent-to-treat Population D3 Summary of Withdrawals Prior To Randomisation – Total Population D4 Summary of Withdrawals After Randomisation – Intent-to-treat Population D5 Summary of Withdrawals After Randomisation By Time – Intent-to-treat Population D6 Summary of Attendance at Each Clinic Visit - Intent-to-treat Population D7 Summary of Entry Criteria Failure – Total Population D8 Summary of Reasons for Exclusion from the Per-protocol Population - Intent-to-treat Population D9 Summary of Baseline Characteristics - Intent-to-treat Population D10 Summary of Baseline Characteristics - Per-protocol Population D11 Summary of Child Bearing Potential - Intent-to-treat Population D12 Summary of Asthma History - Intent-to-treat Population D13 Summary of Exacerbations During The Last Year - Intent-to-treat Population D14 Summary of Smoking Status - Intent-to-treat Population D15 Summary of Baseline Lung Function Characteristics - Intent-to-treat Population D16 Summary of Baseline Lung Function Characteristics - Per-protocol Population D17 Summary of Current Medical Conditions - Intent-to-treat Population D18 Summary of Asthma Medication Started Prior To Treatment Start Date - Intent-to-treat Population D19 Summary of Asthma Medication Started After Treatment Start Date - Intent-to-treat Population D20 Summary of Non-asthma Medication Started After Treatment Start Date - Intent-to-treat Population D21 Summary of Baseline Diary Card (Day 0 to -7) - Intent-to-treat Population D22 Summary of Baseline Diary Card (Day 0 to -7) – Per-protocol Population D23 Summary of Asthma Control Assessment Using Asthma Control Questionnaire – Intent-to-treat Population D24 Summary of Percentage Compliance - Intent-to-treat Population

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E1 Summary of the Rate of Exacerbations - Intent-to-treat Population E2 Summary of the Rate of Exacerbations – Per-protocol Population E3 Statistical Analysis of the Rate of Exacerbations - Intent-to-treat Population E4 Statistical Analysis of the Rate of Exacerbations – Per-protocol Population E5 Summary of the Number of Exacerbations – Intent-to-treat Population E6 Statistical Analysis On The Proportion of Subjects With At Least One Exacerbation – Intent-to- treat Population E7 Summary of the Severity of Exacerbations - Intent-to-treat Population E8 Summary of the Time to First Exacerbation - Intent-to-treat Population E9 Summary of Time to First Exacerbation – Cox’s Proportional Hazards - Intent-to-treat Population (or alternate template if non-parametric analysis used) E10 Summary of Exacerbations Commencing Prior to Treatment – Intent-to-treat population E11 Summary of Mean Morning PEF (L/min): Raw Values and Change from Baseline - Intent-to- treat Population E12 Statistical Analysis of Mean Change in Morning PEF (L/min) – Intent-to-Treat Population E13 Summary of Mean Evening PEF (L/min): Raw Values and Change from Baseline - Intent-to- treat Population E14 Statistical Analysis of Mean Change in Evening PEF (L/min) – Intent-to-Treat Population E15 Summary of % Predicted Morning PEF (L/min): Raw Values and Change from Baseline – Intent-to-Treat Population E16 Statistical Analysis of Mean Change in % Predicted Morning PEF (L/min) (Weeks 1-24) – Intent-to-Treat Population E17 Summary of % Predicted Evening PEF (L/min): Raw Values and Change from Baseline – Intent-to-Treat Population E18 Statistical Analysis of Mean Change in % Predicted Evening PEF (L/min) (Weeks 1-24) – Intent-to-Treat Population E19 Summary of Circadian Variation in Peak Flow (Weeks 1-24) - Intent-to-treat Population E20 Summary of Clinic FEV1 - Intent-to-treat Population E21 Summary of Clinic FEV1: Raw Values and Change from Baseline To Week 24 - Intent-to- treat Population

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E22 Statistical Analysis of Mean Change in Clinic FEV1 (Week 24) – Intent-to-Treat Population E23 Summary of Daytime Symptom Scores: Raw Values and Change from Baseline (Weeks 1-24) – Intent-to-treat Population E24 Statistical Analysis of Mean Change in Daytime Symptom Scores (Weeks 1-24) – Intent-to- Treat Population E25 Summary of Night-time Symptom Scores: Raw Values and Change from Baseline (Weeks 1- 24) - Intent-to-treat Population E26 Statistical Analysis of Mean Change in Night-time Symptom Scores (Weeks 1-24) – Intent-to- Treat Population E27 Summary of Percentage of Symptom-free Days (Weeks 1-24) – Intent-to-treat Population E28 Statistical Analysis of Percentage of Symptom-Free Days (Weeks 1-24) – Intent-to-treat population E29 Summary of Percentage Symptom-free Nights (Weeks 1-24) - Intent-to-treat Population E30 Statistical Analysis of Percentage of Symptom-Free Nights (Weeks 1-24) – Intent-to-treat population E31 Summary of Percentage Of Days With No Relief Medication (Weeks 1-24) - Intent-to-treat Population E32 Statistical Analysis of Percentage of Days With No Relief Medication (Weeks 1-24) – Intent-to- treat population E33 Summary of Percentage of Nights With No Relief Medication (Weeks 1-24) - Intent-to-treat Population E34 Statistical Analysis of Percentage of Nights With No Relief Medication (Weeks 1- 24) – Intent- to-treat population E35 Summary of Mean Daily Ventolin Use - Intent-to-treat population E36 Summary and Analysis of the Number of Withdrawals Due to Lack Of Efficacy - Intent-to-treat Population E37 Summary and Analysis of the Proportion of Subjects with Well-Controlled Asthma - Intent-to- treat Population E38 Summary of Number of Weeks with ‘Well-controlled’ Asthma - Intent-to-treat Population E39 Summary of Asthma Control Questionnaire (ACQ) – Intent-to-treat population E40 Summary of Asthma Control Questionnaire: Raw Values and Change from Baseline – Intent-to- treat population E41 Statistical Analysis of Mean Change in Asthma Control Questionnaire Score (Weeks 1-24) –

FINAL 03-Dec-02 33

CONFIDENTIAL YM2002/00030/00 SAM40040

Intent-to-Treat Population E42 Summary of Data Excluded Due To Use of Rescue Medication - Intent-to-Treat Population

H1 Summary of Unscheduled Asthma Related Healthcare Contacts - Intent-to-treat population H2 Summary of Time Missed from Work or Usual Activities - Intent-to-treat population

S1 Summary of Exposure to Study Medication - Safety Population S2 Overall Summary of Adverse Events - Safety Population S3 Summary of All Adverse Events (Starting Pre Treatment) – Safety Population S4 Summary of All Adverse Events (Starting During Treatment) – Safety Population S5 Summary of All Adverse Events (Started post-treatment) - Safety Population S6 Summary of Drug-Related Adverse Events - Safety Population S7 Summary of Serious Adverse Events - Safety Population S8 Summary of Adverse Events Leading to Withdrawal - Safety Population S9 Summary of the Most Common Adverse Events During Treatment - Safety Population

Figures 1 Kaplan Meier Survival Curve of Time to First Exacerbation – Intent-to-Treat Population

19.2. Data Display Specifications

FINAL 03-Dec-02 34

CONFIDENTIAL GM2004/00056/00 SAM40040

Subject number IDSG abcd Version 04.02 - 01 NOV 00

CONFIDENTIAL

CASE REPORT FORM

SAM40040

A Twenty-four Week, Randomised, Double-dummy, Double-blind, Parallel Group Study to Compare the Occurrence of Exacerbations Between Seretide Diskus 50/250mcg bd and Symbicort Breath-Actuated Dry Powder Inhaler 4.5/160mcg 2 Inhalations bd in Subjects with Moderate to Severe Asthma

Treatment number Investigator number

Glaxo Wellcome Research and Development Stockley Park West Uxbridge, Middlesex, UB11 1BT, UK Telephone:

GlaxoWellcome, a GlaxoSmithKline company 1 Draft 2 - 31 AUG 01

1 CONFIDENTIAL GM2004/00056/00 SAM40040

IDSG abcd Version 02.05 - 26 MAR 01 CONFIDENTIAL

Standard Completion Guidelines For Case Report Forms (CRFs)

In studies where a study reference manual is used, additional guidelines for completion of specific CRF pages (laboratory data, concurrent medications, etc.) may be available.

General Rules for CRF Completion • Complete CRFs in English. • Print neatly and legibly. • Make all entries on the CRF with black ink and press firmly so that all copies are legible. • Do not write in shaded areas unless requested. • Avoid use of abbreviations and acronyms whenever possible. Use only abbreviations that are clear and in standard medical use. • Enter subject number when not preprinted in the space provided at the top of each CRF page. • Use only subject number to identify subject. Do not use the subject’s name or initials. • The treatment number is entered only on the cover page and for pages which are sent in for prompt reporting (e.g., Serious Adverse Event). • Record all values in the units indicated on the CRF. • Boxes must be completed from right to left e.g. 12 written as 0 0 1 2 . • Check that information classified as Other does not fit in one of the listed categories. If a ✔ is present for Other, specify, provide text in the specified field.

Missing Data • Use the following abbreviations for missing information: - NA not available/not applicable - ND not done - UNK unknown (e.g., for dates, if the month is unknown record as UNK/01)

Text Entries • Comments must be clear, concise and in English. • Do not write data on page margins or outside of allocated spaces.

Dates and Times • Record dates in DD MMM YY 0 6 J A N 0 1 format. day month year • Watch for obvious year errors, especially for the months of December, January, and February. • Record time in 24-hour clock format (range 00:00-23:59) with midnight = 00:00. • If the CRF is not completed at time of assessment, record date of assessment, not date of CRF completion. • If a full date is not available, enter the partial date and use UNK for missing data. • Check that all visit dates are in chronological order.

CRF Collation • Ensure that all appropriate pages are present in the CRF and are in the proper sequence. • Number extra pages using the.01 numbering convention, e.g. the first page inserted between pages 5 and 6 is numbered 5.01, with subsequent pages numbered as 5.02, 5.03 etc.

Correction Process • Draw a single line through the incorrect entry. • Do not "write over" or erase an incorrect entry or re-copy the original page. • Do not use correction materials (e.g. correction fluid or tape) on the CRF. • Write the correct data nearby. • Date and initial the correction. • If a correction results in data being located outside the designated space, circle the data and draw an arrow to the correct space.

2 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Time and Events Schedule

Timeline: Visit 1 Visit 2/2a Visit 3 Visit 4 Visit 5 Visit 6 Optional -2w ± 4d (Day 0) 4w ± 1w 8w ± 1w 16w ± 1w 24 ± 1w follow-up

Period Run-in Treatment Follow-up

Treatments Usual Seretide Diskus (50mcg salmeterol xinafoate + 250mcg Appropriate inhaled fluticasone propionate, actuated dose) 1 inhalation bd asthma steroids OR medication Symbicort BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose) 2 inhalations bd Relief Ventolin Relief Ventolin

Visit 1 2/2A 3 4 5 6 7

Informed Consent X

Demography X

Reversibilityª XX

Inclusion/Exclusion Criteria X X

Medical History X

Oropharyngeal exam XXXXXX X b

b Lung Function (FEV1)XXXXXXX

Issue Daily Record Cards X X X X X

Issue Study Medication X XX

ACQ c XXXXX

Collect Daily Record Cards XXXXX

Collect Study Medication XXX X b

Adverse Event XXXXX X b

Concurrent Medication X X X X X X X

ª at only one of the Visits 1, 2/2a or up to 2 years before Visit 2/2a b if follow-up visit required these procedures may be performed c ACQ should be completed by the subject prior to the visit with the investigator/study team

3 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Study Schedule

Run-in Study treatment Follow-up

Seretide Diskus (50mcg salmeterol xinafoate + 250mcg fluticasone propionate, actuated dose), 1 inhalation bd

BDP (1000-2000 mcg/d same as pre-study dose)

or equivalent

Symbicort BADPI (formoterol 4.5mcg + budesonide 160mcg, delivered dose), 2 inhalations bd

Weeks -2 0 4 8 16 24 25

Visits V1 V2 V3 V4 V5 V6 Follow-up contact

4 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 02.01 - 01 AUG 01 Protocol code SAM40040 Inclusion Criteria Worksheet Visit 1

Instructions to Investigator

• Review the worksheet first.

• Answer each question on the worksheet.

• ✔ appropriate box for each Inclusion criterion question.

• Ensure that you maintain the source documents that validate the Inclusion criteria.

Monitor Data Validation Checks

• Check that either a YES or NO box is ✔ for each Inclusion criterion.

5 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.00 - 02 OCT 00 Protocol code Subject number SAM40040 Inclusion Criteria Worksheet Visit 1

Inclusion Criteria ✔ one box for each question: Yes No

1. Is the subject male or an eligible female? NOTE: A female is eligible to enter and participate in the study if she is of:

a) Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal. For the purposes of this study, post-menopausal is defined as one year without menses; or,

b) Child-bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the acceptable contraceptive methods, when used consistently and correctly (i.e., in accordance with the approved product label and the instructions of a physician for the duration of the study - Screening visit to Follow-up contact).

• Complete abstinence from intercourse from two weeks prior to study medication, throughout the 24-week treatment phase, and for one week following study completion; or

• Sterilisation of male partner; or

• Implants of levonorgestrel inserted for at least one month prior to the study drug administration but not beyond the third successive year following insertion; or

• Injectable progestogen administered for at least one month prior to the study drug administration and administered for one month following study completion; or

• Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study drug administration; or

• An intrauterine device (IUD), inserted by a qualified physician with published data showing that the highest expected failure rate is less than 1% per year; or

• Any other method with published data showing that the highest expected failure rate of that method is 1% per year

2. Is the subject at least 18 years of age at the time of Visit 1 (Screening Visit)?

3. Does the subject have a documented clinical history of asthma for at least 6 months prior to Visit 1?

4. Has there been no change in the subjects regular medication and no use of oral/parenteral steroids in the 4 weeks before Visit 1?

If any INCLUSION CRITERIA question is answered NO, this subject must NOT enter this study.

continued,,,

6 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.00 - 02 OCT 00 Protocol code Subject number SAM40040 Inclusion Criteria Worksheet Continued Visit 1

Inclusion Criteria ✔ one box for each question:

5. Is the subject currently receiving 1000-2000mcg/day BDP or equivalent, such Yes No as 800-1600mcg/day budesonide, 500-1000mcg/day fluticasone propionate or QVAR, and has been for at least 4 weeks prior to Visit 1?

6. Has a signed and dated written informed consent been obtained from the subject prior to study participation?

7. Is the subject able to comply with therapy and to complete daily record cards and subject-completed questionnaires correctly?

If any INCLUSION CRITERIA question is answered NO, this subject must NOT enter this study.

7 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 02.01 - 01 AUG 01 Protocol code SAM40040 Exclusion Criteria Worksheet Visit 1

Instructions to Investigator

• Review the worksheet first.

• Answer each question on the worksheet.

• ✔ appropriate box for each Exclusion criterion question.

• Ensure that you maintain the source documents that validate the Exclusion criteria.

Monitor Data Validation Checks

• Check that either a YES or NO box is ✔ for each Exclusion criterion.

8 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.00 - 02 OCT 00 Protocol code Subject number SAM40040 Exclusion Criteria Worksheet Visit 1

Exclusion Criteria ✔ one box for each question: Yes No 1. Does the subject have a history of upper or lower respiratory tract infection, middle ear or sinus infection or has had within 4 weeks prior to Visit 1?

2. Has the subject had an acute asthma exacerbation requiring emergency hospital/clinic treatment and/or hospitalisation within 4 weeks prior to Visit 1?

3. Does the subject have a smoking history of ≥10 pack years, or is likely to change smoking habits during the study, or has given up smoking within 4 weeks of Visit 1?

4. Has the subject previously participated in a clinical study in which they were exposed to investigational or non-investigational medication or device within 30 days prior to Visit 1?

5. Is the subject currently participating in another clinical study in which the they are or will be exposed to an investigational or a non-investigational medication or device?

6. Does the subject have any evidence of, or had any treatment of malignancy (other than localised basal cell, squamous cell skin cancer or localised cancer in situ that has been resected) within the previous five years?

7. Is the subject a pregnant woman or a woman intending to become pregnant?

8. Is the subject a woman breast-feeding an infant(s)?

9. Does the subject have an inability or unwillingness to take study medication (non-compliance), follow directions, or is unable to complete a written Daily Record Card and self-rating questionnaires?

10. Has the subject had previous allergic reaction to study medications or any excipients of the formulations?

11. Is the subject currently receiving any of the following medications: long-acting inhaled β2-agonists, oral β2-agonists or slow-release bronchodilators, combination therapy (containing β2-agonist and/or inhaled corticosteroids for asthma), sodium cromoglycate or nedocromil sodium, ketotifen, leukotriene- receptor antagonists, anticholinergics, short-acting inhaled β2-agonists (other than Ventolin provided at Visit 1), theophyllines? NOTE: these medications must be stopped at Visit 1. (During the run-in, subjects continue on their pre-study dose of inhaled corticosteroids, which are stopped at Visit 2/2a).

If any EXCLUSION CRITERIA question is answered YES, this subject must NOT enter this study.

continued...

9 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.00 - 02 OCT 00 Protocol code Subject number SAM40040 Exclusion Criteria Worksheet Continued Visit 1

Exclusion Criteria ✔ one box for each question: Yes No

12. Did the subject use oral/parenteral corticosteroids for 4 weeks prior to Visit 1?

13. Did the subject use depot corticosteroids for 12 weeks prior to Visit 1?

14. Does the subject have a history of alcohol or medication abuse?

15. Does the subject have pre-bronchodilator FEV1 of <50% of predictive normal values? NOTE: Use ECCS standard ranges. bronchodilators must be withheld for 6 hours previously.

16. Does the subject use any concurrent prohibited medications? NOTE: (subjects must not take prohibited medications during the run-in and must remain off these medications for the duration of the study as listed in Section 3.3.3.1. of the protocol).

If any EXCLUSION CRITERIA question is answered YES, this subject must NOT enter this study.

10 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.04 - 01 NOV 00 Protocol code SAM40040 Inclusion / Exclusion Criteria Visit 1 (Run-in Period)

Instructions to Investigator

Did the subject meet all the entry criteria?

• If the subject met all the entry criteria (all YES answers to the Inclusion questions and all NO answers to the Exclusion questions), ✔ YES. Otherwise ✔ NO.

Inclusion/Exclusion Criteria

•Only ✔ boxes that represent a violation of the Inclusion/Exclusion criteria.

Monitor Data Validation Checks

• If the question “Did the subject meet all entry criteria” is answered YES, check that no ✔ are present in the inclusion or exclusion criteria boxes.

• If the question “Did the subject meet all entry criteria” is answered NO, check that a ✔ is present in at least one inclusion and/or exclusion criteria boxes.

11 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 03.02 - 01 NOV 00 Protocol code Session number Subject number SAM40040 1 Inclusion / Exclusion Criteria Visit 1 (Run-in Period)

Did the subject meet all entry criteria (i.e., All "YES" answers for inclusion criteria, all "NO" answers for exclusion criteria)? See INCLUSION / EXCLUSION Yes Y No N CRITERIA WORKSHEET.

✔ all boxes that represent a violation of the inclusion / exclusion criteria:

Inclusion Criteria

1. 2. 3. 4. 5. 6. 7.

Exclusion Criteria

1. 2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13. 14. 15. 16.

12 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.03 - 02 OCT 00 Protocol code SAM40040 Demography Visit 1 (Run-in Period)

Instructions to Investigator

• Race Check the single most appropriate category based on physical and genetic characteristics, not socioeconomic or geographic factors. Race is collected to determine if there are any genetic differences that may contribute to differences in study responses.

Monitor Data Validation Checks

• Check that the year in the date of birth is not the current year.

• Check that only one response has been ✔ for smoking status.

• Check that the number of pack years has been completed as a whole number if current or former smoker.

• For former smokers’ check that either the YES or NO box is ✔ for the question “Stopped in the last 6 months”

13 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 05.02 - 01 NOV 00 Protocol code Session number Subject number SAM40040 1 Demography / Smoking History Visit 1 (Run-in Period)

Date of assessment day month year

Date of birth day month year

Sex

Male M

Female F

Race, ✔ one:

Origins in the original peoples of Europe, the Middle East, Western Russia, White W Afghanistan, or the white racial groups of Africa.

Black B Origins in any of the black racial groups of Africa.

Origins in the original peoples of the Indian subcontinent, the Far East, Asian A Southeast Asia, or the Pacific islands.

People whose racial group is not represented above, or whose predominant Other X origin cannot be determined.

. Height cm Weight kg

Smoking History

What is the subject’s history of tobacco use? ✔one box only:

Never smoked V

Current smoker C

Former smoker F

14 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.05 - 02 OCT 00 Protocol code SAM40040 Demography for Females Visit 1 (Run-in Period)

Instructions to Investigator

• Childbearing Potential (Demography for Females) Use the following definitions:

Premenarcheal Females who have not begun to menstruate. Sterile Premenopausal women who cannot conceive children. (Do not include postmenopausal women in this category.) Postmenopausal Women who have completed menopause at least one year ago. Potentially able to conceive children Women of childbearing age who are not sterile.

Monitor Data Validation Checks

• Check that the DEMOGRAPHY FOR FEMALES page has not been completed if this is a male subject.

• Check that information on contraceptive drugs (i.e., oral or depot contraceptives) has been recorded on the CONCURRENT MEDICATIONS page of the CRF for subject taking contraceptives.

• If the Pregnancy Test question is ✔ as Not Applicable (Not of Childbearing Potential), check that this is consistent with the answer to the Childbearing Potential question.

15 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.05 - 01 JUN 01 Protocol code Session number Subject number SAM40040 1 Demography for Females Visit 1 (Run-In Period)

Childbearing potential, ✔ one:

Premenarcheal M

Sterile (of childbearing age) S

Postmenopausal P

Potentially able to conceive children A ✔ all type(s) of contraception used below:

Oral contraceptive Y

Intrauterine contraceptive device Y Depot contraceptive (implants, injectables) Y

Abstinence Y

Sterilization of male partner Y

None Y

Other Y specify, ...... Details of any contraceptive drugs must be added to the CONCURRENT MEDICATIONS page.

Pregnancy test result, ✔one:

Positive P

Negative N

Not applicable X (Not of childbearing potential)

16 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.01 - 02 MAY 01 Protocol code SAM40040 Current Medical Conditions Visit 1 (Run-in Period)

Instructions to Investigator

• For each body system listed, place a ✔ in the appropriate YES or NO box.

