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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. Copyright 2004 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1 1 CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040 Synopsis Document Number: GM2004/00056/00 Study Number: SAM40040 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.. 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%)). 2 CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040 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.. 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. 3 CONFIDENTIAL GM2004/00056/00GM2004/00056/00 SAM40040SAM40040 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.. 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