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This study includes documents that were originally reported in a language other than English. All documents that are available in English have been made available via the GSK Clinical Study Register. Any additional documents that have not been translated to English may be made available, redacted in the original language, subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. CONFIDENTIAL GM2008/00234/00GM2008/00234/00 GlaxoSmithKlineThe GlaxoSmithKline group of companiesgroup of companies IPC103711IPC103711

Division: World Wide Development Retention Category: GRS019 Information Type: Condensed Clinical Study Report

A double blind, placebo controlled, repeat dose study to Title: compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers

Phase: I

Compound Number: GSK256066

Effective Date: 30-OCT-2008 Description: This was a single centre, randomised, double-blind, parallel-group, 7 day repeat dose study in 37 healthy volunteers. Subjects were randomised (1:1:1) to receive either placebo (N = 12), GSK256066 25 µg (N = 13) or GSK256066 87.5 µg (N = 12) as a single, once-daily inhaled dose for 7 days (via an ACCUHALER™ device). Overall, there was an observed elevation in cell counts when comparing the 2 h post-dose and the 26 h post-dose saline compartments with the 26 h post-dose lipopolysaccharide (LPS) compartment confirming sensitivity to LPS challenge. This was not formally analysed. Due to the large variability across all treatment groups, there was no statistical evidence of a treatment effect for any endpoint that was formally analysed: total neutrophils, total and differential counts in bronchoalveolar lavage (BAL) 24 h post-LPS exposure, BAL concentrations of protein inflammatory biomarkers and serum concentrations of protein inflammatory biomarkers. Urea-corrected GSK256066 concentrations were at least an order of magnitude greater and declined more slowly over time in the pellet than in the supernatant. The metabolite GSK614917 was not quantifiable in any sample from subjects providing sufficient sample for analysis. Due to sparse pharmacokinetic data, no conclusions could be drawn between the pharmacokinetic and pharmacodynamic parameters. GSK256066 25 µg and 87.5 µg QD were generally well-tolerated by healthy subjects. All adverse events were judged to be mild or moderate in intensity and no serious adverse events were reported in the study.

Subject: GSK256066, cellobiose octaacetate (COA), lipopolysaccharide (LPS), healthy volunteers

Authors:

Initiation Date: 2 October 2007

Completion Date: 16 April 2008

Date of Report: October 2008

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Sponsor Signatory: PhD (and Medical Officer) Director, Discovery Medicine, Respiratory CEDD

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

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Abbreviations

AE Adverse event BAL Bronchoalveolar lavage CC-16 Clara cell protein 16 CVb Between-subject coefficients of variation FVC Forced vital capacity FEV1 Forced expiratory volume in 1 second IL Interleukin LPS Lipopolysaccharide LS Least squares MPO Myeloperoxidase MSE Mean square error QD Once daily RAP Reporting and analysis plan SP-D Surfactant-associated protein D SAE Serious adverse event SAS Statistical Analysis Software TNFα Tumour necrosis factor α

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies ACCUHALER SAS

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TITLE

A double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers.

INVESTIGATOR

Dr.

STUDY CENTRE

Germany.

PUBLICATIONS

None at the time of this report.

STUDY PERIOD

Initiation Date: 2 October 2007

Completion Date: 16 April 2008

PHASE OF DEVELOPMENT

OBJECTIVES

Primary

• To investigate the effects of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) once daily (QD) on lung inflammation following segmental lipopolysaccharide (LPS) challenge in healthy volunteers.

Secondary

• To investigate the safety and tolerability of 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) QD in healthy volunteers.

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• To investigate the response of systemic markers of inflammation following 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) QD in healthy volunteers.

METHODOLOGY

This was a single centre, randomised, double-blind, parallel-group, 7-day repeat dose study in healthy volunteers. All subjects attended the unit for screening within 28 days of their first dosing occasion. Subjects were randomised (1:1:1) to receive one of the following treatments, as a single, inhaled dose QD for 7 days (via an ACCUHALER™ device):

• GSK256066 25 µg. • GSK256066 87.5 µg. • Placebo. Following dosing on Day 7, subjects underwent bronchoscopy, bronchoalveolar lavage (BAL) and segmental LPS challenge. Bronchoscopy and BAL were repeated after 24 h. Subjects attended the unit for a follow-up visit within 7–10 days following their final dose. The overall study duration (screening to follow-up) did not exceed 45 days. Subjects had to follow protocol-specified guidance on consumption of alcohol and contraception (female subjects). Subjects were required to fast from midnight before Day 7 and Day 8 prior to bronchoscopy.

A time and events table is presented in Attachment 1.