• If YES is ✔ specify all conditions concisely, separating multiple conditions with a slash (/).

• Do not record dates or detailed descriptions of signs and symptoms.

• Current medical conditions include:

• Acute conditions (e.g., flu, upper respiratory track infection) • Intermittent conditions (e.g., migraine, seasonal rhinitis) • Conditions from which subject is recovering (e.g., myocardial infarction) • Chronic conditions (e.g., hypertension, asthma)

• Current medical conditions do not include:

• Acute events that have resolved without sequelae (e.g., transient ischemic attack) • Previous surgery without sequelae (e.g., hysterectomy) • Fractures that have healed (e.g., broken collar bone)

Monitor Data Validation Checks

• Check that YES or NO is ✔ for each body system.

• If YES is ✔, check that at least one condition is recorded.

17 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 03.05 - 01 NOV 00 Protocol code Session number Subject number SAM40040 1 Current Medical Conditions Visit 1 (Run-in Period)

Indicate current medical conditions (excluding the illness(es) being treated in the study) by ✔ the appropriate boxes. If YES, specify condition(s).

Yes No If YES, specify condition(s): Y N 1. Ear, nose, and throat ......

2. Eyes ......

3. Respiratory ......

4. Cardiovascular ......

5. Gastrointestinal ......

6. Hepatobiliary and pancreas ......

7. Urinary system ......

8. Reproductive system ......

9. Neurology ......

10. Blood and lymphatic ......

11. Endocrine and metabolic ......

12. Musculoskeletal ......

13. Skin ......

14. Psychiatry ......

15. Allergies ......

18 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd Version 01.00 : 11 AUG 99 CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Duration of Asthma / Duration of Inhaled Corticosteroid Use / Asthma Exacerbations Visit 1 (Run-in Period)

Monitor Data Validation Checks

Duration of Asthma

• Check that duration is recorded correctly.

• Check that the duration is not greater than the subject’s age.

• Check that only one box is ✔ for range of duration, and that the bottom of the range is not greater than the subject’s age.

Duration of inhaled corticosteroid use

• Check that duration is recorded correctly.

• Check that only one box is ✔ for range of duration, and that the bottom of the range is not greater than the subject’s age.

19 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd Version 01.01 : 09 MAR 00 CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 1 Duration of Asthma / Duration of Inhaled Corticosteroid Use / Asthma Exacerbations Visit 1 (Run-in Period)

Duration of Asthma

✔ one box only:

≥ 6 months to ≥ 1 year to ≥ 5 years to < 6 months 1 < 1 year 2 < 5 years 18 < 10 years 4

≥ 10 years to ≥ 15 years to ≥ 20 years to < 15years 5 < 20 years 13 < 25 years 14 ≥ 25 years 15

Duration of Inhaled Corticosteroid Use

✔ one box only:

≥ 6 months to ≥ 1 year to ≥ 5 years to < 6 months 1 < 1 year 2 < 5 years 18 < 10 years 4

≥ 10 years to ≥ 15 years to ≥ 20 years to ≥ < 15years 5 < 20 years 13 < 25 years 14 25 years 15

Asthma Exacerbations Number of exacerbations of asthma in the previous 12 months that required:

antibiotics and/or oral corticosteroids (not requiring hospitalisation) If none, enter ’00’.

in-patient hospitalisation If none, enter ’00’.

20 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Current and Previous Corticosteroid Use For Asthma / Visit 1 (Run-in Period)

Instructions to Investigator

For the inhaled corticosteroid currently used at this visit, leave the stop date blank and ✔if drug continued column.

The dose and frequency should be recorded as shown by the following example: If the subject takes 50 µg per puff, 2 puffs bd (i.e., 100 µg bd) The dose column should be recorded as 100. The µg should be circled in the units column. The frequency column should be recorded as bd.

Monitor’s Data Validation Check

• Check that the inhaled corticosteroid the subject is currently receiving has been recorded as ‘continued’.

• Check that oral or parenteral corticosteroids have been recorded as stopped during the last 4 weeks.

• Check that depot corticosteroids have been recorded as stopped during the last 12 weeks.

21 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 1 Current and Previous Corticosteroid Use For Asthma Visit 1 (Run-in Period)

Is the subject currently receiving, or have they received within the last 12 months, any inhaled, oral or parenteral corticosteroid treatment for asthma? Yes Y No N

Drug Dose Units Fre- Route Date ✔ Date For inhaled Trade name quency started If drug stopped use indicate preferred continued device type

day month year day month year

Example 1 µg/mg IH/PO Flixotide 50 BID 01 AUG 01 ✔ MDI

Example 2 µg/mg IH/PO DUOVENT (100 / 40 µg) 1 PUFF BD 01 AUG 01 ✔ MDI µg/mg IH/PO 1. µg/mg IH/PO 2. µg/mg IH/PO 3. µg/mg IH/PO 4. µg/mg IH/PO 5. µg/mg IH/PO 6. µg/mg IH/PO 7. µg/mg IH/PO 8. µg/mg IH/PO 9. µg/mg IH/PO 10

22 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Pulmonary Function Visit 1 (Run-in Period)

Instructions to Investigator

Pulmonary Function It is mandatory to only use spirometers that can print out FEV1 values. Where possible the FEV1 measurements should be made using the same spirometer throughout the study and recordings should be made at the same time of day on each clinic visit day, with the subject in consistently in the same position (i.e., standing). Issue mini-Wright PEF meter and explain to the subject how to use it.

• The highest of three technically acceptable FEV1 measurements, before and 15 minutes after inhalation of 200-400mcg of short acting β2-agonist should be recorded whilst the subject is in a standing position.

• Record % predicted normal to 1 decimal place.

• Record FEV1 to 2 decimal places.

• Lung function printouts must be labelled with the Subject Initials, Subject Number, Visit Number, date and time of assessment and the signature of the person responsible for the data.

Monitor Data Validation Checks

Pulmonary Function

• Check that predicted normal(s) is correct from the table provided.

• Check that % Predicted normal has been rounded to 1 decimal place.

•

• Check that FEV1 has been rounded to 2 decimal places.

• Check that all spirometry printouts are signed and dated by the responsible person and clearly indicate the clinic visit, the date of the visit, the time of assessment, the subject’s initials and the Glaxo Wellcome subject number. The spirometry printouts must be stored in the subject’s notes. If spirometry printouts are on thermal paper the pages must be copied.

23 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 1 Pulmonary Function Visit 1 (Run-in Period)

β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N If YES, remind the subject not to take any before the next visit.

Does the subject have documented evidence of reversibility ≥12% ≥ (and 200mls) in FEV1 measured within the last 2 years? Yes Y No N If YES, complete only the first table below.

If NO, perform reversibility assessment and complete both tables below.

Time of Actual assessment measurement % pre- pre-Ventolin Predicted Predicted Ventolin normal Test (highest of 3 normal measurements)

A 00:00-23:59 x100 ABB

e.g. FEV1 (L) 08:00 1.75 3.25 53.8

FEV1 (L) :...

< NOTE: If the subjects FEV1 is 50% of predicted normal, they should be withdrawn from the study.

Actual Time of measurement assessment within 15 post- % minutes Ventolin Reversibility Test post-Ventolin (highest of 3 measurements) C-A 00:00-23:59 x100 C B

e.g. FEV1 (L) 08:15 1.82 2.2

FEV1 (L) :..

≥ NOTE: If subject does not have documented evidence of 12% FEV1 reversibility within the last 2 years or did not have a reversibility of ≥12% (and ≥200mls) at this visit, they must have their reversibility measured again at Visit 2.

24 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Oropharyngeal Candidiasis / Relief Medication / Concurrent Medications Visit 1 (Run-in Period)

Instructions to Investigator

Oropharyngeal Candidiasis

• Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Take swab and send to a local laboratory for analysis.

• Complete CURRENT MEDICAL CONDITIONS page if swab is positive.

Monitor Data Validation Checks

Oropharyngeal Candidiasis

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that oropharyngeal candidiasis when present is recorded on the CURRENT MEDICAL CONDITIONS page.

• If swab result will never be known check that Not Available is ✔.

25 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 1 Oropharyngeal Candidiasis / Relief Medication / Concurrent Medications Visit 1 (Run-in Period)

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the CURRENT MEDICAL CONDITIONS page(s), if appropriate.

Relief Medication

Provide the subject with relief medication and record the inhaler provided below, ✔ one box only:

MDI propellant 11/12 M11

MDI non-CFC (HFA134a) HFA1

Diskus / Accuhaler DSKS

NOTE: Subject using Ventolin pressurised MDI should be instructed to take two consecutive actuations for each occasion requiring relief medication. Subjects using Ventolin Diskus/Accuhaler should be instructed to take one dose for each occasion requiring relief medication.

Concurrent Medications Record details of all concurrent medications for asthma and other disorders, (see appropriate page within the Concurrent Medication section).

β • Stop subject’s own 2-agonist and record the stop date on ASTHMA CONCURRENT MEDICATIONS page.

• Ventolin provided as relief medication by the sponsor must not be recorded on the ASTHMA CONCURRENT MEDICATIONS page.

26 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Investigator’s Checklist Visit 1 (Start of Run-in Period)

• Ensure written informed consent has been obtained.

• Ensure subject’s Primary Care Physician has been informed of the subject’s participation in the study.

• Issue the Run-in Daily Record Card, explain to the subject how to complete the DRC and instruct them to commence completion on the evening of this visit.

• Issue subject with a Peak Flow Meter and instruct them on how to measure their PEF.

•Issue Ventolin for use as a relief medication on an ‘as required’ basis. (NOTE: This should NOT be recorded in the CRF, but must be recorded in the drug accountability record provided separately).

• Explain and demonstrate the correct use of the Diskus/Accuhaler or MDI.

• Explain the procedure in case of an exacerbation of asthma.

• Ensure a urinary pregnancy test has been performed (if required).

• Make an appointment for the subject to return in 2 weeks (± 4 days) time.

• Review inclusion / exclusion criteria and ensure all Visit 1 sections have been completed.

Remind the subject of the following:

• To return their Run-In Daily Record Card and mini-Wright peak flow meter at their next clinic visit.

• Withhold Ventolin for six hours before Visit 2.

• Continue to use their current inhaled corticosteroid asthma medication plus Ventolin and remind the subject to take the last dose on the evening before Visit 2.

• Bring to the next visit: completed DRC, peak flow meter, appointment card and any unused Ventolin.

27 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Daily Record Card / ACQ Visit 2 (Start of Treatment Period)

Instructions to Investigator

Daily Record Card Check that:

• The subject has recorded all the required data into their DRC for a minimum of 10 days. Subjects not meeting this requirement may repeat the run-in period once only, at the discretion of the investigator.

• All the dates have been entered correctly and are in chronological order.

• A “0” has been entered where no relief medication was taken that day.

• Transcribe any medications from the medication section into the appropriate CONCURRENT MEDICATION page in this Case Report Form. • Transcribe any Adverse Events that have been reported into the appropriate ADVERSE EVENT page(s) of this CRF.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated.

If the subject is to repeat the Run-In Period:

• Make an appointment for the subject to return in 2 weeks (± 4 days) time for Visit 2a. • Issue new DRC and remind the subject to bring his/her Run-in Daily Record Card to the next clinic visit.

Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed. • Ensure that either a YES or NO box has been ✔.

• ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card • Check that the visit date is 2 weeks (± 4 days) after Visit 1. If date is outside this window, request investigator to initial and date entry.

• Check that the Run-In Daily Record Card for the period between Visit 1 and Visit 2 has been returned fully completed. Ensure that any adverse events and changes in medication reported in the Run-In Daily Record Card have been transcribed to the appropriate ADVERSE EVENT and CONCURRENT MEDICATION page(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them. • Check that there are no inappropriate blank boxes.

Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

28 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2 Daily Record Card / ACQ Visit 2 (Start of Treatment Period)

Date of Assessment day month year

Daily Record Card

Has the Daily Record Card been completed correctly? Yes Y No N If the subject has not completed the Run-In Daily Record Card satisfactorily or not returned it, do NOT continue with any remaining assessments. The subject may repeat the Run-In once only if appropriate.

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

29 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma Visit 2 (Start of Treatment Period)

Instructions to Investigator Adverse Event • An ADVERSE EVENT is any untoward medical occurrence in a patient or a clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Monitor Data Validation Checks Adverse Event / Concurrent Medication • Check that any adverse events are recorded in the ADVERSE EVENT section and any new medications are recorded in the CONCURRENT MEDICATION section of the Case Report Form. NOTE: ✔ if done box should always be completed to confirm these questions have been asked, regardless of whether an adverse event has occurred or new medicine has been taken. Exacerbation of Asthma • If the subject has experienced an exacerbation since their last visit, check that the ASTHMA CONCURRENT MEDICATION, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT and if appropriate the ADVERSE EVENT page(s) have been completed. NOTE: - An adverse event must only be recorded if an exacerbation meets the definition of a serious adverse event. - ✔ if done box should always be completed to confirm these questions have been asked, regardless of whether the subject has experienced an exacerbation. Definition of a Moderate and Severe Asthma Exacerbation For the purpose of this study an asthma exacerbation will be defined as follows:

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

• Individual courses of oral corticosteroids are classified as separate exacerbations only if they are administered >1 week apart. Any course started within one week of finishing the previous course is considered part of the previous exacerbation. Severe Exacerbations • deterioration in asthma which requires hospital admission.

30 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma Visit 2 (Start of Treatment Period)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

31 CONFIDENTIAL GM2004/00056/00 SAM40040

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Protocol code SAM40040 Pulmonary Function Tests Visit 2 (Start of Treatment Period)

Instructions to Investigator

It is mandatory to only use spirometers that can print out FEV1 values. Where possible the FEV1 measurements should be made using the same spirometer throughout the study and recordings should be made at the same time of day on each of the clinic visit days with the subject in a standing position.

• Lung function printouts must be labelled with the Subject Initials, Subject Number, Visit Number, date and time of assessment and the signature of the person responsible for the data.

• Record FEV1 to 2 decimal places.

Monitor Data Validation Checks

• Check that predicted normal(s) is correct from the table provided.

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

• Check that FEV1 has been rounded to 2 decimal places.

32 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2 Pulmonary Function Tests Visit 2 (Start of Treatment Period)

β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N If YES, remind the subject not to take any before the next visit.

If the subject had documented evidence or demonstrated reversibility at Visit 1, complete only the first table below. ≥ ≥ If the subject did not have documented evidence of FEV1 reversibility of 12% (and 200mls) FEV1 in the 2 years prior to Visit 1 or demonstrated at Visit 1, perform reversibility assessment and complete both tables below.

Time of Actual assessment measurement pre- pre-Ventolin Predicted Ventolin normal Test (highest of 3 measurements)

00:00-23:59 AB

e.g. FEV1 (L) 08:00 1.75 3.25

FEV1 (L) :..

Actual Time of measurement assessment within 15 post- % minutes Ventolin Reversibility Test post-Ventolin (highest of 3 measurements) C-A 00:00-23:59 x100 C B

e.g. FEV1 (L) 08:15 1.82 2.2

FEV1 (L) :..

33 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 02.01 - 01 AUG 01 Protocol code SAM40040 Inclusion Criteria Worksheet Visit 2 (Start of Treatment Period)

Instructions to Investigator

• Review the worksheet first.

• Answer each question on the worksheet.

• ✔ appropriate box for each Inclusion criterion question.

• Ensure that you maintain the source documents that validate the Inclusion criteria.

Monitor Data Validation Checks

• Check that either a YES or NO box is ✔ for each Inclusion criterion.

34 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.00 - 02 OCT 00 Protocol code Subject number SAM40040 Inclusion Criteria Worksheet Visit 2 (Start of Treatment Period)

Inclusion Criteria ✔ one box for each question:

1. Did the subject demonstrate reversible increase in FEV1 of at least 12% (and ≥ 200mls), 15 minutes after inhaling 200-400mcg of Ventolin? or does the subject have documented evidence (at any time during the last 2 Yes No ≥ years) of a reversible increase in FEV1, of at least 12% (and 200mls), 15 mins after inhaling a short-acting bronchodilator?

2. During the 2-week run-in period (10 to 18 days), did the subject have an asthma symptom score (day and night combined) of a least 2 (see Appendix 2, Protocol Section 12.2) recorded in their daily record card on at least 4 of the last 7 evaluable days?

3. During the 2-week run-in period, did the subject complete daily record cards on at least 10 days (run-in window is 10-18 days)? (Subjects who fail to meet this criteria are permitted to repeat the run-in once, at the investigators discretion).

If any INCLUSION CRITERIA question is answered NO, this subject must repeat the Run-In.

35 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.04 - 01 NOV 00 Protocol code SAM40040 Inclusion Criteria Visit 2 (Start of Treatment Period)

Instructions to Investigator

Did the subject meet all the entry criteria?

• If the subject met all the entry criteria (all YES answers to the Inclusion questions), ✔ YES. Otherwise ✔ NO.

Inclusion Criteria

•Only ✔ boxes that represent a violation of the Inclusion criteria.

Monitor Data Validation Checks

• If the question “Did the subject meet all entry criteria” is answered YES, check that no ✔ are present in the inclusion criteria boxes.

• If the question “Did the subject meet all entry criteria” is answered NO, check that a ✔ is present in at least one inclusion criteria box.

36 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 03.02 - 01 NOV 00 Protocol code Session number Subject number SAM40040 2 Inclusion Criteria Visit 2 (Start of Treatment Period)

Did the subject meet all entry criteria (i.e., All "YES" answers for inclusion criteria)? See INCLUSION CRITERIA WORKSHEET. Yes Y No N

✔ all boxes that represent a violation of the inclusion criteria:

Inclusion Criteria

1. 2. 3.

37 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Investigator Instructions Visit 2 (Start of Treatment Period)

If the subject is eligible to enter the Treatment Period:

• Confirm that an asthma symptom score of 2 (day and night combined) on at least 4 of the last 7 evaluable days of the run-in period has been achieved. Record score • Record 30% Peak Flow alert value below:

L/min

If the subject is ineligible to enter the Treatment Period and is repeating the run-in: • Issue new Repeat Run-in Daily Record Card. • Issue more relief Ventolin if necessary. • Remind the subject of the procedure in the case of an exacerbation. • Make an appointment for the subject to return in 2 weeks (± 4 days) time for Visit 2a. • Remind the subject to bring his/her Run-In Daily Record Card, appointment card and peak flow meter to the next clinic visit. • Remind the subject to withhold their Ventolin for at least 6 hours prior to Visit 2a if possible. • Remind subject to continue with corticosteroids they are currently receiving until Visit 2a.

Monitor Data Validation Checks

If the subject enters the Treatment Period:

• Check that all boxes for the inclusion criteria are ticked ‘YES’.

• Check that the stop date for the subject’s own inhaled corticosteroid has been entered on the ASTHMA CONCURRENT MEDICATIONS page.

38 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Oropharyngeal Candidiasis Visit 2 (Start of Treatment Period)

Instructions to Investigator

Oropharyngeal Candidiasis

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis:

• Take swab and send to a local laboratory for analysis.

• Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks

Oropharyngeal Candidiasis

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis:

• Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

39 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2 Oropharyngeal Candidiasis Visit 2 (Start of Treatment Period)

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

40 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Treatment Allocation / Current Corticosteroid Use For Asthma Visit 2 (Start of Treatment Period)

Instructions to Investigator

• To randomise the subject into this study complete the relevant SCAD worksheet and access SCAD via the IVR system to obtain the subject’s treatment number and pack number (dispensing unit number).

• The IVR system will require a few questions to be answered and will read to you the subject’s treatment number, which must be recorded on the FRONT COVER of this Case Report Form.

• The IVR system will then read out a pack number (dispensing unit number), this must be recorded on the facing page.

Monitor Data Validation Checks

• Check that the Date Treatment Allocated corresponds with the Visit 2 date.

• Check that the treatment start date has been recorded on the STUDY DRUG page.

• Check that stop date for subject’s own inhaled corticosteroid has been recorded on the facing page.

41 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2 Treatment Allocation / Current Corticosteroid Use For Asthma Visit 2 (Start of Treatment Period)

Treatment Allocation Using the IVR system, obtain the treatment number for this subject and pack number (dispensing unit number) for this visit.

Enter the treatment number on the FRONT COVER of the Case Report Form. Enter pack number (dispensing unit number) in the box below.

According to pack number given by the IVR system, give the first dose of study medication from the 8 week study pack to the subject. The subject must inhale once from the Diskus/Accuhaler and then twice from the BADPI. Each inhaler must be used within two minutes of the previous one NOTE: The Diskus must be used first.

...... Investigator’s or Designee's signature

...... Investigator’s or Designee's name - print

Pack Number (dispensing unit number)

Date Treatment Allocated day month year

NOTE: ENTER THE TREATMENT START DATE ON THE STUDY DRUG PAGE IN THIS CASE REPORT FORM.

Current Corticosteroid Use For Asthma

Instruct the subject to discontinue their usual asthma medication, record the stop date of subject’s own previous inhaled corticosteroid below:

Stop date of subject’s own inhaled corticosteroid day month year Record the stop date of any other asthma medication on the ASTHMA CONCURRENT MEDICATION page.

Pharmacy (if applicable) Dispense SAM40040 Treatment Pack for weeks 1-8 with the appropriate pack number (dispensing unit number) for this subject.

42 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Investigator’s Checklist Visit 2 (Start of Treatment Period)

If the subject is to continue in the study:

• Record 30% Peak Flow alert value on front of Daily Record Card.

• Issue new Daily Record Card for the treatment period and re-emphasize to the subject the importance of completing the Daily Record Card correctly.

• Issue relief Ventolin if necessary.

• Issue study medication.

• Check subjects ability to measure their PEF.

• Make an appointment for the subject to return in 4 weeks (± 1 week) time.

• Ensure all Visit 2 sections have been completed.

Remind the subject of the following:

• Discontinue any inhaled corticosteroid medication other than the study medication.

• To use Ventolin ‘as required’.

• Withhold Ventolin for six hours before Visit 3.

• Not to take their study medication on the morning of Visit 3. Study medication should be taken at the clinic once the FEV1 has been performed.

• Remind the subject of the procedure in the case of an exacerbation of asthma.

• Bring to the next visit: completed DRC, peak flow meter and appointment card.

NOTE: If the subject has been withdrawn, complete END OF STUDY RECORD in the Case Report Form.

43 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Daily Record Card / ACQ Visit 2a (Start of Treatment Period)

Instructions to Investigator

Daily Record Card Check that:

• The subject has recorded all the required data into their DRC for a minimum of 10 days. Subjects not meeting this requirement must be withdrawn.

• All the dates have been entered correctly and are in chronological order.

• A “0” has been entered where no relief medication was taken that day.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated.

Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed. • Ensure that either a YES or NO box has been ✔.

• ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card • Check that the visit date is 2 weeks (± 8 days) after Visit 2. If date is outside this window, request investigator to initial and date entry.

• Check that the Run-In Daily Record Card for the period between Visit 2 and Visit 2a has been returned fully completed. Ensure that any adverse events and changes in medication reported in the Run-In Daily Record Card have been transcribed to the appropriate ADVERSE EVENT and CONCURRENT MEDICATION page(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them. • Check that there are no inappropriate blank boxes.

Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

44 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2.1 Daily Record Card / ACQ Visit 2a (Start of Treatment Period)

Date of Assessment day month year

Daily Record Card

Has the Daily Record Card been completed correctly? Yes Y No N If the subject has not completed the Daily Record Card satisfactorily or not returned it, do NOT continue with any remaining assessments. The subject must be withdrawn.

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

45 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma Visit 2a (Start of Treatment Period)

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

46 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma Visit 2a (Start of Treatment Period)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

47 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Pulmonary Function Tests Visit 2a (Start of Treatment Period)

Instructions to Investigator

• Lung function printouts must be labelled with the Subject Initials, Subject Number, Visit Number, date and time of assessment and the signature of the person responsible for the data.

• Record FEV1 to 2 decimal places.

Monitor Data Validation Checks

• Check that predicted normal(s) is correct from the table provided.

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

• Check that FEV1 has been rounded to 2 decimal places.

48 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2.1 Pulmonary Function Tests Visit 2a (Start of Treatment Period)

β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N If YES, remind the subject not to take any before the next visit.

Time of Actual assessment measurement pre- pre-Ventolin Predicted Ventolin normal Test (highest of 3 measurements)

00:00-23:59 AB

e.g. FEV1 (L) 08:00 1.75 3.25

FEV1 (L) :..

Actual Time of measurement assessment within 15 post- % minutes Ventolin Reversibility Test post-Ventolin (highest of 3 measurements) C-A 00:00-23:59 x100 C B

e.g. FEV1 (L) 08:15 1.82 2.2

FEV1 (L) :..

≥ NOTE: If subject does not have documented evidence of 12% FEV1 reversibility within the last 2 years or did not have a reversibility of ≥12% (and ≥200mls) at this visit, they must be withdrawn.

49 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 02.01 - 01 AUG 01 Protocol code SAM40040 Inclusion Criteria Worksheet

Instructions to Investigator

• Review the worksheet first.

• Answer each question on the worksheet.

• ✔ appropriate box for each Inclusion criterion question.

• Ensure that you maintain the source documents that validate the Inclusion criteria.

Monitor Data Validation Checks

• Check that either a YES or NO box is ✔ for each Inclusion criterion.

50 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 04.00 - 02 OCT 00 Protocol code Subject number SAM40040 Inclusion Criteria Worksheet Visit 2a (Start of Treatment Period)

Inclusion Criteria ✔ one box for each question:

3. During the 2-week run-in period, did the subject complete daily record cards on at least 10 days (run-in window is 10-18 days)?

If any INCLUSION CRITERIA question is answered NO, this subject must NOT enter this study.

51 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.04 - 01 NOV 00 Protocol code SAM40040 Inclusion Criteria Visit 2a (Start of Treatment Period)

Instructions to Investigator

Did the subject meet all the entry criteria?

• If the subject met all the entry criteria (all YES answers to the Inclusion questions), ✔ YES. Otherwise ✔ NO.

Inclusion Criteria

•Only ✔ boxes that represent a violation of the Inclusion criteria.

Monitor Data Validation Checks

• If the question “Did the subject meet all entry criteria” is answered YES, check that no ✔ are present in the inclusion criteria boxes.

• If the question “Did the subject meet all entry criteria” is answered NO, check that a ✔ is present in at least one inclusion criteria box.

52 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 03.02 - 01 NOV 00 Protocol code Session number Subject number SAM40040 2.1 Inclusion Criteria Visit 2a (Start of Treatment Period)

Did the subject meet all entry criteria (i.e., All "YES" answers for inclusion criteria)? See INCLUSION CRITERIA WORKSHEET. Yes Y No N

✔ all boxes that represent a violation of the inclusion criteria:

Inclusion Criteria

1. 2. 3.

53 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Investigator Instructions Visit 2a (Start of Treatment Period)

If the subject is eligible to enter the Treatment Period:

L/min

Monitor Data Validation Checks

If the subject enters the Treatment Period:

• Check that all boxes for the inclusion criteria are ticked ‘YES’.

• Check that the stop date for the subject’s own inhaled corticosteroid has been entered on the ASTHMA CONCURRENT MEDICATIONS page.

54 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Oropharyngeal Candidiasis Visit 2a (Start of Treatment Period)

Instructions to Investigator

Oropharyngeal Candidiasis

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis:

• Take swab and send to a local laboratory for analysis.

• Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks

Oropharyngeal Candidiasis

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis:

• Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

55 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 2.1 Oropharyngeal Candidiasis Visit 2a (Start of Treatment Period)

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

56 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Treatment Allocation Visit 2a (Start of Treatment Period)

Instructions to Investigator

• The IVR system will require a few questions to be answered and will read to you the subject’s treatment number, which must be recorded on the FRONT COVER of this Case Report Form.

• The IVR system will then read out a pack number (dispensing unit number), this must be recorded on the facing page.

Monitor Data Validation Checks

• Check that the Date Treatment Allocated corresponds with the Visit 2a date.

• Check that the treatment start date has been recorded on the STUDY DRUG page.

• Check that stop date for subject’s own inhaled corticosteroid has been recorded on the facing page.

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Protocol code Session number Subject number SAM40040 2.1 Treatment Allocation / Current Corticosteroid Use For Asthma Visit 2a (Start of Treatment Period)

Treatment Allocation Using the IVR system, obtain the treatment number for this subject and pack number (dispensing unit number) for this visit.

Enter the treatment number on the FRONT COVER of the Case Report Form. Enter pack number (dispensing unit number) in the box below.

...... Investigator’s or Designee's signature

...... Investigator’s or Designee's name - print

Pack Number (dispensing unit number)

Date Treatment Allocated day month year

NOTE: ENTER THE TREATMENT START DATE ON THE STUDY DRUG PAGE IN THIS CASE REPORT FORM.

Current Corticosteroid Use For Asthma

Instruct the subject to discontinue their usual asthma medication, record the stop date of subject’s own previous inhaled corticosteroid below:

Stop date of subject’s own inhaled corticosteroid day month year Record the stop date of any other asthma medication on the ASTHMA CONCURRENT MEDICATION page.

Pharmacy (if applicable) Dispense SAM40040 Treatment Pack for weeks 1-8 with the appropriate pack number (dispensing unit number) for this subject.

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Protocol code SAM40040 Investigator’s Checklist Visit 2a (Start of Treatment Period)

If the subject is to continue in the study:

• Record 30% Peak Flow alert value on front of Daily Record Card for Visit 2/2a - 3.

• Issue new Daily Record Card for the treatment period and re-emphasize to the subject the importance of completing the Daily Record Card correctly.

• Issue relief Ventolin if necessary.

• Issue study medication.

• Check subjects ability to measure their PEF.

• Make an appointment for the subject to return in 4 weeks (± 1 week) time.

• Ensure all Visit 2a sections have been completed.

Remind the subject of the following:

• Discontinue any inhaled corticosteroid medication other than the study medication.

• To use Ventolin ‘as required’.

• Withhold Ventolin for six hours before Visit 3.

• Not to take their study medication on the morning of Visit 3. Study medication should be taken at the clinic once the FEV1 has been performed.

• Remind the subject of the procedure in the case of an exacerbation of asthma.

• Bring to the next visit: completed DRC, peak flow meter and appointment card.

If the subject has been withdrawn:

• Collect Daily Record Card.

• Collect Study Medication (Ventolin).

• Collect mini-Wright Peak Flow meter.

• Make an appointment for subject to return for follow-up in 1 weeks (± 2 days)time (if applicable).

• Complete END OF STUDY RECORD page.

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Protocol code SAM40040 Daily Record Card / ACQ Visit 3 (Treatment Period)

Instructions to Investigator

Daily Record Card Check that:

• All the dates have been entered correctly and are in chronological order.

• A “0” has been entered where no relief medication was taken that day. • Transcribe any medications from the medication section into the appropriate CONCURRENT MEDICATION page in this Case Report Form.

• Transcribe any Adverse Events that have been reported into the appropriate ADVERSE EVENT page(s) of this CRF.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated. Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed.

• Ensure that either a YES or NO box has been ✔. • ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card

• Check that the visit date is 4 weeks (± 1 week) after Visit 2/2a. If date is outside this window, request investigator to initial and date entry. • Check that the Daily Record Card for the period Visit 2/2a - 3 has been returned fully completed. Ensure that any adverse events and changes in medication reported in the Daily Record Card have been transcribed to the appropriate ADVERSE EVENT and CONCURRENT MEDICATION page(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them.

• Check that there are no inappropriate blank boxes. Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

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Protocol code Session number Subject number SAM40040 3 Daily Record Card / ACQ Visit 3 (Treatment Period)

Date of Assessment day month year

Daily Record Card

Has the Daily Record Card been completed correctly? Yes Y No N This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

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Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 3 (Treatment Period)

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Healthcare Contacts • If the subject has had any unscheduled asthma related healthcare contacts, check that the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page has been completed.

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Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 3 (Treatment Period)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

Healthcare Contacts

Ask the following question, (and check Daily Record Card)

"Have you had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit?"

Confirm this healthcare contact question has been asked. ✔ if done

If the subject has had any unscheduled asthma related healthcare contacts, the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACTS page must be completed in this Case Report Form.

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Protocol code SAM40040 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 3 (Treatment Period)

Instructions to Investigator

Pulmonary Function Tests

• The highest of three technically acceptable FEV1 measurements must be recorded. • Lung function printouts must be labelled with the Subject Initials, Subject Number, Visit Number, date and time of assessment and the signature of the person responsible for the data.

• Record FEV1 to 2 decimal places. Oropharyngeal Candidiasis

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Take swab and send to a local laboratory for analysis. • Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks

Pulmonary Function Tests

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

• Check that FEV1 has been rounded to 2 decimal places. • Check that all spirometry printouts are signed and dated by the responsible person and clearly indicate the clinic visit, the date of the visit, the time of assessment, the subject’s initials and the Glaxo Wellcome subject number. The spirometry printouts must be stored in the subject’s notes. If spirometry printouts are on thermal paper the pages must be copied. Oropharyngeal Candidiasis

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

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Protocol code Session number Subject number SAM40040 3 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 3 (Treatment Period)

Pulmonary Function Test β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N If YES, remind the subject not to take any before the next visit.

Record the highest of 3 technically acceptable measurements

. FEV1 L

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

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Protocol code SAM40040 Investigator’s Checklist Visit 3 (Treatment Period)

If the subject is to continue in the study:

• Collect Daily Record Card for Visit 2/2a - 3.

• Record 30% Peak Flow alert value on front of Daily Record Card for Visit 3-4.

• Issue new Daily Record Card for the treatment period and re-emphasize to the subject the importance of completing the Daily Record Card correctly.

• Issue relief Ventolin if necessary.

• Check subjects ability to measure their PEF.

• Make an appointment for the subject to return in 4 weeks (± 1 week) time.

• Ensure all Visit 3 sections have been completed.

Remind the subject of the following:

• To use Ventolin ‘as required’.

• Withhold Ventolin for six hours before Visit 4.

• Not to take their study medication on the morning of Visit 4. Study medication should be taken at the clinic once the FEV1 has been performed. • Remind the subject of the procedure in the case of an exacerbation of asthma.

• Bring to the next visit: completed DRC, peak flow meter, appointment card and all medication.

If the subject has been withdrawn:

• Collect Daily Record Card.

• Collect all Study Medication.

• Collect mini-Wright Peak Flow meter.

• Make an appointment for subject to return for follow-up in 1 weeks time (if applicable).

• Complete END OF STUDY RECORD page.

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Protocol code SAM40040 Daily Record Card / ACQ Visit 4 (Treatment Period)

Instructions to Investigator

Daily Record Card Check that:

• All the dates have been entered correctly and are in chronological order.

• Transcribe any Adverse Events that have been reported into the appropriate ADVERSE EVENT page(s) of this CRF.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated. Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed.

• Ensure that either a YES or NO box has been ✔. • ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card

• Check that the visit date is 4 weeks (± 1 week) after Visit 3. If date is outside this window, request investigator to initial and date entry. • Check that the Daily Record Card for the period Visit 3-4 has been returned fully completed. Ensure that any adverse events and changes in medication reported in the Daily Record Card have been transcribed to the appropriate ADVERSE EVENT and CONCURRENT MEDICATION page(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them.

• Check that there are no inappropriate blank boxes. Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

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Protocol code Session number Subject number SAM40040 4 Daily Record Card / ACQ Visit 4 (Treatment Period)

Date of Assessment day month year

Daily Record Card

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Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 4 (Treatment Period)

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Healthcare Contacts • If the subject has had any unscheduled asthma related healthcare contacts, check that the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page has been completed.

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Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 4 (Treatment Period)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

Healthcare Contacts

Ask the following question, (and check Daily Record Card)

"Have you had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit?"

Confirm this healthcare contact question has been asked. ✔ if done

If the subject has had any unscheduled asthma related healthcare contacts, the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACTS page must be completed in this Case Report Form.

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Protocol code SAM40040 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 4 (Treatment Period)

Instructions to Investigator

Pulmonary Function Tests

• Record FEV1 to 2 decimal places. Oropharyngeal Candidiasis

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Take swab and send to a local laboratory for analysis. • Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks

Pulmonary Function Tests

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

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Protocol code Session number Subject number SAM40040 4 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 4 (Treatment Period)

Pulmonary Function Test β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N If YES, remind the subject not to take any before the next visit.

Record the highest of 3 technically acceptable measurements

. FEV1 L

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

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Protocol code SAM40040 Treatment Allocation Visit 4 (Treatment Period)

Instructions to Investigator

• Complete the relevant SCAD worksheet and access SCAD via the IVR system to obtain the subject’s next pack number (dispensing unit number).

• You will be required to enter the subject’s treatment number into the IVR system and the system will read out to you the next pack number (dispensing unit number) to be dispensed to the subject at this visit. Record the pack number (dispensing unit number) on the facing page.

Monitor Data Validation Checks

• Check that the Date Treatment Allocated corresponds with the Visit 4 date.

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Protocol code Session number Subject number SAM40040 4 Treatment Allocation Visit 4 (Treatment Period)

Treatment Allocation Using the IVR system, obtain the pack number (dispensing unit number) for this visit.

Enter pack number (dispensing unit number) in the box below.

...... Investigator’s or Designee's signature

...... Investigator’s or Designee's name - print

Pack Number (dispensing unit number)

Date Treatment Allocated day month year

Pharmacy (if applicable) Dispense SAM40040 Treatment Pack for weeks 9-16 with the appropriate pack number (dispensing unit number) for this subject.

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Protocol code SAM40040 Investigator’s Checklist Visit 4 (Treatment Period)

If the subject is to continue in the study:

• Collect Daily Record Card for Visit 3-4.

• Collect study medication issued at Visit 2 and complete COMPLIANCE page.

• Record 30% Peak Flow alert value on front of Daily Record Card for Visit 4-5.

• Issue new Daily Record Card for the treatment period and re-emphasize to the subject the importance of completing the Daily Record Card correctly.

• Issue relief Ventolin if necessary.

• Issue Study Medication.

• Check subjects ability to measure their PEF.

• Make an appointment for the subject to return in 8 weeks (± 1 week) time.

• Ensure all Visit 4 sections have been completed.

Remind the subject of the following:

• To use Ventolin ‘as required’.

• Withhold Ventolin for six hours before Visit 5.

• Not to take their study medication on the morning of Visit 5. Study medication should be taken at the clinic once the FEV1 has been performed. • Remind the subject of the procedure in the case of an exacerbation of asthma.

• Bring to the next visit: completed DRC, peak flow meter, appointment card and all medication.

If the subject has been withdrawn:

• Collect Daily Record Card.

• Collect all Study Medication.

• Collect mini-Wright Peak Flow meter.

• Make an appointment for subject to return for follow-up in 1 weeks (± 2 days) time (if applicable).

• Complete END OF STUDY RECORD page.

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Protocol code SAM40040 Daily Record Card / ACQ Visit 5 (Treatment Period)

Instructions to Investigator

Daily Record Card Check that:

• All the dates have been entered correctly and are in chronological order.

• Transcribe any Adverse Events that have been reported into the appropriate ADVERSE EVENT page(s) of this CRF.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated. Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed.

• Ensure that either a YES or NO box has been ✔. • ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card

• Check that the visit date is 8 weeks (± 1 week) after Visit 4. If date is outside this window, request investigator to initial and date entry. • Check that the Daily Record Card for the period Visit 4-5 has been returned fully completed. Ensure that any adverse events and changes in medication reported in the Daily Record Card have been transcribed to the appropriate ADVERSE EVENT and CONCURRENT MEDICATION page(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them.

• Check that there are no inappropriate blank boxes. Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

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Protocol code Session number Subject number SAM40040 5 Daily Record Card / ACQ Visit 5 (Treatment Period)

Date of Assessment day month year

Daily Record Card

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Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 5 (Treatment Period)

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Healthcare Contacts • If the subject has had any unscheduled asthma related healthcare contacts, check that the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page has been completed.

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Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 5 (Treatment Period)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

Healthcare Contacts

Ask the following question, (and check Daily Record Card)

"Have you had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit?"

Confirm this healthcare contact question has been asked. ✔ if done

If the subject has had any unscheduled asthma related healthcare contacts, the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACTS page must be completed in this Case Report Form.

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Protocol code SAM40040 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 5 (Treatment Period)

Instructions to Investigator

Pulmonary Function Tests

• Record FEV1 to 2 decimal places. Oropharyngeal Candidiasis

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Take swab and send to a local laboratory for analysis. • Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks

Pulmonary Function Tests

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

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Protocol code Session number Subject number SAM40040 5 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 5 (Treatment Period)

Pulmonary Function Test β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N If YES, remind the subject not to take any before the next visit.

Record the highest of 3 technically acceptable measurements

. FEV1 L

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

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Protocol code SAM40040 Treatment Allocation Visit 5 (Treatment Period)

Instructions to Investigator

• Complete the relevant SCAD worksheet and access SCAD via the IVR system to obtain the subject’s next pack number (dispensing unit number).

Monitor Data Validation Checks

• Check that the Date Treatment Allocated corresponds with the Visit 5 date.

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Protocol code Session number Subject number SAM40040 5 Treatment Allocation Visit 5 (Treatment Period)

Treatment Allocation Using the IVR system, obtain the pack number (dispensing unit number) for this visit.

Enter pack number (dispensing unit number) in the box below.

...... Investigator’s or Designee's signature

...... Investigator’s or Designee's name - print

Pack Number (dispensing unit number)

Date Treatment Allocated day month year

Pharmacy (if applicable)

Dispense SAM40040 Treatment Pack for weeks 17-24 with the appropriate pack number (dispensing unit number) for this subject.

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Protocol code SAM40040 Investigator’s Checklist Visit 5 (Treatment Period)

If the subject is to continue in the study:

• Collect Daily Record Card for Visit 4-5.

• Collect study medication issued at Visit 4 and complete COMPLIANCE page.

• Record 30% Peak Flow alert value on front of Daily Record Card for Visit 5-6.

• Issue new Daily Record Card for the treatment period and re-emphasize to the subject the importance of completing the Daily Record Card correctly.

• Issue relief Ventolin if necessary.

• Issue Study Medication.

• Check subjects ability to measure their PEF.

• Make an appointment for the subject to return in 8 weeks (± 1 week) time.

• Ensure all Visit 5 sections have been completed.

Remind the subject of the following:

• To use Ventolin ‘as required’.

• Withhold Ventolin for six hours before Visit 6.

• Not to take their study medication on the morning of Visit 6. Study medication should be taken at the clinic once the FEV1 has been performed. • Remind the subject of the procedure in the case of an exacerbation of asthma.

• Bring to the next visit: completed DRC, peak flow meter, appointment card and all medication.

If the subject has been withdrawn:

• Collect Daily Record Card.

• Collect all Study Medication.

• Collect mini-Wright Peak Flow meter.

• Make an appointment for subject to return for follow-up in 1 weeks (± 2 days) time (if applicable).

• Complete END OF STUDY RECORD page.

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Protocol code SAM40040 Daily Record Card / ACQ Visit 6 (End of Treatment Period)

Instructions to Investigator

Daily Record Card Check that:

• All the dates have been entered correctly and are in chronological order.

• Transcribe any Adverse Events that have been reported into the appropriate ADVERSE EVENT page(s) of this CRF.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated. Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed.

• Ensure that either a YES or NO box has been ✔. • ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card

• Check that the visit date is 8 weeks (± 1 week) after Visit 5. If date is outside this window, request investigator to initial and date entry. • Check that the Daily Record Card for the period Visit 5-6 has been returned fully completed. Ensure that any adverse events and changes in medication reported in the Daily Record Card have been transcribed to the appropriate ADVERSE EVENT and CONCURRENT MEDICATION page(s) of the Case Report Form.

• If any corrections are made, the investigator must initial and date them.

• Check that there are no inappropriate blank boxes. Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

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Protocol code Session number Subject number SAM40040 6 Daily Record Card / ACQ Visit 6 (End of Treatment Period)

Date of Assessment day month year

Daily Record Card

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Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 6 (End of Treatment Period)

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Healthcare Contacts • If the subject has had any unscheduled asthma related healthcare contacts, check that the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page has been completed.

87 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Visit 6 (End of Treatment Period)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

Healthcare Contacts

Ask the following question, (and check Daily Record Card)

"Have you had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit?"

Confirm this healthcare contact question has been asked. ✔ if done

If the subject has had any unscheduled asthma related healthcare contacts, the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACTS page must be completed in this Case Report Form.

88 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Pulmonary Function Tests / Oropharyngeal Candidiasis / Pregnancy Test Visit 6 (End of Treatment Period)

Instructions to Investigator Pulmonary Function Tests

• Record FEV1 to 2 decimal places. Oropharyngeal Candidiasis • Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis. If there is clinical evidence of oropharyngeal candidiasis: • Take swab and send to a local laboratory for analysis. • Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks Pulmonary Function Tests

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

If there is clinical evidence of oropharyngeal candidiasis:

• Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

Pregnancy Test • If the Pregnancy Test question is ✔ as Not Applicable (Not of Childbearing Potential), check that this is consistent with the answer to the Childbearing Potential question.

89 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd Version 01.01 : 11 NOV 00 CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 6 Pulmonary Function Tests / Oropharyngeal Candidiasis / Pregnancy Test Visit 6 (End of Treatment Period)

Pulmonary Function Tests β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N

Record the highest of 3 technically acceptable measurements

. FEV1 L

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

Pregnancy Test

Pregnancy test result, ✔one:

Positive P

Negative N

Not applicable X (Not of childbearing potential)

90 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Investigator’s Checklist Visit 6 (End of Treatment Period)

• Collect Daily Record Card for Visit 5-6.

• Collect study medication issued at Visit 5 and complete COMPLIANCE page.

• Record study medication stop date on STUDY DRUG page.

• Record date of subject completion on the END OF STUDY RECORD page.

• Ensure a urinary pregnancy test has been performed (if required).

• Make an appointment for the subject to return for follow-up in 1 weeks (± 2 days) time.

• Ensure all Visit 6 sections have been completed.

• Access the IVR system to register the subject as completed treatment.

91 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Adverse Event / Concurrent Medication Visit 7 (Optional Follow-up)

92 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication Visit 7 (Optional Follow-up)

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

93 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 7 (Optional Follow-up)

Instructions to Investigator

Pulmonary Function Tests

• Record FEV1 to 2 decimal places. Oropharyngeal Candidiasis

• Swab need only be taken if there is clinical evidence of Oropharyngeal Candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Take swab and send to a local laboratory for analysis.

• Complete the ADVERSE EVENT page if the swab is positive.

Monitor Data Validation Checks

Pulmonary Function Tests

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

Oropharyngeal Candidiasis

• Check that either the Yes or No box is ✔ for evidence of oropharyngeal candidiasis.

If there is clinical evidence of oropharyngeal candidiasis: • Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

94 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 0 Pulmonary Function Tests / Oropharyngeal Candidiasis Visit 7 (Optional Follow-up)

Pulmonary Function Tests β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N

Record the highest of 3 technically acceptable measurements

. FEV1 L

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

95 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Investigator’s Checklist Visit 7 (Optional Follow-up)

• Collect Daily Record Card not previously collected at Visit 6.

• Collect study medication and complete COMPLIANCE page.

• Record study medication stop date on STUDY DRUG page.

• Record date of subject completion on the END OF STUDY RECORD page.

• Ensure all Visit 7 sections have been completed.

• Prescribe appropriate asthma medication.

• Access the IVR system to register the subject as completed treatment.

96 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Daily Record Card / ACQ Premature Discontinuation

Instructions to Investigator

Daily Record Card Check that:

• All the dates have been entered correctly and are in chronological order.

• Transcribe any Adverse Events that have been reported into the appropriate ADVERSE EVENT page(s) of this CRF.

• Any changes, corrections or explanations that you have made regarding dates must be initialled and dated. Asthma Control Questionnaire (where available)

• Check that the ACQ has been completed.

• Ensure that either a YES or NO box has been ✔. • ✔ NO if Asthma Control Questionnaire not available.

Monitor Data Validation Checks

Daily Record Card

• If any corrections are made, the investigator must initial and date them.

• Check that there are no inappropriate blank boxes. Asthma Control Questionnaire

• Check that the ACQ has been completed if the question ‘Has Asthma Control Questionnaire been completed?’ has been answered ‘YES’.

97 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 0 Daily Record Card / ACQ Premature Discontinuation

Date of Assessment day month year

Daily Record Card

98 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Premature Discontinuation

Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either:

a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or;

b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment

Healthcare Contacts • If the subject has had any unscheduled asthma related healthcare contacts, check that the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page has been completed.

99 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Adverse Event / Concurrent Medication / Exacerbation of Asthma / Healthcare Contacts Premature Discontinuation

Adverse Event / Concurrent Medication

Ask the following question, (and check Daily Record Card)

(a) "Have you had any other medical problems since your last visit?"

(b) "Have you taken any new medicines, other than those given to you within this study since your last visit?"

Adverse events should be recorded on the appropriate ADVERSE EVENTS page(s). Concurrent medications should be recorded on the CONCURRENT MEDICATIONS page(s).

Confirm these adverse event and concurrent medication questions have been asked. ✔ if done

Exacerbation of Asthma

Ask the following question, (and check Daily Record Card)

Have you experienced an exacerbation of your asthma (according to definition on facing page) since the last visit?

Complete the appropriate CONCURRENT MEDICATION page, ASTHMA EXACERBATION, UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACT page(s) and if appropriate, the ADVERSE EVENTS page in this Case Report Form.

Confirm this exacerbation question has been asked. ✔ if done

Healthcare Contacts

Ask the following question, (and check Daily Record Card)

"Have you had any need to seek medical treatment for asthma or an asthma-related episode since the previous scheduled visit?"

Confirm this healthcare contact question has been asked. ✔ if done

If the subject has had any unscheduled asthma related healthcare contacts, the UNSCHEDULED ASTHMA RELATED HEALTHCARE CONTACTS page must be completed in this Case Report Form.

100 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Pulmonary Function Tests / Oropharyngeal Candidiasis / Pregnancy Test Premature Discontinuation

Instructions to Investigator Pulmonary Function Tests

Monitor Data Validation Checks Pulmonary Function Tests

• Ensure that the highest of 3 technically acceptable measurements for FEV1 has been recorded.

If there is clinical evidence of oropharyngeal candidiasis:

• Check that a swab has been taken.

• Check that only one result of the swab has been recorded.

• Check that all medications used to treat the infection were recorded on the CONCURRENT MEDICATION page.

• Check that the oropharyngeal candidiasis when present is recorded on the ADVERSE EVENT page.

• If swab result will never be known check that Not Available is ✔.

Pregnancy Test • If the Pregnancy Test question is ✔ as Not Applicable (Not of Childbearing Potential), check that this is consistent with the answer to the Childbearing Potential question.

101 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd Version 01.01 : 11 NOV 00 CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 0 Pulmonary Function Tests / Oropharyngeal Candidiasis / Pregnancy Test Premature Discontinuation

Pulmonary Function Tests β Has the subject taken any short-acting 2-agonist in the last 6 hours? Yes Y No N

Record the highest of 3 technically acceptable measurements

. FEV1 L

Oropharyngeal Candidiasis

Does the subject have clinical evidence of oropharyngeal candidiasis? Yes Y No N

NOTE: Swab need only to be taken if there is clinical evidence of Oropharyngeal candidiasis.

Swab taken? Yes Y No N Result of swab if taken, ✔one box only:

Negative N Positive P Not available V

Complete the CONCURRENT MEDICATIONS page and the ADVERSE EVENT page(s), if appropriate.

Pregnancy Test

Pregnancy test result, ✔one:

Positive P

Negative N

Not applicable X (Not of childbearing potential)

102 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Investigator’s Checklist Premature Discontinuation

Instructions to Investigator

• Ensure subject has completed an ACQ.

• Collect any used/unused study medication.

• Ensure all ADVERSE EVENT and CONCURRENT MEDICATION pages been completed if appropriate.

• If appropriate, ensure ASTHMA EXACERBATION page has been completed.

• Collect the subject Daily Record Card.

• Ensure the Unscheduled/Emergency Visit page been completed, if applicable.

• Complete the STUDY DRUG, COMPLIANCE LOG and END OF STUDY RECORD page(s) in this Case Report Form.

• Schedule an appointment for the subject to return in 1 weeks (± 2 days) time for a follow-up visit.

• Ensure all premature discontinuation sections have been completed.

• Access the IVR system to register the subject as discontinued.

103 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Unscheduled / Emergency Visits

Instructions to Investigator

If the unscheduled visit / contact is due to an adverse event, complete the ADVERSE EVENT form. If study medication is withdrawn at the unscheduled visit, complete the PREMATURE DISCONTINUATION section and make an appointment for the subject to return for 2 week follow-up visit.

Monitor’s Data Validation Checks

• Check either the YES or NO box has been ✔.

• If the YES box has been ✔, ensure that at least one unscheduled visit has been recorded.

• Check that data is within the time period of subject’s participation in the study.

• Check that type of contact has been recorded as either V or P.

• Check that reason for contact is in precise and legible text.

• Check that either a Y or N has been recorded to indicate whether subject’s medication has been discontinued or not.

• If study medication withdrawn is answered ‘Y’, check that the PREMATURE DISCONTINUATION and END OF STUDY RECORD pages have been completed correctly.

104 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 0 Unscheduled / Emergency Visits

Did the subject make any unscheduled emergency visits or contacts during the study? Yes Y No N If YES, indicate below. This page should be completed each time the subject makes an UNSCHEDULED / EMERGENCY VISIT or TELEPHONE CONTACT.

Ensure that any ADVERSE EVENTS, ASTHMA MEDICATIONS and/or changes in CONCURRENT MEDICATION are also documented on the appropriate pages of the CRF. If the subject is withdrawn, complete PREMATURE DISCONTINUATION SECTION, END OF STUDY RECORD and make an appointment for the subject to return for 2 week follow-up visit.

Date Type of Contact Subject Withdrawn V = Visit Reason for Contact Y/N P = Telephone day month year Y=Yes N=No

NOTE: If the subject returns study medication at an unscheduled / emergency visit, complete the COMPLIANCE page and the STUDY DRUG page at the back of the Case Report Form.

105 CONFIDENTIAL GM2004/00056/00 SAM40040 abcd IDSG Version 01.00 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code SAM40040 Study Drug

Monitor Data Validation Checks

• Check that start and stop dates are recorded and that start date is before, or the same as, stop date.

• Check that study drug start occurs on or after the initial date of assessment (on DEMOGRAPHY page).

• If "Were there any significant changes to study drug?" is ✔YES, check that a concise text entry is present on the line provided.

106 CONFIDENTIAL GM2004/00056/00 SAM40040 abcd IDSG Version 03.00 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Session number Subject number SAM40040 0 Study Drug

Start date Stop date

day month year day month year

Study drug

Were there any significant changes to study drug? Yes Y No N

If YES, specify study drug changes, dates, and reasons, ......

......

107 abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code SAM40040 Compliance

Instructions to Investigator

• Ensure that either a ‘Y’ or ‘N’ has been recorded for each inhaler returned.

• If the inhaler has been returned record the number of doses remaining for the Diskus.

Monitor Data Validation Checks CONFIDENTIAL

• Check that the compliance section has been completed appropriately. 108 • Check that the number of remaining doses for the Diskus corresponds with the dose counter on the inhaler. GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Compliance

DISKUS/ACCUHALER 1 BADPI 1 DISKUS/ACCUHALER 2 BADPI 2 DISKUS/ACCUHALER 3 BADPI 3 Diskus/ Number of BADPI Diskus/ Number of BADPI Diskus/ Number of BADPI Accuhaler remaining Returned? Accuhaler remaining Returned? Accuhaler remaining Returned? Study drug returned? doses returned? doses returned? doses

Y = Yes Y = Yes Y = Yes Y = Yes Y = Yes Y = Yes N = No N = No N = No N = No N = No N = No

e.g. Visit 2-4 Y 6 Y Y 7 Y Y 7 Y CONFIDENTIAL

Visit 2-4 109 Visit 4-5 35 Visit 5-6

Visit 7 (If drug not returned at Visit 6)

Premature Discontinuation GM2004/00056/00 SAM40040

CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.01 - 01 DEC 00 Protocol code SAM40040 Status of Treatment Blind

Instructions to Investigator

• Check whether the treatment blind was broken during the study.

• If YES, provide the date the blind was broken and the reason the blind was broken.

Monitor Data Validation Checks

• Check that either the YES or NO box at the top of the page is answered.

• If YES is ✔, check that a date and reason are present and that the appropriate NON-SERIOUS ADVERSE EVENT, SERIOUS ADVERSE EVENT and END OF STUDY RECORD pages are completed.

• Check that only one reason is given.

• If the reason for breaking the blind is ✔ “Other”, check that a concise text entry is present in the space provided.

110 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 02.02 - 01 NOV 00 Protocol code Session number Subject number SAM40040 0 Status of Treatment Blind

Was the treatment blind for this subject broken during the study? Yes Y No N

If YES, complete the following:

Date day month year

Reason, ✔one:

Medical emergency requiring identity of study drug for further treatment E

Other X specify, ......

Complete NON-SERIOUS ADVERSE EVENT, SERIOUS ADVERSE EVENT, and/or STUDY DRUG pages as appropriate.

111 abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code SAM40040 Unscheduled Asthma Related Healthcare Contacts

Instructions to Investigator

• Record only unscheduled asthma related healthcare contacts that are related to asthma or the treatment of asthma. Unscheduled asthma-related healthcare contacts may occur with the investigator or another healthcare provider and are defined as those visits or telephone contacts not associated with a scheduled study visit or a routinely scheduled appointment. These contacts often include visits or contacts associated with the treatment of an asthma exacerbation or an adverse event.

• Use a separate row for each asthma-related episode. An episode is defined as an event requiring one or more contacts to be made with the investigator or CONFIDENTIAL another healthcare provider until there is resolution of the initiating event. (e.g., The subject goes to the Emergency Department for treatment of asthma exacerbation and is later admitted to the general hospital ward for treatment. This represents one event that was associated with an Emergency

112 Department visit and a hospitalization).

• Provide the date of contact for each episode. The date of contact is defined as the date when the initial contact concerning an episode is made by the subject with the investigator or another healthcare provider.

• When the subject has made contact with the investigator or another healthcare provider in association with an episode (e.g., asthma exacerbation, adverse event or other non-routinely scheduled asthma-related care), the quantity of each of the following contacts occurring as part of the asthma-related episode should be recorded. -Telephone contacts - Home/day, Home/night, Office/practice, Outpatients clinic - Emergency Department Visits - Inpatient Hospitalisation (ICU and General Ward)

Enter only non-zero data GM2004/00056/00

• Indicate if the contact was the result of an exacerbation of asthma. If YES, the ASTHMA EXACERBATION page in this Case Report Form must be completed. SAM40040 • Indicate if the contact was a result of an adverse event. If YES, the ADVERSE EVENTS page(s) in this Case Report Form must be completed.

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Unscheduled Asthma Related Healthcare Contacts

Yes Y No N Were there any unscheduled asthma related healthcare contacts during the study? Please use a separate section for each asthma-related episode. Enter only non-zero data.

Contact Method / Treatment Site Is this Was the Date of * episode If ‘Y’, record the contact Contact Emergency related to adverse event because of an Home / Home / Office / Outpatients Inpatient Episode Telephone Room / an adverse page number and asthma Day Night Practice Clinic Hospitalization event? row exacerbation? number A & E Dept. CONFIDENTIAL number Calls Visits Visits Visits Visits Visits ICU Gen. Ward day month year Y/N Y/N

113 (number) (number) (number) (number) (number) (number) (days) (days) Page Row

Example 07 / AUG / 01 1 1 2½ Y 45 2 Y

37 1 //

2 //

3 //

4 //

5 // GM2004/00056/00 6 //

7 // SAM40040 8 //

If the Unscheduled Healthcare contact was the result of an adverse event, then complete the ADVERSE EVENTS section at the back of this Case Report Form and record the adverse event row number in the column, here denoted by an asterisk (*). If the Unscheduled Healthcare contact was the result of an exacerbation of asthma, then complete the ASTHMA EXACERBATION page in the Case Report Form.

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code SAM40040 Asthma Exacerbations

Instructions to Investigator Cold air / Cold weather C Air pollution P Stress / Emotions SE Other NSAIDS ON Tobacco smoke T Allergy HA Beta-blockers BB Witholding or reducing asthma medication AM Respiratory infection R Exercise E Aspirin AS Unknown etiology U Other X Definition of a Moderate and Severe Asthma Exacerbation

For the purpose of this study an asthma exacerbation will be defined as follows: CONFIDENTIAL Moderate Exacerbations • A deterioration in asthma requiring treatment with oral prednisolone 40-60mg per day for 7-10 days. This may be either: 114 a) morning PEF >30% below baseline (mean of last 7 days of run-in) for ≥ 2 consecutive days, or; b) a clinical deterioration assessed by the investigating physician as requiring oral steroid treatment • Individual courses of oral corticosteroids are classified as separate exacerbations only if they are administered >1 week apart. Any course started within one week of finishing the previous course is considered part of the previous exacerbation. Severe Exacerbations • deterioration in asthma which requires hospital admission. Monitor Data Validation Checks

• Check that Yes/No question is completed.

• Ensure that Date of onset is a complete date. GM2004/00056/00

• Ensure outcome is completed, and is a valid value. If ’F’ (fatal), check that a corresponding SERIOUS ADVERSE EVENT page is completed.

• Ensure that Date of resolution or death is complete, if Outcome is resolved or fatal. SAM40040

• Check that severity result is present and within the protocol specifications.

• Check that response to "Was the subject withdrawn due to this exacerbation?" corresponds to End of Study Record reason for withdrawal.

• Check that Primary cause of exacerbation is completed and within the protocol specifications. abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Asthma Exacerbations

Were there any moderate or severe Asthma exacerbations during the study? Yes Y No N If YES, record below:

Date of onset Outcome Date of resolution Severity Was the subject Primary Did the If ‘Y’ record the Was the subject If ‘Y’ record the or death withdrawn cause of exacerbation asthma concurrent hospitalised or had unscheduled asthma due to this exacerbation require medication page an unscheduled related healthcare exacerbation? treatment number and row emergency visit due contacts page number number to this exacerbation? and row number CONFIDENTIAL R = Resolved 2 = Moderate (See codes on F = Fatal Y = Yes Y = Yes Y = Yes day month year N = Not resolved day month year 3 = Severe N = No opposite page) N = No Page Row N = No Page Row

115 e.g. 21 MAY 01 R 29 MAY 01 3 Y R Y 39 2 Y 45 2

1. 38 2.

6. GM2004/00056/00 7.

8. SAM40040

Enter details on the ASTHMA RELATED HEALTHCARE CONTACT, ASTHMA CONCURRENT MEDICATION and SERIOUS ADVERSE EVENT section and END OF STUDY RECORD if applicable.

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code SAM40040 Asthma Concurrent Medications

Instructions to Investigator

• Check that either the YES or NO box is checked for the leading question "Were any Asthma concurrent medications taken by the subject during the study?" If YES, check that at least one drug is recorded.

• Check that the drug name (trade name preferred) is spelled correctly.

• Check that combination drugs are recorded as shown in Example 2. CONFIDENTIAL

• Check that the dose is recorded as a single unit. 116 • If text has been entered in the box check that it is not one of the pre-printed units and that nothing has been circled.

• Check that the units/frequency/route are abbreviated appropriately.

• Check that for units/route only one abbreviation is circled or one abbreviation is written in the box.

• Check that Date started is accurate and complete, partial dates are not acceptable.

• If Start Pre-study is ✔ check that Date started is blank.

• Check that Date stopped is accurate and complete, partial dates are not acceptable.

• If Continued Post-study is ✔ check that Date stopped is blank. GM2004/00056/00 • Check that the question "Was drug administered for an adverse event?" is answered Y or N. If Y, check that a corresponding adverse event is recorded on the Adverse Event page(s).

• Check that the question "Was drug administered as a relief medication? " is answered Y or N. SAM40040

• Check that the drug name (trade name preferred) is spelled correctly.

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Asthma Concurrent Medications

Were any Asthma concurrent medications taken by the subject prior to screening and/or during the study? Yes Y No N If YES, record below:

Was drug Was drug Drug 1 Dose Units Fre- Route Date ✔ if Date ✔ if admin- administered Trade name preferred quency started started stopped continued istered as a relief Pre-study Post-study for an medication?

adverse CONFIDENTIAL event?

day month year day month year Y/N Y/N µ 117 Example 1 g/mg IH/PO Serevent 50 BID 01 AUG 01 ✔ NN µg/mg IH/PO 39 Example 2 DUOVENT (100 / 40 µg) 1 PUFF BD ✔ 07 AUG 98 N N µg/mg IH/PO 1. µg/mg IH/PO 2. µg/mg IH/PO 3. µg/mg IH/PO 4. µg/mg IH/PO GM2004/00056/00 5. µg/mg IH/PO

4. SAM40040 µg/mg IH/PO 5. 1 If medication is given to treat an exacerbation that meets the definition of serious, then complete the SERIOUS ADVERSE EVENT page(s).

continued... abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code SAM40040 Asthma Concurrent Medications

Instructions to Investigator

• Check that the drug name (trade name preferred) is spelled correctly.

• Check that combination drugs are recorded as shown in Example 2. CONFIDENTIAL

• Check that the dose is recorded as a single unit. 118 • If text has been entered in the box check that it is not one of the pre-printed units and that nothing has been circled.

• Check that the units/frequency/route are abbreviated appropriately.

• Check that for units/route only one abbreviation is circled or one abbreviation is written in the box.

• Check that Date started is accurate and complete, partial dates are not acceptable.

• If Start Pre-study is ✔ check that Date started is blank.

• Check that Date stopped is accurate and complete, partial dates are not acceptable.

• Check that the question "Was drug administered as a relief medication? " is answered Y or N. SAM40040

• Check that the drug name (trade name preferred) is spelled correctly.

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Asthma Concurrent Medications Continued

day month year day month year Y/N Y/N µg/mg IH/PO Example 1 CONFIDENTIAL Serevent 50 BID 01 AUG 01 ✔ NN µ Example 2 g/mg IH/PO

119 DUOVENT (100 / 40 µg) 1 PUFF BD ✔ 07 AUG 98 N N µg/mg IH/PO

40 1. µg/mg IH/PO 2. µg/mg IH/PO 3. µg/mg IH/PO 4. µg/mg IH/PO 5. µg/mg IH/PO GM2004/00056/00 4. µg/mg IH/PO 5. SAM40040

1 If medication is given to treat an exacerbation that meets the definition of serious, then complete the SERIOUS ADVERSE EVENT page(s).

continued... abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code SAM40040 Asthma Concurrent Medications

Instructions to Investigator

• Check that the drug name (trade name preferred) is spelled correctly.

• Check that combination drugs are recorded as shown in Example 2. CONFIDENTIAL

• Check that the dose is recorded as a single unit. 120 • If text has been entered in the box check that it is not one of the pre-printed units and that nothing has been circled.

• Check that the units/frequency/route are abbreviated appropriately.

• Check that for units/route only one abbreviation is circled or one abbreviation is written in the box.

• Check that Date started is accurate and complete, partial dates are not acceptable.

• If Start Pre-study is ✔ check that Date started is blank.

• Check that Date stopped is accurate and complete, partial dates are not acceptable.

• Check that the question "Was drug administered as a relief medication? " is answered Y or N. SAM40040

• Check that the drug name (trade name preferred) is spelled correctly.

abcd CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Asthma Concurrent Medications Continued

day month year day month year Y/N Y/N µg/mg IH/PO Example 1 CONFIDENTIAL Serevent 50 BID 01 AUG 01 ✔ NN µ Example 2 g/mg IH/PO

121 DUOVENT (100 / 40 µg) 1 PUFF BD ✔ 07 AUG 98 N N µg/mg IH/PO

41 1. µg/mg IH/PO 2. µg/mg IH/PO 3. µg/mg IH/PO 4. µg/mg IH/PO 5. µg/mg IH/PO GM2004/00056/00 4. µg/mg IH/PO 5. SAM40040

1 If medication is given to treat an exacerbation that meets the definition of serious, then complete the SERIOUS ADVERSE EVENT page(s).

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.03 - 03 APR 01 Protocol code SAM40040 Other Concurrent Medications Instructions to Investigator

• ✔ either the YES or NO box at the top of the page. • Record all concurrent medications. Trade names are preferred for all medications; this is particularly encouraged for all combination medications, e.g. multivitamins and cold medications. The subject should be encouraged to disclose all medications he/she is taking, including non-prescribed medications, herbal remedies, and nutritional supplements.

• Record the start date, if known e.g., 0 6 J A N 0 1 . Partial dates are acceptable; i.e. JUN 99 or 99. day month year • If the concurrent medication start date is prior to the study start date, ✔ ‘✔ if started pre-study’. • Record the stop date if concurrent medication is stopped prior to the end of the study. CONFIDENTIAL • If the subject is to continue taking the concurrent medication after the study is over, ✔ ‘✔ if continued Post-Study’.

122 • If a concurrent medication was taken in association with an adverse event, record a Y for ‘YES’ or N for ‘NO’. If a medication was taken for an adverse event, complete the appropriate ADVERSE EVENTS page(s). Monitor Data Validation Checks • Check that either the YES or NO box at the top of the page is ✔. • If NO is ✔, check that no concurrent medications are present. • If YES is ✔, check that at least one concurrent medication is present. • Check that either the ‘Date started’ is completed or ‘✔ if started pre-study’ is ✔. At least one must be completed, but it is acceptable if both are completed. • If a pre-study drug start date is unknown, check that a ✔ is recorded for ‘✔ if started Pre-study’. • If both ‘Date started’ and ‘✔ if started Pre-study’ are completed, check that the start date is pre-study.

• Check that either the ‘Date stopped’ box is completed or the ‘✔ if continued Post-study’ is ✔. Only one must be completed. GM2004/00056/00

• Check that the drug start date is before or equal to the drug stop date. • Check that the drug name (trade name preferred) is spelled correctly. SAM40040 • If the subject is female, cross-check with the DEMOGRAPHY FOR FEMALES page that any contraceptive drugs taken by the subject are recorded. • If a concurrent medication was started pre-study, check that the indication is recorded on the CURRENT MEDICAL CONDITIONS page. • If the concurrent medication was taken for an adverse event, check that the event is entered on the appropriate ADVERSE EVENTS page(s) and that the

dates are consistent with the event. IDSG abcd Version 05.06 - 01 FEB 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Other Concurrent Medications

Were any concurrent medications taken by the subject during the study? Yes Y No N If YES, record below: Was drug administered Drug 1 Date ✔ if Date ✔ if Conditions treated/ for an (Trade name started started stopped continued indication adverse preferred 2) Pre- Post- event? study study Y=Yes CONFIDENTIAL day month year day month year N=No e.g. ZANTAC ✔ 27 JAN 01 Gastric ulcer N 123 1. 42 2.

6. GM2004/00056/00

7. SAM40040

8. 1 If medication is given to treat an adverse event, then the ADVERSE EVENT must be recorded on the NON-SERIOUS ADVERSE EVENT or SERIOUS ADVERSE EVENT page(s) at the back of the CRF. 2 Use generic names for studies conducted in Greece, Egypt, China, or other countries where a pharmacopoeia in Latin script is not available.

IDSG Version 06.06 - 01 NOV 00 Draft 2 - 31 AUG 01

Does This Event Meet the Definition of Serious?

An SAE is any adverse event that results in any of the following outcomes: a) death b) a life threatening adverse event c) inpatient hospitalization or prolongation of existing hospitalization d) a disability or incapacity

e) a congenital anomaly in the offspring of a subject who received study drug(s) CONFIDENTIAL f) an important medical event which, though not included in (a-e) above, may (AE Instruction page 1) Instruction (AE jeopardize the subject and may require medical or surgical intervention to prevent

124 one of the outcomes listed in (a-e). For more details see AE Instruction page 3.

YES NO GM2004/00056/00 SAM40040 Complete SAE pages Complete Non-serious AE page (in next section) (in this section)

IDSG Version 06.06 - 01 NOV 00 Draft 2 - 31 AUG 01 NON-SERIOUS ADVERSE EVENT

DEFINITION OF AN ADVERSE EVENT

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

An adverse event (AE) can therefore be any unfavorable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. CONFIDENTIAL

(AE Instruction page 2) Instruction (AE An adverse event does include: An adverse event does NOT include: 125 • An exacerbation of a pre-existing illness. • Medical or surgical procedures (e.g., surgery endoscopy, tooth extraction, • Increase in frequency or intensity of a pre-existing transfusion); the condition that leads to the procedure is an AE. episodic event or condition. • Pre-existing disease or conditions present or detected at the start of the study • A condition detected or diagnosed after study drug(s) that do not worsen. administration even though it may have been present • Situations where an untoward medical occurrence has not occurred prior to the start of the study (e.g., hospitalizations for cosmetic elective surgery, social and / or convenience • Continuous persistent disease or symptoms present at admissions). baseline that worsen following the start of the study. • The disease or disorder being studied or sign or symptom associated with the disease or disorder unless more severe than expected for the subject’s condition.

• Overdose of either study drug or concurrent medication without any signs or GM2004/00056/00 symptoms.

For GW clinical trials, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modifications of subject’s previous therapeutic regimen). SAM40040

IDSG Version 06.06 - 01 NOV 00 Draft 2 - 31 AUG 01

If the event meets the definition of serious, do not complete this non-serious AE page. Complete the SAE pages in the next section. SERIOUS ADVERSE EVENT

"Serious" is a regulatory designation and may not necessarily imply clinical seriousness or severity. A serious adverse event is any adverse event occurring at any dose1 that results in any of the following outcomes: a) death

b) a life threatening adverse event • The subject was, in the view of the investigator, at immediate risk of death from the event as it occurred. This definition does not include an event that, had it occurred in a more severe form, might have caused death.

c) inpatient hospitalization or prolongation of existing hospitalization CONFIDENTIAL

(AE Instruction page 3) Instruction (AE • Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not considered an adverse event. • Complications that occur during hospitalization are adverse events. If a complication prolongs hospitalization, the event is serious. 126 • "Inpatient" hospitalization means the subject has been formally admitted to the hospital for medical reasons. This may or may not be overnight. It does not include presentation at casualty/emergency room.

d) a disability or incapacity

e) a congenital anomaly in the offspring of a subject who received study drug(s)

f) Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. • Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. Medical and GM2004/00056/00 scientific judgment should be used in deciding whether prompt reporting is appropriate in these situations.

1 NOTE: The phrase "occurring at any dose", does not imply that the subject is receiving study drug(s). SAM40040

IDSG Version 06.06 - 01 NOV 00 Draft 2 - 31 AUG 01

INSTRUCTIONS FOR COMPLETING THE NON-SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible

DETAILS OF ADVERSE EVENT(S)

Diagnosis Enter only the diagnosis (if known); otherwise each sign and symptom should be entered on a separate line. If a diagnosis subsequently becomes available, then this should be entered and the signs and symptoms crossed out.

Date of Onset Record the date of onset of the first occurrence of the AE.

Maximum Intensity Record the maximum intensity that occurred over the duration of the event. Amend the intensity if it increases. CONFIDENTIAL

(AE Instruction page 4) Instruction (AE Outcome All AEs must be followed until the events are resolved, the condition stabilizes, the events are otherwise explained, or the

127 subject is lost to follow-up. Indicate if the event was "Resolved" or "Resolved with sequelae". If the adverse event is ongoing at the time the subject completes the study or becomes lost to follow-up, the outcome must be recorded as "Not resolved". Also enter "Not resolved" if the AE was ongoing at the time of death, but was not the cause of death.

Date of Resolution Record the date of resolution. This is the last date of occurrence of the AE. If the event resolved with sequelae, enter the date the subject’s medical condition stabilized. Leave blank if the AE is "Not resolved".

Action Taken with Indicate only for the specific event(s) that were directly responsible for the action taken with study drug(s): None Study drug(s) continue(s) even though an adverse event has occurred. Study Drug(s) as a Dose adjusted Dose is increased or decreased for one or more study drug(s). Result of the AE Temporarily interrupted Administration of one or more study drug(s) was stopped temporarily but then restarted. Permanently discontinued Administration of one or more study drug(s) was stopped permanently and not restarted. Not applicable Subject was not receiving study drug(s) when the event occurred (e.g., pre-or postdosing). GM2004/00056/00

Withdrawal Indicate only the event(s) directly responsible for the subject’s withdrawal as indicated on the End of Study Record page.

Relationship to It is a regulatory requirement for investigators to assess relationship to study drug(s) based on information available. The SAM40040 assessment should be reviewed on receipt of any new information and amended if necessary. "A reasonable possibility" is Study Drug(s) meant to convey that there are facts/evidence or arguments to suggest a causal relationship. Facts/evidence/arguments that may support "A reasonable possibility" include, for example, a temporal relationship, a pharmacologically-predicted event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, or relevant medical history, should also be considered.

IDSG abcd Version 04.05 - 01 FEB 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Non-Serious Adverse Events

Did the subject experience any non-serious adverse events during the study? Yes Y No N If YES, indicate below: Action taken Date Relationship Maximum Date of with study drug(s) Non-serious adverse events of Outcome Withdrawal to study Seriousness intensity resolution as a result of the onset drug(s) non-serious AE 1= Mild R = Resolved 0 = None Did subject Is there a Does the 2 = Moderate S = Resolved 1 = Dose adjusted withdraw from reasonable AE meet the CONFIDENTIAL Diagnosis only (if known) 3= Severe with 2 = Temporarily study as a possibility that the definition of or X= Not sequelae interrupted result of this non-serious AE serious? signs / symptoms applicable N= Not 3 = Permanently non-serious AE? may have been

128 (list one per line) resolved discontinued caused by the X = Not applicable study drug(s)?

Y = Yes Y = Yes Y = Yes 43 day month year day month year N = No N = No N = No e.g. HEADACHE 25 JAN 01 3 R 27 JAN 01 0 N Y N

1. N

2. N

3. N

4. N GM2004/00056/00

5. N

6. N SAM40040

7. N

8. N

continued... IDSG Version 06.06 - 01 NOV 00 Draft 2 - 31 AUG 01

INSTRUCTIONS FOR COMPLETING THE NON-SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible

DETAILS OF ADVERSE EVENT(S)

Date of Onset Record the date of onset of the first occurrence of the AE.

Maximum Intensity Record the maximum intensity that occurred over the duration of the event. Amend the intensity if it increases. CONFIDENTIAL

(AE Instruction page 4) Instruction (AE Outcome All AEs must be followed until the events are resolved, the condition stabilizes, the events are otherwise explained, or the

129 subject is lost to follow-up. Indicate if the event was "Resolved" or "Resolved with sequelae". If the adverse event is ongoing at the time the subject completes the study or becomes lost to follow-up, the outcome must be recorded as "Not resolved". Also enter "Not resolved" if the AE was ongoing at the time of death, but was not the cause of death.

Withdrawal Indicate only the event(s) directly responsible for the subject’s withdrawal as indicated on the End of Study Record page.

IDSG abcd Version 04.05 - 01 FEB 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Non-Serious Adverse Events Continued

Action taken Date Relationship Maximum Date of with study drug(s) Non-serious adverse events of Outcome Withdrawal to study Seriousness intensity resolution as a result of the onset drug(s) non-serious AE 1= Mild R = Resolved 0 = None Did subject Is there a Does the 2 = Moderate S = Resolved 1 = Dose adjusted withdraw from reasonable AE meet the Diagnosis only (if known) 3= Severe with 2 = Temporarily study as a possibility that the definition of or X= Not sequelae interrupted result of this non-serious AE serious? signs / symptoms applicable N= Not 3 = Permanently non-serious AE? may have been (list one per line) resolved discontinued caused by the CONFIDENTIAL X = Not applicable study drug(s)?

Y = Yes Y = Yes Y = Yes

130 day month year day month year N = No N = No N = No e.g. HEADACHE 25 JAN 01 3 R 27 JAN 01 0 N Y N

44 1. N

2. N

3. N

4. N

5. N GM2004/00056/00

6. N SAM40040 7. N

8. N

Can be pre-filled with Can be pre-filled Required Required Required Required Required code for non drug / Required with code for non Required single dose studies drug studies IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01 SERIOUS ADVERSE EVENT If the subject has experienced an SAE (see definition on next page) then: IMMEDIATE ACTION IS REQUIRED

1) Complete the Serious Adverse Event pages A separate set of SAE pages should be used for each SAE. However, if at the time of initial reporting,

multiple SAEs are apparent that are temporally and/or clinically related, then they can be reported on CONFIDENTIAL (SAE Instruction page 1) page Instruction (SAE the same page. 131 2) Inform Glaxo Wellcome • The investigator must inform GW of fatal or life-threatening events by fax or telephone (fax preferred) within 24 hours of becoming aware of the event, with completed SAE pages faxed within 48 hours.

• Other SAEs must be faxed within 48 hours of the investigator becoming aware of the event.

The original SAE pages remain in the Case Report Form

FOLLOW-UP INFORMATION GM2004/00056/00 The investigator and others responsible for subject care should institute any supplementary investigations of SAEs based on their clinical judgment of the likely causative factors. This may include seeking a further opinion from a specialist in the field of the adverse event. Glaxo Wellcome may also request extra tests or extra follow-up information. If a subject dies, any postmortem findings, including SAM40040 histopathology, must be provided to Glaxo Wellcome.

On receipt of follow-up information (e.g., diagnosis, dates of resolution, changes in intensity or causality) the appropriate SAE pages must be amended/updated. These changes must be initialed and dated by the investigator. A copy of the full set of SAE pages must always be faxed or mailed to Glaxo Wellcome within 24 or 48 hours (as specified above) of the investigator becoming aware of the new information.

IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01

If the event meets the definition of serious, complete these SAE pages. If not, complete a Non-serious AE page (previous section).

SERIOUS ADVERSE EVENT

a) death

(SAE Instruction page 2) page Instruction (SAE c) inpatient hospitalization or prolongation of existing hospitalization • Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not considered an adverse event. 132 • Complications that occur during hospitalization are adverse events. If a complication prolongs hospitalization, the event is serious. • "Inpatient" hospitalization means the subject has been formally admitted to the hospital for medical reasons. This may or may not be overnight. It does not include presentation at casualty/emergency room.

d) a disability or incapacity

e) a congenital anomaly in the offspring of a subject who received study drug(s)

• Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias GM2004/00056/00 or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. Medical and scientific judgment should be used in deciding whether prompt reporting is appropriate in these situations.

1 NOTE: The phrase "occurring at any dose", does not imply that the subject is receiving study drug(s). SAM40040

IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01

SERIOUS ADVERSE EVENT CONFIDENTIAL (SAE Instruction page 3) page Instruction (SAE

133 IMMEDIATE ACTION IS REQUIRED

(GW will provide separately a list of contact names and information) GM2004/00056/00 SAM40040

IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01 INSTRUCTIONS FOR COMPLETING THE SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible SECTION 1 DEMOGRAPHY Complete this section using the information recorded in the "Demography" or "Vital Signs" page. Record the most recently measured height and weight. SECTION 2 DETAILS OF SERIOUS ADVERSE EVENT Diagnosis Enter only the diagnosis (if known); otherwise each serious sign and symptom should be entered on a separate line. If a diagnosis subsequently becomes available, then this should be entered and the signs and symptoms crossed out. Date of Onset Record the date of onset of the first occurrence of the SAE. Maximum Intensity Record the maximum intensity that occurred over the duration of the SAE. Amend the intensity if it increases. Outcome All SAEs must be followed until the events are resolved, the condition stabilizes, the events are otherwise explained, or the subject is lost to follow-up. Indicate if the event was "Resolved", "Resolved with sequelae", or was "Fatal". If the SAE is ongoing at the time the subject completes the study or becomes lost to follow-up, the outcome must be recorded as "Not CONFIDENTIAL

(SAE Instruction page 4) page Instruction (SAE resolved". Also enter "Not resolved" if the SAE was ongoing at the time of death, but was not the cause of death.

134 Date of Resolution Record the date of resolution or the date of death. If the event resolved with sequelae, enter the date the subject’s or Death medical condition stabilized. Leave blank if the event is "Not resolved". Action Taken with Indicate only for the specific event(s) that were directly responsible for the action taken with study drug(s): None Study drug(s) continue(s) even though an adverse event has occurred. Study Drug(s) Dose adjusted Dose is increased or decreased for one or more study drug(s). Temporarily interrupted Administration of one or more study drug(s) was stopped temporarily but then restarted. Permanently discontinued Administration of one or more study drug(s) was stopped permanently and not restarted. Not applicable Subject was not receiving study drug(s) (e.g., pre-or postdosing). Withdrawal Indicate only the event(s) directly responsible for the subject’s withdrawal as indicated on the End of Study Record page. Relationship to It is a regulatory requirement for investigators to assess relationship to study drug(s) based on information available. The assessment should be reviewed on receipt of any new information and amended if necessary. "A reasonable possibility" is Study Drug(s) meant to convey that there are facts/evidence or arguments to suggest a causal relationship. Facts/evidence/arguments GM2004/00056/00 that may support "A reasonable possibility" include, for example, a temporal relationship, a pharmacologically-predicted event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, or relevant medical history, should also be considered. SAM40040 SECTION 3 POSSIBLE CAUSES OF THE SERIOUS EVENT OTHER THAN STUDY DRUG(S) Indicate all possible explanations/circumstances that may have contributed to the SAE, regardless of the relationship to study drug(s). SECTION 4 SERIOUSNESS

Indicate all reasons why this adverse event meets the definition of seriousness. IDSG abcd Version 06.08 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Investigator number Treatment number Subject number SAM40040 0 Serious Adverse Event (SAE)

Did the subject experience any serious adverse events during the study? Yes Y No N If YES, indicate below: SECTION 1 Demography Date of birth Sex Race Weight Height Male White Black . kg cm day month year Female Asian Other

SECTION 2 Serious Adverse Events Date Action taken with

Maximum Outcome Relationship CONFIDENTIAL Serious adverse events Date of onset of resolution or study drug(s) as a Withdrawal Seriousness intensity to study drug(s) death result of the SAE 1 = Mild R = Resolved 0 = None Did the subject Is there a Does the AE 1 = Dose adjusted withdraw from reasonable meet the 135 2 = Moderate S = Resolved possibility the SAE Diagnosis only (if known) with 2 = Temporarily study as a result definition of 3=Severe Sequelae interrupted may have been OR of this SAE? serious? X= Not F=Fatal 3 = Permanently caused by the study 45 Serious signs / symptoms discontinued drug(s)? (list one per line) applicable N=Not Resolved X = Not applicable Y = Yes Y = Yes Y = Yes day month year day month year N = No N = No N = No e.g. ANAPHYLAXIS 25 JAN 01 3 R 26 JAN 01 3 Y Y Y

1. Y

2. Y

3. Y

SECTION 3 Possible Causes of SAE other than Study Drug(s), ✔ all that apply GM2004/00056/00

Disease under study Activity related to study participation Concurrent disorder specify, ...... (e.g. procedures) specify, ...... Treatment failure Concurrent medication specify, ...... Other Withdrawal of study drug(s) specify, ...... SAM40040 SECTION 4 Seriousness, ✔ all that apply

a. Death d. Disabling or incapacitating If fatal, was an autopsy done/to be performed? Yes No (Send autopsy report when available). b. Life threatening e. Congenital anomaly

c. Hospitalization required or prolonged f. Other (see definition) specify, ......

continued... IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01 INSTRUCTIONS FOR COMPLETING THE SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible SECTION 1 DEMOGRAPHY Complete this section using the information recorded in the "Demography" or "Vital Signs" page. Record the most recently measured height and weight. SECTION 2 DETAILS OF SERIOUS ADVERSE EVENT Diagnosis Enter only the diagnosis (if known); otherwise each serious sign and symptom should be entered on a separate line. If a diagnosis subsequently becomes available, then this should be entered and the signs and symptoms crossed out. Date of Onset Record the date of onset of the first occurrence of the SAE. Maximum Intensity Record the maximum intensity that occurred over the duration of the SAE. Amend the intensity if it increases. Outcome All SAEs must be followed until the events are resolved, the condition stabilizes, the events are otherwise explained, or the subject is lost to follow-up. Indicate if the event was "Resolved", "Resolved with sequelae", or was "Fatal". If the SAE is ongoing at the time the subject completes the study or becomes lost to follow-up, the outcome must be recorded as "Not CONFIDENTIAL

(SAE Instruction page 4) page Instruction (SAE resolved". Also enter "Not resolved" if the SAE was ongoing at the time of death, but was not the cause of death.

136 Date of Resolution Record the date of resolution or the date of death. If the event resolved with sequelae, enter the date the subject’s or Death medical condition stabilized. Leave blank if the event is "Not resolved". Action Taken with Indicate only for the specific event(s) that were directly responsible for the action taken with study drug(s): None Study drug(s) continue(s) even though an adverse event has occurred. Study Drug(s) Dose adjusted Dose is increased or decreased for one or more study drug(s). Temporarily interrupted Administration of one or more study drug(s) was stopped temporarily but then restarted. Permanently discontinued Administration of one or more study drug(s) was stopped permanently and not restarted. Not applicable Subject was not receiving study drug(s) (e.g., pre-or postdosing). Withdrawal Indicate only the event(s) directly responsible for the subject’s withdrawal as indicated on the End of Study Record page. Relationship to It is a regulatory requirement for investigators to assess relationship to study drug(s) based on information available. The assessment should be reviewed on receipt of any new information and amended if necessary. "A reasonable possibility" is Study Drug(s) meant to convey that there are facts/evidence or arguments to suggest a causal relationship. Facts/evidence/arguments GM2004/00056/00 that may support "A reasonable possibility" include, for example, a temporal relationship, a pharmacologically-predicted event, or positive dechallenge or rechallenge. Confounding factors, such as concomitant medication, a concurrent illness, or relevant medical history, should also be considered. SAM40040 SECTION 3 POSSIBLE CAUSES OF THE SERIOUS EVENT OTHER THAN STUDY DRUG(S) Indicate all possible explanations/circumstances that may have contributed to the SAE, regardless of the relationship to study drug(s). SECTION 4 SERIOUSNESS

Indicate all reasons why this adverse event meets the definition of seriousness. IDSG abcd Version 06.08 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Serious Adverse Event (SAE) Continued

SECTION 1 Demography Date of birth Sex Race Weight Height Male White Black . kg cm day month year Female Asian Other

SECTION 2 Serious Adverse Events Date Action taken with Maximum Outcome Relationship Serious adverse events Date of onset of resolution or study drug(s) as a Withdrawal Seriousness CONFIDENTIAL intensity to study drug(s) death result of the SAE 1 = Mild R = Resolved 0 = None Did the subject Is there a Does the AE 1 = Dose adjusted withdraw from reasonable meet the 137 2 = Moderate S = Resolved possibility the SAE Diagnosis only (if known) with 2 = Temporarily study as a result definition of 3=Severe Sequelae interrupted may have been OR of this SAE? serious? X= Not F=Fatal 3 = Permanently caused by the study 46 Serious signs / symptoms discontinued drug(s)? (list one per line) applicable N=Not Resolved X = Not applicable Y = Yes Y = Yes Y = Yes day month year day month year N = No N = No N = No e.g. ANAPHYLAXIS 25 JAN 01 3 R 26 JAN 01 3 Y Y Y

1. Y

2. Y

3. Y ✔ SECTION 3 Possible Causes of SAE other than Study Drug(s), all that apply GM2004/00056/00

Disease under study Activity related to study participation Concurrent disorder specify, ...... (e.g. procedures) specify, ...... Treatment failure

Withdrawal of study drug(s) Concurrent medication specify, ...... Other specify, ...... SAM40040 SECTION 4 Seriousness, ✔ all that apply

a. Death d. Disabling or incapacitating If fatal, was an autopsy done/to be performed? Yes No (Send autopsy report when available). b. Life threatening e. Congenital anomaly

c. Hospitalization required or prolonged f. Other (see definition) specify, ...... IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01

INSTRUCTIONS FOR COMPLETING THE SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible

SECTION 5 RELEVANT MEDICAL CONDITIONS

Provide details of relevant current medical conditions. Include any past medical conditions that may be appropriate. Provide details of the date of onset of these conditions and/or whether they were still present at the time of the SAE.

SECTION 6 OTHER RELEVANT RISK FACTORS

Specify any family history or any social history (e.g. smoking, alcohol, diet, drug abuse, occupational hazard) relevant to the SAE. CONFIDENTIAL (SAE Instruction page 5) page Instruction (SAE SECTION 7 DETAILS OF STUDY DRUG(S) 138

Complete this section using the information in the "Study Drug" page.

Details of all study drug(s) taken until the time of the SAE should be included. Provide specific details in the narrative if the subject has taken an overdose of study drug(s), including whether it was accidental or intentional.

SECTION 8 RELEVANT CONCURRENT MEDICATIONS

Provide details of relevant concurrent medications that the investigator thinks may have contributed to the occurrence of the SAE or otherwise explain it. This may include any concurrent medication taken at the time of the SAE (including any oral contraceptives or prophylactic medication) or other medications temporally associated with the SAE (i.e. preceding the SAE or withdrawn prior to the SAE).

Only if there are extensive relevant concurrent medications should the Concurrent Medications page (if used) be faxed or mailed with the SAE pages. GM2004/00056/00

Medications used to treat the SAE should not be included here but recorded in the narrative instead. SAM40040

IDSG abcd Version 06.08 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Serious Adverse Event Continued

SECTION 5 Relevant Medical Conditions Specify any relevant past or current medical disorders, Condition present at time Date of onset If NO, date of last occurrence allergies, surgeries, etc. that can help explain the SAE. of the SAE

day month year Y = Yes, N = No day month year 1.

3. CONFIDENTIAL

4. SECTION 6 Other Relevant Risk Factors 139 Specify any family history or any social history (e.g. smoking, alcohol, diet, drug abuse, occupational hazard) relevant to the SAE. 47

SECTION 7 Details of Study Drug(s)

Start date Stop date day month year day month year

SECTION 8 Relevant Concurrent Medications Include any concurrent medications that may contribute to the occurrence of the SAE

Date Date GM2004/00056/00 ✔ if ✔ if Drug Freq- Route started stopped Dose Unit Conditions treated / indication (Trade name preferred) uency started continued Pre-study Post-SAE day month year day month year

e.g. ZANTAC 150 mg BID PO ✔ 27 JAN 01 Gastric ulcer SAM40040 1.

continued... IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01

INSTRUCTIONS FOR COMPLETING THE SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible

SECTION 9 NARRATIVE/COMMENTS

Provide a textual description of the SAE. This should include but not be limited to the following:

• Any previous occurrences of this type of event • Any relevant non-serious adverse events that occurred prior to the SAE • The full clinical presentation and sequelae/evolution of the SAE • Any associated signs and symptoms of the SAE

• Explain any possible causes of the SAE CONFIDENTIAL

(SAE Instruction page 6) page Instruction (SAE • Treatment for the SAE (including any specific medications administered or non-drug treatment) • Any other action taken for the management of the SAE or the subject

140 • Duration and outcome of the SAE • If the SAE is associated with an overdose of study drug(s), details of the amount of overdose and whether it was intentional or accidental.

SECTION 10 DETAILS OF RELEVANT ASSESSMENTS

Provide details of any other assessments or supplementary investigations/examinations that were conducted as part of the subject’s care and/or based on clinical judgment of the likely causative factors of the SAE. This may include, but not be limited to:

• Laboratory data. Always provide the reference range and baseline values (fax or mail pages if extensive supporting data) • Findings of ECGs, X-rays, etc. • Results of other diagnostic tests or assays • Key findings from hospital discharge or pathology reports GM2004/00056/00 SECTION 11 REPORTING INVESTIGATOR SIGNATURE

The reporting investigator (not the study nurse or study monitor) must sign and date the SAE page. SAM40040

IDSG abcd Version 06.08 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Serious Adverse Event Continued

SECTION 9 Narrative / Comments

Provide a textual description of the serious adverse event (including treatment of the event). CONFIDENTIAL 141 48

SECTION 10 Details of Relevant Assessments

Provide details of other assessments (e.g. laboratory data with normal ranges) or supplemental examinations. GM2004/00056/00

SECTION 11 Reporting Investigator SAM40040 To the best of my knowledge, all information entered on these Serious Adverse Event pages for this subject is correct.

Name (print) Address Signature Date day month year

continued... IDSG Version 06.03 - 01 DEC 00 Draft 2 - 31 AUG 01

INSTRUCTIONS FOR COMPLETING THE SERIOUS ADVERSE EVENT CRF Ensure all hand writing is clear and legible

ADDITIONAL OR FOLLOW-UP INFORMATION

Use this page to provide any additional details or follow-up information on the SAE not already recorded on the previous pages. On receipt of follow-up information, the appropriate section(s) [1 to 11] must be amended/updated with any changes (i.e., diagnosis, date of resolution of death, change in intensity, or causality). These changes must be initialed and dated by the investigator. The investigator must inform GW of fatal or life-threatening events by fax or telephone (fax preferred) within 24 hours of becoming aware of the event, with completed SAE pages faxed within 48 hours. Other SAEs must be faxed within 48 hours of the investigator becoming aware of the event.

The investigator and others responsible for subject care should institute any supplementary investigations of SAEs based on their clinical judgment of the CONFIDENTIAL

(SAE Instruction page 7) page Instruction (SAE likely causative factors. This may include seeking a further opinion from a specialist in the field of the adverse event. Glaxo Wellcome may also request extra tests or extra follow-up information. If a subject dies, any postmortem findings, including histopathology, must be provided to Glaxo Wellcome. 142

REPORTING INVESTIGATOR SIGNATURE

The reporting investigator (not the study nurse or study monitor) must sign and date any additional or follow-up information relating to the SAE. GM2004/00056/00 SAM40040

IDSG abcd Version 06.08 - 01 AUG 01 CONFIDENTIAL Draft 2 - 31 AUG 01 Protocol code Session number Subject number SAM40040 0 Serious Adverse Event Continued

Additional or follow-up information Use this page to provide any additional details on the serious adverse event not already captured on the previous pages. The appropriate section(s) (1-11) of SAE CRF must be amended/updated with any changes and re-faxed/mailed. CONFIDENTIAL 143 49 GM2004/00056/00

Reporting Investigator SAM40040 To the best of my knowledge, all information entered on these Serious Adverse Event pages for this subject is correct. Name (print) Address Signature Date day month year

CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.02 - 02 MAY 01 Protocol code SAM40040 End of Study Record

Instructions to Investigator

• Completion of the study is defined as .

• “Did the subject become pregnant during the study?” • This question must be answered for all subjects. For females not of childbearing potential or males, ✔ NOT APPLICABLE. • If no pregnancy was known before a subject was lost to follow-up, ✔ NO. • If the subject became pregnant before either premature discontinuation from the study or completion of the study, ✔ YES.

Monitor Data Validation Checks

• Check that the “Date of subject completion or discontinuation from the study” is on or after the last treatment stop date on the STUDY DRUG page.

• Check that the pregnancy question is completed. If the pregnancy question is answered YES, check that the PREGNANCY NOTIFICATION FORM is completed.

• If “Did the subject discontinue the study prematurely?” is ✔YES, check that one “primary reason for discontinuation” is ✔.

• If “Adverse Event” is ✔ as reason for discontinuation, check that consistent details are recorded on the NON-SERIOUS ADVERSE EVENTS or SERIOUS ADVERSE EVENT page(s).

• If the primary reason for discontinuation is ✔ “Other”, check that a concise text entry is present in the space provided.

144 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 06.02 - 04 JAN 01 Protocol code Session number Subject number SAM40040 0 End of Study Record

Date of subject completion or discontinuation from the study day month year

Did the subject become pregnant during the study? ✔one:

Not applicable X (Not of childbearing potential or male)

Yes Y If YES, record details on PREGNANCY NOTIFICATION FORM.

No N

Did the subject discontinue the study prematurely? Yes Y No N If YES, ✔the primary reason for discontinuation. ✔one:

Record details on NON-SERIOUS ADVERSE EVENTS or Adverse event A SERIOUS ADVERSE EVENT page as appropriate.

Consent Withdrawn C

Lost to follow up L

Protocol violation P

Lack of efficacy E

AE related to lack of efficacy AER

Did not fulfil entry criteria EC

Other X specify, ......

NOTE TO INVESTIGATOR: Ensure that either the YES or NO response box has been ✔ for the first question on the NON-SERIOUS ADVERSE EVENTS, SERIOUS ADVERSE EVENT and CONCURRENT MEDICATIONS pages.

145 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 01.02 - 01 DEC 00 Protocol code SAM40040 Investigator’s Statement

Instructions to Investigator

• Sign and date this page after all relevant CRF pages, including outstanding test results, are completed.

Monitor Data Validation Checks

• Check that the date of signature is on or after the completion of all protocol activities.

146 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd IDSG CONFIDENTIAL Draft 2 - 31 AUG 01 Version 02.02 - 01 NOV 00 Protocol code Session number Subject number SAM40040 0 Investigator’s Statement

I confirm that I have carefully examined all entries on the Case Report Form for this subject. All information entered by myself or my colleagues is, to the best of my knowledge, correct as of the date below.

...... Investigator’s signature day month year

...... Investigator’s name - print

147 CONFIDENTIAL GM2004/00056/00 SAM40040

abcd CONFIDENTIAL Draft 2 - 31 AUG 01

Protocol code Subject number SAM40040 Page Count (For Glaxo Wellcome Use Only)

• Complete this page for all subjects. • Return this page with the CRF transmission. • Indicate below, if the subject was a screen failure. • Place an “X” through the page number of pages that have no data recorded on them and will not be transmitted. • Enter any additional page numbers in the empty boxes below.

1 2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20

21 22 23 24 25 26 27 28 29 30

31 32 33 34 35 36 37 38 39 40

41 42 43 44 45 46 47 48 49 50

Notes:......

...... Glaxo Wellcome clinical monitor’s signature day month year

9999

148 abcd If you have any medical problems or need to take any new medications, TREATMENT make a note of them below:

Date PER

Medical Problem Treatment VISIT 2/2a -3 IOD day month year e.g. 12/04/00 Chest Infection Antibiotics Daily Record Card TREATMENT PERIOD SAM40040

Subject Number CONFIDENTIAL

30% Peak Flow alert value: L/min 149 Doctor’s name:......

Hospital/Clinic address: ......

......

Hospital/Clinic telephone number: ......

Date and time of next clinic visit : Day Month Year hours mins GM2004/00056/00 This Daily Record Card should be consistently filled in by the same person. FOR OFFICE USE ONLY All adverse events and medications have been reported in the Case Report Form Important: If this Daily Record Card is found, return immediately to the above address. SAM40040 ...... Monitor’s signature FOR OFFICE USE ONLY MIDDLE PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGE OF PAGE MIDDLE 20% Peak Flow alert value: Date L/min Day Month Year 1 Treatment 8 English Treatment English

Draft 1 : 24 JUL 01 Draft 1 : 24 JUL 01

If you have a feeling of chest tightness, feel wheezy or breathless, use your VentolinTM Inhaler provided, to relieve the symptoms.

Relief Medication Dose Frequency ASTHMA SYMPTOM SCORES

VentolinTM Aerosol 1 or 2 puffs When needed OR Ventolin DiskusTM/AccuhalerTM 1 Dose When needed Night-time Symptom Score

Try not to take your Ventolin for 6 hours before your next clinic visit. 0 = No symptoms during the night 1 = Symptoms causing me to wake once or to wake early 2 = Symptoms causing me to wake twice or more (including waking early) 1. How to fill in the diary: 3 = Symptoms causing me to be awake for most of the night • Fill in one column each day at the following times: CONFIDENTIAL - morning section: (when you get up) at about 7:00 a.m.; 4 = Symptoms so severe that I did not sleep at all - evening section: at about 7:00 p.m. • As far as possible, keep to the same times each day. 150 2. Peak flow: Daytime Symptom Score • Always sit down to do your peak flow. • Always do your peak flow before taking any medicine, particularly your inhalers, at the following times: 0 = No symptoms during the day - when you get up (about 7:00 a.m.); 1 = Symptoms for one short period during the day - in the early evening (about 7:00 p.m.). • Your doctor will explain to you how to measure your peak flow. 2 = Symptoms for two or more short periods during the day • If you have not made a measurement, put a * in the appropriate box. 3 = Symptoms for most of the day which did not affect my normal daily • Remember to bring your peak flow meter to your next clinic visit. activities 4 = Symptoms for most of the day which did affect my normal daily activities

5 = Symptoms so severe that I could not go to school or perform GM2004/00056/00 normal daily activities If you have any medical problems, please make a note of them on the back cover of this Daily Record Card SAM40040 MIDDLE PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGE OF PAGE MIDDLE

Treatment English Treatment English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

COMPLETE EACH MORNING This Daily Record Card should be consistently filled Complete this section when you wake up each morning, in by the same person. before taking your own asthma medication and your relief medication (VentolinTM inhaler). Day Example 1234567

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during the night? CONFIDENTIAL Have you used your VentolinTM inhaler in the last six hours? (Yes/No) NO

151 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

COMPLETE EACH EVENING Complete this section in the evening, before taking your own asthma medication and your relief medication If you have any medical problems, please make a (VentolinTM inhaler). note of them on the back of this Daily Record Card.

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

How was your asthma during today? Please answer according to 2 the Daytime Symptom Scores. Score (0 - 5) None None None None None None None None Have you missed any time from work or usual activities in the last SAM40040 24 hours because of your asthma? Half Day Half Day Half Day Half Day Half Day Half Day Half Day Half Day

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 2 English Treatment 3 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

152 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 2 English Treatment 3 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

153 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 2 English Treatment 3 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

154 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 4 English Treatment 5 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

155 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 6 English Treatment 7 English

abcd If you have any medical problems or need to take any new medications, TREATMENT make a note of them below:

Date PER

Medical Problem Treatment VISIT 2/2a -3 IOD day month year e.g. 12/04/00 Chest Infection Antibiotics Daily Record Card TREATMENT PERIOD SAM40040

Subject Number CONFIDENTIAL

30% Peak Flow alert value: L/min 156 Doctor’s name:......

Hospital/Clinic address: ......

......

Hospital/Clinic telephone number: ......

Draft 1 : 24 JUL 01 Draft 1 : 24 JUL 01

If you have a feeling of chest tightness, feel wheezy or breathless, use your VentolinTM Inhaler provided, to relieve the symptoms.

Relief Medication Dose Frequency ASTHMA SYMPTOM SCORES

VentolinTM Aerosol 1 or 2 puffs When needed OR Ventolin DiskusTM/AccuhalerTM 1 Dose When needed Night-time Symptom Score

Try not to take your Ventolin for 6 hours before your next clinic visit. 0 = No symptoms during the night 1 = Symptoms causing me to wake once or to wake early 2 = Symptoms causing me to wake twice or more (including waking early) 1. How to fill in the diary: 3 = Symptoms causing me to be awake for most of the night • Fill in one column each day at the following times: CONFIDENTIAL - morning section: (when you get up) at about 7:00 a.m.; 4 = Symptoms so severe that I did not sleep at all - evening section: at about 7:00 p.m. • As far as possible, keep to the same times each day. 157 2. Peak flow: Daytime Symptom Score • Always sit down to do your peak flow. • Always do your peak flow before taking any medicine, particularly your inhalers, at the following times: 0 = No symptoms during the day - when you get up (about 7:00 a.m.); 1 = Symptoms for one short period during the day - in the early evening (about 7:00 p.m.). • Your doctor will explain to you how to measure your peak flow. 2 = Symptoms for two or more short periods during the day • If you have not made a measurement, put a * in the appropriate box. 3 = Symptoms for most of the day which did not affect my normal daily • Remember to bring your peak flow meter to your next clinic visit. activities 4 = Symptoms for most of the day which did affect my normal daily activities

Treatment English Treatment English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

158 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 2 English Treatment 3 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

159 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 2 English Treatment 3 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

160 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 2 English Treatment 3 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

161 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 4 English Treatment 5 English

abcd Draft 1 : 24 JUL 01 abcd Draft 1 : 24 JUL 01

Protocol code Subject number Protocol code Subject number SAM40040 SAM40040

Date 03/01/01 / // // // // // // /

Measure your Peak Flow three times and enter the highest value. 210

162 How was your asthma during last night? Please answer according 1 to the Night-time Symptom Scores Score (0 - 4)

Measure your Peak Flow three times and enter the highest value. 230

TM How many occasions (not puffs) did you use your Ventolin inhaler 2 to relieve your asthma symptoms during today? Have you used your VentolinTM inhaler in the last six NO

hours? (Yes/No) GM2004/00056/00

Circle (None, Half Day or Full day) Full Day PAGEMIDDLE OF MIDDLE OF PAGE MIDDLEPAGE OF MIDDLE OF PAGEFull OF PAGE MIDDLE Day Full Day Full Day Full Day Full Day Full Day Full Day

Treatment 6 English Treatment 7 English

CONFIDENTIAL GM2004/00056/00 SAM40040

LIST OF INVESTIGATORS AND IECS/IRBS FOR SAM40040 (GM2004/00056/00)

Investigator Investigator/ Site no. Hospital/ Institution and Address IEC/IRB Committee Chair and Name of Committee Austria

AUSTRIA

AUSTRIA AUSTRIA

CONFIDENTIAL

AUSTRIA AUSTRIA

1 AUSTRIA AUSTRIA

AUSTRIA

AUSTRIA Belgium Dr.

GM2004/00056/00 BELGIUM BELGIUM

Dr. SAM40040 BELGIUM BELGIUM

1 CONFIDENTIAL GM2004/00056/00 SAM40040

Dr.

BELGIUM BELGIUM

Belgium BELGIUM

Dr.

BELGIUM BELGIUM Prof. Belgium

Belgium CONFIDENTIAL

2 BELGIUM BELGIUM Prof. Dr.

BELGIUM BELGIUM Czech Republic

CZECH CZECH REPUBLIC REPUBLIC GM2004/00056/00 GM2004/00056/00

CZECH REPUBLIC CZECH REPUBLIC SAM40040 SAM40040

2 CONFIDENTIAL GM2004/00056/00 SAM40040

CZECH REPUBLIC

CZECH REPUBLIC CZECH REPUBLIC

CZECH REPUBLIC CZECH REPUBLIC CONFIDENTIAL Denmark Professor, Dr.

3 DENMARK DENMARK Professor, Dr. DENMARK

DENMARK Professor, Dr.

DENMARK

DENMARK GM2004/00056/00 Professor, Dr. DENMARK

SAM40040 SAM40040 DENMARK

3 CONFIDENTIAL GM2004/00056/00 SAM40040

Professor, Dr.

DENMARK DENMARK Estonia Prof. ESTONIA

ESTONIA Prof. ESTONIA

ESTONIA Prof. CONFIDENTIAL ESTONIA

ESTONIA 4 Prof. ESTONIA

ESTONIA Prof. ESTONIA

ESTONIA Prof.

ESTONIA GM2004/00056/00

ESTONIA SAM40040 SAM40040

4 CONFIDENTIAL GM2004/00056/00 SAM40040

France Doctor

FRANCE FRANCE Doctor FRANCE

FRANCE Doctor

FRANCE FRANCE Doctor CONFIDENTIAL FRANCE

FRANCE 5 Doctor FRANCE

FRANCE Doctor FRANCE

FRANCE Doctor

FRANCE GM2004/00056/00

FRANCE Doctor SAM40040 SAM40040 France

FRANCE

5 CONFIDENTIAL GM2004/00056/00 SAM40040

Doctor

FRANCE FRANCE Doctor France

FRANCE Doctor

France FRANCE Doctor France CONFIDENTIAL

FRANCE Doctor 6

FRANCE FRANCE Doctor FRANCE

FRANCE Doctor France

GM2004/00056/00 GM2004/00056/00 FRANCE Doctor

France SAM40040 FRANCE

6 CONFIDENTIAL GM2004/00056/00 SAM40040

Doctor France

FRANCE Doctor France

FRANCE Doctor FRANCE

FRANCE Doctor

CONFIDENTIAL France FRANCE Doctor 7 FRANCE FRANCE Doctor France

FRANCE Doctor France

GM2004/00056/00 GM2004/00056/00 FRANCE Doctor

France SAM40040 FRANCE

7 CONFIDENTIAL GM2004/00056/00 SAM40040

Doctor FRANCE

FRANCE Germany Dr Prof.Dr. GERMANY

Drs Prof.dr. GERMANY

Dr. Prof.Dr.

GERMANY CONFIDENTIAL Drs Prof.dr. GERMANY

8 Dr. Prof. Dr. GERMANY

Dr. Prof. Dr.

GERMANY Dr.

GERMANY

Drs. Dr. GM2004/00056/00

GERMANY Dr. Prof.dr. SAM40040 SAM40040 GERMANY

8 CONFIDENTIAL GM2004/00056/00 SAM40040

Dr GERMANY

Dr. Prof.dr. GERMANY

Dr. Prof.Dr.

GERMANY Dr. Dr.

GERMANY Dr. Prof.Dr.

CONFIDENTIAL GERMANY Dr. Prof.Dr. GERMANY 9 Drs

GERMANY Dr Dr.

GERMANY Greece Professor

GM2004/00056/00 GREECE

GREECE SAM40040 SAM40040

9 CONFIDENTIAL GM2004/00056/00 SAM40040

Professor

GREECE

GREECE Professor

GREECE

GREECE Professor

GREECE

CONFIDENTIAL GREECE Professor

10 GREECE

GREECE Professor

GREECE

GREECE Ireland Dr GM2004/00056/00 GM2004/00056/00 IRELAND

IRELAND SAM40040

10 CONFIDENTIAL GM2004/00056/00 SAM40040

Professor

IRELAND IRELAND

IRELAND

IRELAND Dr IRELAND

IRELAND CONFIDENTIAL

IRELAND

11 IRELAND Dr IRELAND

IRELAND

IRELAND IRELAND GM2004/00056/00 GM2004/00056/00 Dr IRELAND

SAM40040 IRELAND

11 CONFIDENTIAL GM2004/00056/00 SAM40040

Italy

ITALY

ITALY CONFIDENTIAL ITALY

12 ITALY

ITALY

ITALY GM2004/00056/00 Netherlands Dr

SAM40040 NETHERLANDS

NETHERLANDS

12 CONFIDENTIAL GM2004/00056/00 SAM40040

NETHERLANDS

NETHERLANDS Dr Dr

NETHERLANDS

NETHERLANDS Dr

NETHERLANDS

CONFIDENTIAL NETHERLANDS Dr

13 NETHERLANDS

NETHERLANDS Dr

NETHERLANDS

NETHERLANDS Dr

GM2004/00056/00 GM2004/00056/00 NETHERLANDS

NETHERLANDS SAM40040 SAM40040

13 CONFIDENTIAL GM2004/00056/00 SAM40040

NETHERLANDS

NETHERLANDS Dr

NETHERLANDS

NETHERLANDS Dr

NETHERLANDS

CONFIDENTIAL NETHERLANDS Dr

14 NETHERLANDS

NETHERLANDS Dr

NETHERLANDS

NETHERLANDS Dr NETHERLANDS GM2004/00056/00 GM2004/00056/00

NETHERLANDS SAM40040 SAM40040

14 CONFIDENTIAL GM2004/00056/00 SAM40040

NETHERLANDS

NETHERLANDS Dr

NETHERLANDS

NETHERLANDS Norway

NORWAY

CONFIDENTIAL

15 Norway

NORWAY

Norway

NORWAY GM2004/00056/00 GM2004/00056/00

SAM40040 Norway

15 CONFIDENTIAL GM2004/00056/00 SAM40040

NORWAY

Norway

NORWAY

Norway CONFIDENTIAL Portugal Prof Dr.

16 PORTUGAL Prof. Dr.

PORTUGAL Dr.

PORTUGAL Dr. PORTUGAL GM2004/00056/00 GM2004/00056/00

Dr.

PORTUGAL SAM40040

16 CONFIDENTIAL GM2004/00056/00 SAM40040

Dr. Prof. PORTUGAL Russia Prof.

RUSSIA Prof.

RUSSIA

Prof. CONFIDENTIAL

RUSSIA

17 Spain Dr SPAIN

SPAIN Dr SPAIN

SPAIN Dr Dr

SPAIN GM2004/00056/00

SPAIN SAM40040 SAM40040

17 CONFIDENTIAL GM2004/00056/00 SAM40040

SPAIN SPAIN Dr

SPAIN SPAIN

CONFIDENTIAL SPAIN SPAIN

18 SPAIN

SPAIN

GM2004/00056/00 GM2004/00056/00 SPAIN SPAIN SAM40040 SAM40040

18 CONFIDENTIAL GM2004/00056/00 SAM40040

SPAIN

SPAIN SPAIN

CONFIDENTIAL

SPAIN

19 SPAIN Sweden

SWEDEN SWEDEN

GM2004/00056/00 SWEDEN SWEDEN

SWEDEN SAM40040 SAM40040 SWEDEN

19 CONFIDENTIAL GM2004/00056/00 SAM40040

SWEDEN SWEDEN

SWEDEN SWEDEN Switzerland Prof.

SWITZERLAND

SWITZERLAND Prof. SWITZERLAND CONFIDENTIAL SWITZERLAND Prof.

20 SWITZERLAND

SWITZERLAND Prof.

SWITZERLAND SWITZERLAND Prof.

SWITZERLAND GM2004/00056/00

SWITZERLAND SAM40040 SAM40040

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United Kingdom

Dr CONFIDENTIAL

GM2004/00056/00 GM2004/00056/00 Mr

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GM2004/00056/00 GM2004/00056/00

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Dr CONFIDENTIAL

GM2004/00056/00 GM2004/00056/00

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Dr GM2004/00056/00 GM2004/00056/00

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25 This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

CONFIDENTIAL GM2004/00056/00 SAM40040

INFORMED CONSENT FORM FOR PROTOCOL SAM40040 Protocol title: A TWENTY-FOUR WEEK, RANDOMISED, DOUBLE-DUMMY, DOUBLE BLIND, PARALLEL GROUP STUDY TO COMPARE THE OCCURRENCE OF EXACERBATIONS BETWEEN SERETIDE DISKUS (ACCUHALER) 50/250mcg 1 INHALATION BD AND SYMBICORT BREATH-ACTUATED DRY POWDER INHALER 4.5/160mcg 2 INHALATIONS BD IN SUBJECTS WITH MODERATE TO SEVERE ASTHMA

You have been asked to take part in a clinical research study comparing two medicines Seretide and Symbicort for treatment of asthma. The purpose of this study is to compare the effect of the two medicines on your asthma exacerbations (attacks). At least 1312 men and women with asthma will be asked to take part in the study from 300 centres across Europe and Canada. You have been asked to take part in the study because you suffer from asthma. For your information, this study is sponsored by GlaxoWellcome, and the study doctor is paid to conduct this study. This research study has been reviewed and approved by your local Independent Research Ethics Committee.

Do I have to take part? Before you decide whether to take part it is important for you to understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it if you wish with friends, relatives and your personal doctor (i.e., general practitioner or primary care physician). Ask the study doctor if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part.

What is the purpose of the study? The main purpose of this study is to compare the effect of the two treatments, Seretide and Symbicort on your asthma exacerbations (attacks). Throughout the study, we will ask you to complete a daily record card each morning and evening, recording your blowing measurement (Peak Expiratory Flow or PEF), your use of relief medication (Ventolin/ Salbutamol), and any other medications used. All this information and the information we collect at the visits when you see the studydoctor or nurse will help us determine the effect of the two treatments on your asthma exacerbations.

What are the possible benefits? Your participation in this study may add to the medical knowledge about the use of the treatments, Seretide and Symbicort. We hope that the study treatments will help you, but this cannot be guaranteed. The information we get from this study may help us to improve our management of the treatment of asthma in future patients.

Are you suitable for the study? If you decide to take part, at your first visit (Visit 1) you will be asked about your medical history, your current asthma treatment(s), your mouth and throat will be examined, and your lung function (i.e. the amount of air you can breathe out in one breath) will be measured. Your doctor will check that you are suitable to take part in the study and if you meet the requirements, you will be entered into the initial 2-week, run-in period of the study. If you are a woman capable of having children, you will be asked to provide a urine sample for a pregnancy test before entering the study and again at the end of study treatment. You will be given a paper daily record card on which to record your asthma symptoms and any effect on daily activities and to record details should you feel unwell at any time. Your doctor or study nurse will show you how to complete the daily record card. You will be asked to continue taking your usual asthma treatment and asked to return after 2 weeks (Visit 2). You will be asked not to use your relief medication (Ventolin/Salbutamol) for 6 hours before your next visit (Visit 2). Any additional drugs that you take must be recorded in the paper daily record card. Your study doctor will discuss with you which treatments you can and cannot take during this period. At Visit 2, your doctor will check again to see whether you are suitable to into the main part of the study; this FINAL ICF Date: 10th September 2001, ICF Version 1 Page 1 of 7

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Informed Consent form SAM40040 will depend on how your asthma has been over the last 2-weeks and your completion of the daily record card. If your lung function test was not completed at Visit 1, it may be performed now or repeated. If you are not suitable to particpate in the study, your doctor will advise you on what treatment you should receive. If you are suitable, you can continue into the main part of the study. How long will the study last? The study will last a total of 27 weeks during which you will attend for 7 visits (this can be extended to 29 weeks and 8 visits if the study doctor decides run-in period can be repeated). There is a 2-week run-in period, a 24-week treatment period during which you will receive study treatment, and a 1-week follow-up period after the study treatment has stopped. What does the study involve? If you agree to take part in the study and if you meet all of the conditions required to enter the study, you will have the tests and procedures shown in the table below, these will be performed at the Visits indicated:

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Follow-up (Run-in) (Week 0) (Week 4 ) (Week 8) (Week 16) (Week 24) Contact * Medical history, X X previous medications Urine pregnancy X X test Lung function X X X X X X X**

Mouth and throat X X X X X X X** examination Questionnaire X X X X X (time to complete) (5 mins) (5 mins) (5 mins) (5 mins) (5 mins) Daily record card completion X X X X X X (symptom scores, blowing test, reliever (twice daily) (twice daily) (twice daily) (twice daily) (twice daily) (twice daily) use & questions) Ventolin for use as X X X X X X If needed prescribed Study treatment (existing (Non-study (twice a day ) asthma X------ÆX asthma treatment) treatment) * Follow up contact - can be a visit or a telephone call ** Performed at a follow-up visit only

At Visit 2, your doctor will ask you to stop taking your current asthma medication for 24-weeks (the duration of the study treatment period). This is necessary so we can fully measure the effects of Seretide and Symbicort without any interference from your current medication. You will be given the study medication and advised on how to use the inhalers. Any additional drugs (eg paracetamol for headache) that you take must be recorded in the paper daily record card. Your study doctor will discuss with you which treatments you can and cannot take during this period.

What are Seretide and Symbicort? The two treatments tested in this study Seretide and Symbicort are marketed products available to you to treat your asthma. Both the treatments are combination products, this means they each contain two asthma drugs in one inhaler. Seretide contains salmeterol and fluticasone propionate (FP) in the Diskus inhaler and Symbicort contains formoterol and budesonide in a breath-actuated dry powder inhaler (shortened to BADPI).

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Can I tell the difference between the Seretide and Symbicort? This study is designed so that neither you nor your doctor are able to tell which of the treatments Seretide or Symbicort, you are receiving (although if your doctor needs to find out he/she can do so). As the medicines are dispensed in different inhalers it is impossible to make them look the same, so you will be provided with both types of inhaler, but only one will contain drug, the other will be a dummy (placebo). You should take one inhalation from the Diskus (the round one) and two inhalations from the BADPI (tube) each morning and evening. You should always take the Diskus first followed (within 2 minutes) by the BADPI.

Which treatment will I receive? Allocation to either Seretide or Symbicort is by chance. You have an equal chance or receiving Seretide or Symbicort. The treatment you are allocated to receive is selected by a computer, which has no information about the individualstaking part. Throughout the study, all participants will be dispensed relief medication (Ventolin/Salbutamol) for use as needed.

What do I have to do to complete the Daily Record Card properly? Daily record cards will be issued at visits you attend with the study doctor or nurse. You will have to record any illnesses/symptoms that you have, any changes in medications that you are taking and any unplanned visits to a doctor or nurse. You will also have to record your asthma symptoms each morning and evening and record the number of occasions you have used your relief medication (Ventolin/Salbutamol) to relieve your symptoms. In addition, you should measure your lung function (blowing test) each morning and evening using a device called a Peak Flow Meter. Your study doctor or nurse will give you a Peak Flow Meter and teach you how to use it. You should take measurements three times every morning and every evening before taking study treatment, and record the highest value in the daily record card. At each visit your should bring back your completed daily record card and all the study treatments including your relief medication (Ventolin).

At some visits you will be given this questionnaire to complete when you attend for the visit but before you see the study doctor or nurse. There are no right or wrong answers, you should complete the questionnaire to the best of your ability and give it to the study doctor or nurse when you see them.

What are the available alternative treatments? Before you decide whether or not to take part in this study, you may wish to consider other treatment options. Your study doctor will describe these to you based on your medical history and the treatment you have received to date: [list country specific alternatives].

You do not have to participate in this study to receive treatment of your asthma. If you decide not to participate, or you are not eligible to participate in the main part of the study, your doctor will continue to treat you. Your doctor will recommend the most appropriate course of treatment for your particular symptoms, this treatment will be a standard marketed treatment.

Alternative treatment may include inhaled short or long acting bronchodilators such as salbutamol or salmeterol or other inhaled corticosteroids such as beclomethasone, budesonide or fluticasone. In some cases oral therapy may be recommended. Important potential benefits and side effects of the alternative treatments are outlined below. Short acting bronchodilators such as salbutamol, are known as reliever medications. These medications have the benefit of working very quickly to relieve asthma but do not have a very long duration of action and do not prevent further asthma attacks. Long acting bronchodilators have a longer duration of action in opening up the airways but do not work as quickly as drugs like salbutamol. The side effects for both short acting and long acting agents are similar and are as follows; tremor, nervous tension such tingling of the finger tips and fine shaking of the hands, headache, peripheral vasodilation (flushing), and palpitations (heart flutters or racing). FINAL ICF Date: 10Th September 2001, ICF Version 1 Page 3 of 7

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Inhaled medications such as beclomethasone, budesonide or fluticasone are known as preventers. These preventative medications have the benefit of reducing inflammation in the lungs but do not relieve acute asthma symptoms. The main potential side effects of preventer medications are oral thrush and hoarseness of the throat. At high doses there may be suppression of adrenal function, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. Oral medications such as theophylline may be suggested as an alternative treatment in some cases. This medication acts as a bronchodilator and relaxes the muscles in the airways. The main side effects are nausea, restlessness, vomiting and irritability, although there is the possibility of severe side effects if a very high dose is used, including low blood pressure and convulsions. Please ask your doctor if you do not understand some of the terminology or you would like further information. What are the side-effects of the study treatments and procedures? As with all inhalation therapy an immediate increase in wheezing may occur after dosing. This would need to be treated with a fast and short acting inhaled bronchodilator and study treatment discontinued immediately and reported to the doctor for an alternative therapy. You may experience some of the following with Seretide: candida (thrush) infection of the mouth or throat, hoarseness, difficulty or pain in speaking, throat irritation, tremor, palpitations (heart flutters or racing) and headache. Heart beat changes may occur, in susceptible patients. There have also been reports of sore joints and sore muscles, muscle cramps, and hypersensitivity reactions including rash, swelling and swelling of the face, mouth and extremities. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. You may experience some of the following with Symbicort: headache, palpitations (heart flutters or racing), tremor, candida infection in the mouth and throat, mild irritation in the throat, coughing, hoarseness, an increase in heart rate, muscle cramps, agitation, restlessness, nausea, dizziness, sleep disturbances, red rashes, hives, itchy skin, tightness of the chest (lungs), depression, behaioural disturbances (mainly in children), signs or symptoms of systemic glucocorticosteroid disease, immediate or delayed hypersensitivity reactions (including skin reactions, swelling of the face, mouth and extremities, tightness of the chest (lungs)), bruising, angina pectoris, high blood sugar, taste disturbances, and variations in blood pressure.

If you need to use the asthma relief medication, salbutamol (Ventolin) during the study, you may experience side-effects from that drug. These are described on the label of the medicine and can be explained to you by your doctor. There may be risks or side effects that are not known at this time. There may be unknown risks to the unborn child (fetus) if you become pregnant while participating in this study. For this reason, if you are pregnant or intending to become pregnant or nursing an infant you are not eligible to be involved in this study. If you become pregnant during the course of your involvement in this study please stop taking the study medication and contact your doctor immediately.

Again, please ask your doctor if you do not understand some of the words used above or if you would like further information.

Your voluntary participation It is up to you to decide whether or not to take part in this study. If you do decide to take part you will be given this information to keep and be asked to sign this consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. This will not affect the standard of care you receive outside the study.

You may refuse to take part in this study or if you are in the study you may decide to stop participating at any time. You must inform your study doctor if you decide to do this. Your decision not to take part in the study FINAL ICF Date: 10Th September 2001, ICF Version 1 Page 4 of 7

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Informed Consent form SAM40040 or to stop participating in the study will not affect your current or future medical care or any benefits to which you may be entitled.

What happens if I don’t want to continue in the study? You are encouraged to contact the investigator or clinic should you decide not to continue your participation in the study. He/she will explain the best way for you to discontinue your participation in the research study.

Your participation in the study may be stopped for any of the following reasons: • If you don’t follow the investigator's instructions. • Something serious happens to you which may require treatment. • The investigator decides it is in the best interest of your health and welfare to discontinue. • There aren’t enough participants in the study. • Glaxo Wellcome stops the study at this study site for other reasons not known now. If you choose to leave the study before the last visit, you must return the study treatments and return to see the study doctor. This is requested of you to ensure your safety.

What if something goes wrong? If you become ill or injured while participating in this study, Dr...... will help you obtain medical treatment. Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). This applies in cases where it is likely that such injury results from giving any new drug or any other procedure carried out in accordance with the protocol for the study. The Sponsor will not compensate you where such injury results from any procedure not carried out in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected. A copy of the guidelines covering compensation for a possible injury/disablement that occurs while taking part in this study can be obtained from your doctor. For medicines which have already been approved by the Medical Authorities to treat this illness, normal legal rules on compensation will apply.

Will my taking part in the study be kept confidential? To protect your identity, your personal information (some examples are sex, age, details of your medical conditions) and other information (data) arising from the study and collected by Glaxo Wellcome will be identified by a number. Your name will not appear in any publications or reports produced from this study. Maintaining confidentiality is important to Glaxo Wellcome. Glaxo Wellcome will keep the information and the results collected about you in this study, but your name is not included in this information. Only your study doctor, not Glaxo Wellcome, keeps your name. Glaxo Wellcome has told your study doctor to keep information on you in a secure place. Glaxo Wellcome will control access to its own files that hold your information and results, and will take steps to protect the confidentiality of your identity but cannot guarantee that the data or results from this study could never be linked to you. By agreeing to take part in this research study you will be allowing certain persons to see your information (both personal (including your name) and other) to confirm it is correct and that it is about you and no one else. These persons include people working for GlaxoWellcome and organizations acting on behalf of Glaxo Wellcome, [Include here IECs/IRBs where local practices allow it], and government regulatory authorities. Glaxo Wellcome may use your information for other medical/health care purposes. Your information will be processed electronically (i.e. by a computer) or manually and analysed. Your information may/could be sent to the regulatory authorities, the IEC/IRB, to other doctors and/or organisations working with Glaxo Wellcome, and to other GlaxoWellcome sites in this country and in other countries where there may be variable standards for looking after it. Glaxo Wellcome will take steps to protect your information to adequate levels.

What if new information becomes available? Sometimes during the course of a research project, new information becomes available about the FINAL ICF Date: 10Th September 2001, ICF Version 1 Page 5 of 7

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Informed Consent form SAM40040 treatment/drug that is being studied. If this happens, we will tell you about new information that may affect your willingness to stay in this study.

Will my Primary Care Physician know I am in the study? (if he is not the study doctor) If your primary care physician is not the study doctor, he/she will contact your primary care physician (General Practitioner) to inform him/her that you are participating in the study.

What will happen to the results of the research study? The results of the study may be submitted to the appropriate regulatory authorities and may also be published. You will not be identified in any publications resulting from the study without your permission. Contact for further information If you have any questions regarding this study, need emergency medical treatment, experience a side-effect or a research-related injury while participating in this study, contact Dr...... or his/her associates at ...... While you are a patient in this study, you agree to follow the instructions of your doctor and to call your doctor immediately if you become ill or experience any side effects. If you have any questions regarding your rights as a research patient, you may contact or write to ...... at telephone number ...... Do not sign this form unless you have had a chance to ask questions and have satisfactory answers to all your questions. You will be given a copy of this information sheet and a signed consent form to keep. Reasonable travel expenses may be reimbursed. Therefore, you should discuss this further with your doctor, but you will not be paid for participating in this trial. There are no study related costs which you would have to pay if you participate in this study.

Thank you for taking the time to read this information leaflet.

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Informed Consent form SAM40040

INFORMED CONSENT FORM FOR PROTOCOL SAM40040 A TWENTY-FOUR WEEK, RANDOMISED, DOUBLE-DUMMY, DOUBLE BLIND, PARALLEL GROUP STUDY TO COMPARE THE OCCURRENCE OF EXACERBATIONS BETWEEN SERETIDE DISKUS 50/250mcg 1 INHALATION BD AND SYMBICORT BREATH-ACTUATED DRY POWDER INHALER 4.5/160mcg 2 INHALATIONS BD IN SUBJECTS WITH MODERATE TO SEVERE ASTHMA

I confirm that I have read the statements in the informed consent form dated 10th September 2001 for this study SAM40040. I confirm that the study information and procedures have been explained to me by [name(s)] on [date] during the consent process for this study. I confirm that I have had the opportunity to ask questions about this study and I am satisfied with the answers and explanations that have been provided. I have been given time and opportunity to read the information carefully, to discuss it with others and to decide whether or not to take part in this study. I agree to take part in this study.

Signature of subject Printed name Date

Signature of person explaining Printed name Date research

SAM40040 Study Subject Number

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Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160

Denmark SFC 50/250 CONFIDENTIAL Denmark FBC 4.5/160 Denmark SFC 50/250

1 Denmark FBC 4.5/160 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160 Czech Republic FBC 4.5/160 Czech Republic SFC 50/250 GM2004/00056/00 Czech Republic FBC 4.5/160 Czech Republic SFC 50/250

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Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Czech Republic FBC 4.5/160 Czech Republic SFC 50/250 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160 Czech Republic SFC 50/250

Italy SFC 50/250 CONFIDENTIAL Italy FBC 4.5/160 Italy FBC 4.5/160

2 Italy SFC 50/250 Italy FBC 4.5/160 Italy SFC 50/250 Italy SFC 50/250 Italy SFC 50/250 Italy FBC 4.5/160 Italy SFC 50/250 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy FBC 4.5/160 GM2004/00056/00 Italy SFC 50/250 Italy FBC 4.5/160

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Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Italy SFC 50/250 Italy FBC 4.5/160 Italy SFC 50/250 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy FBC 4.5/160 CONFIDENTIAL Italy FBC 4.5/160 Italy SFC 50/250

3 Italy SFC 50/250 Italy SFC 50/250 Italy SFC 50/250 France FBC 4.5/160 France SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 Norway SFC 50/250

United Kingdom SFC 50/250 GM2004/00056/00 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160

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Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom SFC 50/250 United Kingdom SFC 50/250 CONFIDENTIAL United Kingdom SFC 50/250 United Kingdom FBC 4.5/160

4 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 GM2004/00056/00 Netherlands SFC 50/250

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5 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Denmark SFC 50/250 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 GM2004/00056/00 Denmark FBC 4.5/160 Denmark SFC 50/250 SAM40040 SAM40040 Switzerland SFC 50/250 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Page 5 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Switzerland FBC 4.5/160 Switzerland SFC 50/250 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 CONFIDENTIAL France FBC 4.5/160 France SFC 50/250

6 France FBC 4.5/160 Norway SFC 50/250 Norway FBC 4.5/160 Norway FBC 4.5/160 Norway FBC 4.5/160 Norway SFC 50/250 Norway SFC 50/250 Norway SFC 50/250 Norway SFC 50/250 Norway FBC 4.5/160 Norway SFC 50/250 GM2004/00056/00 GM2004/00056/00 Italy FBC 4.5/160 Italy SFC 50/250 SAM40040 SAM40040 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Page 6 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 CONFIDENTIAL Greece SFC 50/250 Greece FBC 4.5/160

7 Greece FBC 4.5/160 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece SFC 50/250 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 GM2004/00056/00 GM2004/00056/00 Netherlands FBC 4.5/160 Netherlands SFC 50/250 SAM40040 SAM40040 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Page 7 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Greece FBC 4.5/160 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece FBC 4.5/160 CONFIDENTIAL Greece SFC 50/250 Greece FBC 4.5/160

8 Greece SFC 50/250 Greece SFC 50/250 Greece SFC 50/250 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal SFC 50/250 GM2004/00056/00 Portugal FBC 4.5/160 Portugal FBC 4.5/160

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Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— United Kingdom SFC 50/250 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 CONFIDENTIAL Estonia FBC 4.5/160 Estonia FBC 4.5/160

9 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia FBC 4.5/160 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 GM2004/00056/00 France FBC 4.5/160

Germany SFC 50/250 SAM40040 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Page 9 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 CONFIDENTIAL Germany FBC 4.5/160 Germany FBC 4.5/160 10 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 GM2004/00056/00 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160

United Kingdom SFC 50/250 SAM40040 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160

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Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 CONFIDENTIAL Netherlands FBC 4.5/160 Netherlands SFC 50/250 11 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250

Netherlands FBC 4.5/160 GM2004/00056/00 Netherlands SFC 50/250 Netherlands FBC 4.5/160

Netherlands SFC 50/250 SAM40040 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Page 11 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Portugal FBC 4.5/160 Portugal SFC 50/250 CONFIDENTIAL Portugal SFC 50/250 Portugal FBC 4.5/160 12 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal SFC 50/250 GM2004/00056/00 Portugal FBC 4.5/160 Portugal SFC 50/250

Portugal FBC 4.5/160 SAM40040 Portugal SFC 50/250 Portugal SFC 50/250 Portugal FBC 4.5/160 Page 12 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Portugal SFC 50/250 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160 CONFIDENTIAL Denmark SFC 50/250 Denmark FBC 4.5/160 13 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark SFC 50/250 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal SFC 50/250 GM2004/00056/00 Portugal FBC 4.5/160 Portugal SFC 50/250

Portugal FBC 4.5/160 SAM40040 Spain SFC 50/250 Spain SFC 50/250 Page 13 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 CONFIDENTIAL Spain SFC 50/250 Spain FBC 4.5/160 14 Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 GM2004/00056/00 Portugal FBC 4.5/160

Portugal SFC 50/250 SAM40040 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal FBC 4.5/160 Page 14 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Portugal SFC 50/250 Portugal SFC 50/250 Portugal FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 CONFIDENTIAL Spain SFC 50/250 Spain FBC 4.5/160 15 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 GM2004/00056/00 Spain FBC 4.5/160 Spain FBC 4.5/160

Spain SFC 50/250 SAM40040 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Page 15 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 CONFIDENTIAL Spain FBC 4.5/160 Spain FBC 4.5/160 16 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 United Kingdom FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 GM2004/00056/00 Netherlands SFC 50/250 Netherlands FBC 4.5/160

Netherlands SFC 50/250 SAM40040 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Page 16 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Netherlands SFC 50/250 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 CONFIDENTIAL Netherlands SFC 50/250 Netherlands FBC 4.5/160 17 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden SFC 50/250 Ireland FBC 4.5/160 Ireland SFC 50/250 GM2004/00056/00 Ireland FBC 4.5/160 Ireland SFC 50/250

Ireland SFC 50/250 SAM40040 France FBC 4.5/160 France SFC 50/250 Page 17 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

18 Czech Republic SFC 50/250 Czech Republic SFC 50/250 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160 Czech Republic FBC 4.5/160 Czech Republic FBC 4.5/160 Czech Republic SFC 50/250 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160 Czech Republic FBC 4.5/160 Czech Republic SFC 50/250

Czech Republic SFC 50/250 GM2004/00056/00 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160

Czech Republic FBC 4.5/160 SAM40040 Estonia SFC 50/250 Estonia FBC 4.5/160 Page 18 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 CONFIDENTIAL Estonia SFC 50/250 Estonia FBC 4.5/160 19 Estonia FBC 4.5/160 Austria SFC 50/250 Austria FBC 4.5/160 Austria SFC 50/250 Austria FBC 4.5/160 Austria FBC 4.5/160 Austria SFC 50/250 Austria SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 GM2004/00056/00 Russia SFC 50/250 Russia SFC 50/250

Russia FBC 4.5/160 SAM40040 Russia SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Page 19 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 CONFIDENTIAL Russia FBC 4.5/160 Russia SFC 50/250 20 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 Belgium FBC 4.5/160 Belgium SFC 50/250 Belgium SFC 50/250 France SFC 50/250 France FBC 4.5/160 GM2004/00056/00 France SFC 50/250 France FBC 4.5/160

France SFC 50/250 SAM40040 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 Page 20 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 CONFIDENTIAL France SFC 50/250 21 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia SFC 50/250 Russia SFC 50/250 GM2004/00056/00 Russia FBC 4.5/160 Russia FBC 4.5/160

Russia FBC 4.5/160 SAM40040 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Page 21 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Russia SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 CONFIDENTIAL Russia FBC 4.5/160 Russia FBC 4.5/160 22 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium FBC 4.5/160 Belgium SFC 50/250 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 GM2004/00056/00 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 SAM40040 SAM40040 Norway SFC 50/250 Norway FBC 4.5/160 Norway SFC 50/250 Page 22 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Norway FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Russia FBC 4.5/160 CONFIDENTIAL Russia SFC 50/250 Russia FBC 4.5/160 23 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 GM2004/00056/00 Russia FBC 4.5/160 Russia SFC 50/250

Russia SFC 50/250 SAM40040 Russia SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Page 23 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 Russia FBC 4.5/160 Russia SFC 50/250 Russia FBC 4.5/160 CONFIDENTIAL Russia SFC 50/250 Russia FBC 4.5/160 24 Russia FBC 4.5/160 Russia SFC 50/250 Russia SFC 50/250 Russia FBC 4.5/160 Russia SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 GM2004/00056/00 Germany FBC 4.5/160

France FBC 4.5/160 SAM40040 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 Page 24 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 CONFIDENTIAL Netherlands FBC 4.5/160 Netherlands SFC 50/250 25 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Italy FBC 4.5/160 Italy SFC 50/250 Italy SFC 50/250 Italy SFC 50/250 GM2004/00056/00 Italy FBC 4.5/160 Italy FBC 4.5/160

Italy FBC 4.5/160 SAM40040 France SFC 50/250 France SFC 50/250 Page 25 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— France FBC 4.5/160 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 France FBC 4.5/160 CONFIDENTIAL France SFC 50/250 France SFC 50/250 26 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 Netherlands SFC 50/250 Netherlands SFC 50/250 GM2004/00056/00 Netherlands FBC 4.5/160

Netherlands SFC 50/250 SAM40040 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250 Page 26 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250

United Kingdom FBC 4.5/160 CONFIDENTIAL United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 27 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160 Czech Republic SFC 50/250 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 GM2004/00056/00 France SFC 50/250 France FBC 4.5/160 SAM40040 SAM40040 Sweden FBC 4.5/160 Sweden FBC 4.5/160 Sweden SFC 50/250 Page 27 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Sweden SFC 50/250 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden SFC 50/250 CONFIDENTIAL Sweden FBC 4.5/160 Sweden FBC 4.5/160 28 Sweden SFC 50/250 Sweden SFC 50/250 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 GM2004/00056/00 France FBC 4.5/160 France SFC 50/250

France FBC 4.5/160 SAM40040 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Page 28 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Netherlands FBC 4.5/160 Netherlands SFC 50/250 Switzerland SFC 50/250 Switzerland SFC 50/250

Belgium FBC 4.5/160 CONFIDENTIAL Belgium SFC 50/250 Belgium FBC 4.5/160 29 Greece FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 GM2004/00056/00 Netherlands SFC 50/250 Netherlands FBC 4.5/160

Netherlands FBC 4.5/160 SAM40040 France SFC 50/250 France FBC 4.5/160 Page 29 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— France SFC 50/250 France FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250 CONFIDENTIAL Netherlands FBC 4.5/160 Netherlands SFC 50/250 30 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 GM2004/00056/00 Germany SFC 50/250 Germany FBC 4.5/160

Germany SFC 50/250 SAM40040 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Page 30 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany SFC 50/250 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160 Denmark SFC 50/250 Denmark FBC 4.5/160 CONFIDENTIAL Denmark SFC 50/250 Denmark FBC 4.5/160 31 Denmark SFC 50/250 Denmark SFC 50/250 Denmark SFC 50/250 Denmark FBC 4.5/160 Denmark FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 GM2004/00056/00 Germany FBC 4.5/160 Germany FBC 4.5/160

Germany SFC 50/250 SAM40040 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Page 31 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 CONFIDENTIAL Germany SFC 50/250 Germany FBC 4.5/160 32 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 GM2004/00056/00 Germany SFC 50/250 Germany SFC 50/250

Germany SFC 50/250 SAM40040 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Page 32 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany FBC 4.5/160 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 CONFIDENTIAL United Kingdom FBC 4.5/160 33 United Kingdom SFC 50/250 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom SFC 50/250 Ireland SFC 50/250 Ireland SFC 50/250 Ireland FBC 4.5/160 Ireland FBC 4.5/160 GM2004/00056/00 Ireland FBC 4.5/160 Ireland SFC 50/250

Ireland SFC 50/250 SAM40040 Ireland FBC 4.5/160 Ireland SFC 50/250 Ireland FBC 4.5/160 Page 33 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 CONFIDENTIAL France SFC 50/250 France FBC 4.5/160 34 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia FBC 4.5/160 GM2004/00056/00 Estonia SFC 50/250 Estonia FBC 4.5/160

Estonia FBC 4.5/160 SAM40040 Estonia SFC 50/250 Germany FBC 4.5/160 Page 34 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 CONFIDENTIAL Germany SFC 50/250 Germany FBC 4.5/160 35 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 GM2004/00056/00 Germany FBC 4.5/160 SAM40040 SAM40040 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Page 35 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Netherlands SFC 50/250 CONFIDENTIAL Netherlands SFC 50/250 Netherlands FBC 4.5/160 36 Netherlands FBC 4.5/160 Netherlands FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 GM2004/00056/00 Germany SFC 50/250 Germany SFC 50/250

Germany FBC 4.5/160 SAM40040 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Page 36 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

37 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 GM2004/00056/00 Germany FBC 4.5/160

Germany SFC 50/250 SAM40040 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Page 37 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 CONFIDENTIAL Germany FBC 4.5/160 Germany FBC 4.5/160 38 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden FBC 4.5/160 GM2004/00056/00 Sweden SFC 50/250 Sweden FBC 4.5/160

Sweden SFC 50/250 SAM40040 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden SFC 50/250 Page 38 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Sweden FBC 4.5/160 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden SFC 50/250 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden SFC 50/250 CONFIDENTIAL Sweden SFC 50/250 Sweden FBC 4.5/160 39 Sweden SFC 50/250 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden SFC 50/250 Sweden SFC 50/250 Sweden FBC 4.5/160 Sweden FBC 4.5/160 Sweden FBC 4.5/160

United Kingdom FBC 4.5/160 GM2004/00056/00 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250

United Kingdom SFC 50/250 SAM40040 Norway FBC 4.5/160 Norway FBC 4.5/160 Page 39 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Estonia FBC 4.5/160 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 CONFIDENTIAL Estonia FBC 4.5/160 Estonia FBC 4.5/160 40 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 GM2004/00056/00 Spain SFC 50/250 Spain FBC 4.5/160

Spain SFC 50/250 SAM40040 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Page 40 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250

United Kingdom FBC 4.5/160 CONFIDENTIAL Italy SFC 50/250 41 Italy SFC 50/250 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy SFC 50/250 Italy SFC 50/250 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy FBC 4.5/160 Italy SFC 50/250 Italy SFC 50/250 GM2004/00056/00 Italy FBC 4.5/160 Italy FBC 4.5/160

Italy FBC 4.5/160 SAM40040 Belgium SFC 50/250 Belgium SFC 50/250 Page 41 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Belgium FBC 4.5/160 Belgium FBC 4.5/160 Belgium FBC 4.5/160 Belgium FBC 4.5/160 Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium SFC 50/250 CONFIDENTIAL Belgium SFC 50/250

42 Belgium SFC 50/250 Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium SFC 50/250 Belgium FBC 4.5/160 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 GM2004/00056/00 GM2004/00056/00 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 SAM40040 SAM40040 Greece SFC 50/250 Greece FBC 4.5/160 Greece SFC 50/250 Page 42 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Greece FBC 4.5/160 Greece SFC 50/250 Greece FBC 4.5/160 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece FBC 4.5/160 CONFIDENTIAL Greece SFC 50/250 Greece SFC 50/250 43 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece SFC 50/250 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Estonia FBC 4.5/160 Estonia FBC 4.5/160 GM2004/00056/00 Estonia SFC 50/250 Estonia SFC 50/250

Estonia SFC 50/250 SAM40040 Estonia FBC 4.5/160 Estonia FBC 4.5/160 Estonia FBC 4.5/160 Page 43 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 Estonia SFC 50/250 Estonia FBC 4.5/160 Estonia SFC 50/250 CONFIDENTIAL Estonia FBC 4.5/160

44 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 GM2004/00056/00 GM2004/00056/00 Sweden FBC 4.5/160 Sweden FBC 4.5/160

Sweden SFC 50/250 SAM40040 Sweden SFC 50/250 Germany FBC 4.5/160 Page 44 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 CONFIDENTIAL Germany FBC 4.5/160 Germany SFC 50/250 45 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany FBC 4.5/160 Germany SFC 50/250 Germany FBC 4.5/160 Germany SFC 50/250 Germany SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 GM2004/00056/00 Spain SFC 50/250 Spain FBC 4.5/160

Spain FBC 4.5/160 SAM40040 Belgium FBC 4.5/160 Belgium SFC 50/250 Page 45 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium SFC 50/250 Belgium SFC 50/250 Belgium FBC 4.5/160 Belgium FBC 4.5/160 CONFIDENTIAL United Kingdom SFC 50/250 46 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal FBC 4.5/160 Portugal SFC 50/250 Portugal SFC 50/250 Belgium SFC 50/250 GM2004/00056/00 GM2004/00056/00 Switzerland SFC 50/250 Switzerland FBC 4.5/160

Switzerland SFC 50/250 SAM40040 Switzerland FBC 4.5/160 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Page 46 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland SFC 50/250 Switzerland SFC 50/250 CONFIDENTIAL Switzerland FBC 4.5/160 Switzerland FBC 4.5/160 47 Switzerland FBC 4.5/160 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland SFC 50/250 GM2004/00056/00 Switzerland FBC 4.5/160 Switzerland SFC 50/250

Switzerland FBC 4.5/160 SAM40040 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland FBC 4.5/160 Page 47 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland SFC 50/250 Switzerland FBC 4.5/160 Switzerland SFC 50/250 CONFIDENTIAL United Kingdom SFC 50/250 48 United Kingdom SFC 50/250 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160 Estonia FBC 4.5/160 Estonia SFC 50/250 Estonia SFC 50/250 GM2004/00056/00 Estonia FBC 4.5/160 Estonia SFC 50/250

Estonia FBC 4.5/160 SAM40040 Estonia FBC 4.5/160 Estonia SFC 50/250

Page 48 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Austria FBC 4.5/160 Austria SFC 50/250 Austria FBC 4.5/160 Austria SFC 50/250 Austria SFC 50/250 Austria SFC 50/250 Austria FBC 4.5/160 CONFIDENTIAL Austria FBC 4.5/160

49 Austria SFC 50/250 Austria SFC 50/250 Austria FBC 4.5/160 Austria FBC 4.5/160 Austria SFC 50/250 Austria FBC 4.5/160 Austria FBC 4.5/160 Austria SFC 50/250 Austria SFC 50/250 Austria FBC 4.5/160 Austria FBC 4.5/160 Austria SFC 50/250 GM2004/00056/00 Austria SFC 50/250

Austria SFC 50/250 SAM40040 Austria SFC 50/250 Austria FBC 4.5/160 Austria FBC 4.5/160 Page 49 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Austria FBC 4.5/160 Austria FBC 4.5/160 Austria SFC 50/250 Austria SFC 50/250 Austria SFC 50/250 Austria SFC 50/250 Austria FBC 4.5/160 CONFIDENTIAL Austria FBC 4.5/160 Austria FBC 4.5/160 50 Austria FBC 4.5/160 Austria SFC 50/250 Austria FBC 4.5/160 Austria FBC 4.5/160 Austria SFC 50/250 Austria FBC 4.5/160 Ireland SFC 50/250 Ireland FBC 4.5/160 Ireland SFC 50/250 Ireland SFC 50/250 GM2004/00056/00 Ireland FBC 4.5/160 Ireland SFC 50/250

Ireland FBC 4.5/160 SAM40040 Ireland FBC 4.5/160 Ireland SFC 50/250

Page 50 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Ireland FBC 4.5/160 Ireland FBC 4.5/160 Ireland SFC 50/250 Ireland SFC 50/250 CONFIDENTIAL Ireland FBC 4.5/160

51 Germany FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 GM2004/00056/00 Spain SFC 50/250 Spain SFC 50/250

Spain FBC 4.5/160 SAM40040 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Page 51 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 CONFIDENTIAL France FBC 4.5/160 France SFC 50/250 52 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 France SFC 50/250 France SFC 50/250 GM2004/00056/00 France FBC 4.5/160

United Kingdom FBC 4.5/160 SAM40040 United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 Page 52 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— United Kingdom SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 CONFIDENTIAL Spain FBC 4.5/160 Spain FBC 4.5/160 53 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 GM2004/00056/00 Spain SFC 50/250 Spain FBC 4.5/160

Spain SFC 50/250 SAM40040 Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Page 53 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Spain FBC 4.5/160 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 CONFIDENTIAL Spain SFC 50/250 Spain SFC 50/250 54 Spain SFC 50/250 Spain SFC 50/250 Spain FBC 4.5/160 Spain FBC 4.5/160 Spain SFC 50/250 Spain FBC 4.5/160 Netherlands FBC 4.5/160 Netherlands SFC 50/250 Netherlands SFC 50/250

Czech Republic SFC 50/250 GM2004/00056/00 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160

Czech Republic FBC 4.5/160 SAM40040 Czech Republic SFC 50/250 Czech Republic FBC 4.5/160 Czech Republic FBC 4.5/160 Page 54 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Czech Republic SFC 50/250 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 CONFIDENTIAL Greece SFC 50/250 Greece SFC 50/250 55 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Greece FBC 4.5/160 Greece SFC 50/250 Greece SFC 50/250 Greece FBC 4.5/160 Greece FBC 4.5/160 Greece SFC 50/250 Greece FBC 4.5/160

United Kingdom SFC 50/250 GM2004/00056/00 United Kingdom SFC 50/250 United Kingdom FBC 4.5/160

United Kingdom FBC 4.5/160 SAM40040 United Kingdom FBC 4.5/160 United Kingdom FBC 4.5/160

Page 55 of 56 Protocol: SAM40040 Population: Intent-to-Treat Listing 1 Listing of Randomisation Code

Treatment Investigator Subject Country Number Treatment — ——————————————————————————————— ————————————————————— Norway FBC 4.5/160 Norway FBC 4.5/160 Norway SFC 50/250 Norway SFC 50/250 Norway SFC 50/250

United Kingdom SFC 50/250 CONFIDENTIAL United Kingdom FBC 4.5/160 United Kingdom SFC 50/250 56 Switzerland SFC 50/250 Switzerland FBC 4.5/160 United Kingdom SFC 50/250 France SFC 50/250 France FBC 4.5/160 France FBC 4.5/160 France SFC 50/250 France FBC 4.5/160 GM2004/00056/00 GM2004/00056/00 Spain FBC 4.5/160 Spain FBC 4.5/160

Spain SFC 50/250 SAM40040

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