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NUMBER OF SUBJECTS

Placebo GSK256066 Dose QD 25 µg 87.5 µg Number of Subjects Number of subjects planned, N: 14 14 14 Number of subjects randomised, N: 12 13 12 Number of subjects included in all subjects 12 (100) 13 (100) 12 (100) population, n (%): Number of subjects included in pharmacokinetic 0 13 (100) 12 (100) population, n (%): Number of subjects included in per-protocol 12 (100) 12 (92) 12 (100) population, n (%): Number of subjects completed as 12 (100) 13 (100) 12 (100) planned, n (%): Number of subjects withdrawn 0 0 0 (any reason), n (%): Demographics Age in Years, Mean (Range) 34.0 (21–50) 29 (19–41) 29.2 (20–47) Sex, n (%) Female: 4 (33%) 6 (46%) 5 (42%) Male: 8 (67%) 7 (54%) 7 (58%) Body Mass Index (kg/m2), Mean (Range) 24.51 23.30 23.35 (20.42–27.47) (19.92–29.26) (20.20–25.54) Height (cm), Mean (Range) 176.3 176.7 176.9 (162–191) (166–188) (164–192) Weight (kg), Mean (Range) 76.6 (59–98) 72.9 (60–98) 73.3 (57–88) Ethnicity, n (%) Hispanic or Latino: 1 (8%) 0 0 Not Hispanic or Latino: 11 (92%) 13 (100%) 12 (100%) Race, n (%) White – White/Caucasian/European Heritage 12 (100%) 12 (92%) 12 (100%) White – Arabic/North African Heritage 0 1 (8%) 0 Source Data: Table 9.1, Table 9.2 and Table 9.3 AE = adverse event, SAE = serious adverse event

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Healthy male and female volunteers aged 18 to 50 years, with a body weight ≥50 kg and body mass index within the range of 19 to 31 kg/m2 inclusive were eligible for the study. Female subjects were either of non-childbearing potential or had a negative pregnancy test at screening and agreed to use one of the acceptable protocol-specified contraceptive methods.

Subjects were eligible with a screening pre-bronchodilator forced expiratory volume in one second (FEV1) ≥80% predicted and FEV1/forced vital capacity (FVC) ratio >0.7.

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Predicted values were based on the European Community for Coal and Steel (1993) normal ranges.

TREATMENT ADMINISTRATION

Subjects were dosed in the clinical study unit on the mornings of Day 1 and Day 7. On Day 2 to Day 6, subjects self-administrated medication at home. Two ACCUHALERs were provided per subject. Each subject took one inhalation from each inhaler each morning. A summary of treatment administration is presented in Table 1.

Table 1 Summary of treatment administration

Description Batch Details Use by date GSK256066 12.5 µg Batch/Lot number: 071131084 30th June 2008 GSK256066 37.5 µg Batch/Lot number: 071131086 30th June 2008 GSK256066 50 µg Batch/Lot number: 071131108 30th June 2008 Placebo Batch: R230656; Lot Number: 061120114 30th June 2008

CRITERIA FOR EVALUATION

The primary endpoints for this study were:

• Absolute BAL neutrophils at 24 h post-LPS exposure. • The total and differential cell count in BAL (absolute and percentage cell counts) at 24 h post-LPS exposure. The secondary endpoints for this study were:

• Safety and tolerability: • Vital signs: systolic and diastolic blood pressure and heart rate. • Holter monitoring. • Twelve-lead electrocardiograph (ECG) including QTc(B), QT, QRS, PR and ventricular rate.

• Lung function (FEV1 and FVC). • Laboratory safety tests (haematology, clinical chemistry, urinalysis). • Adverse events. • Serum concentration of protein inflammatory biomarkers (e.g., surfactant-associated protein D [SP-D], Clara cell protein 16 [CC-16]). • Bronchoalveolar lavage concentration of protein inflammatory biomarkers (e.g., interleukin (IL)-8, tumour necrosis factor α (TNFα), IL-6, myeloperoxidase (MPO)). • Bronchoalveolar lavage concentrations of GSK256066 and metabolite GSK614917.

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STATISTICAL METHODS

Full details of the planned analyses for this study are presented in Attachment 2 (reporting and analysis plan (RAP)).

Sample Size

The sample size was determined by feasibility and not statistical considerations. A total of 42 subjects (14 per arm) were to be recruited in order to obtain 36 evaluable subjects (12 per arm). Thirty-seven subjects were recruited.

Analysis Populations

The ‘All Subjects’ population was defined as all subjects randomised to receive at least one dose of study treatment (including placebo). The ‘All Subjects’ population was used for all study population and safety outputs.

This subject was excluded from the ‘All Subjects’ population because of a neutrophilic inflammation following both LPS and saline instillation. The subject complained about systemic LPS side effect (fever) and the site noticed elevated leukocyte count and C-reactive protein. The site had never seen such a systemic reaction with local LPS challenge, and a neutrophilic inflammation in the post saline segment. The ‘Per- Protocol’ population was used for all pharmacodynamic and biomarker outputs.

The ‘Pharmacokinetic Population' was defined as subjects in the ‘All Subjects’ population for whom a pharmacokinetic sample was obtained and analysed.

Interim Analyses

No interim analyses were planned or performed.

Final Analyses

Safety data were listed and summarised. No formal statistical analysis was performed on safety data.

For the pharmacodynamic endpoints, a formal statistical analysis was carried out on loge- transformed neutrophil count, total leukocyte count, macrophage count data and % macrophages, and untransformed % neutrophils, % eosinophils and eosinophil count data using a fixed effects model adjusting for treatment. The 26 h post-dose post-saline reading was also included as a covariate to obtain a better goodness of fit of the model for the neutrophil count, total leukocyte count, macrophage count and eosinophil count endpoints. This reading was loge-transformed for the neutrophil count, total leukocyte count and macrophage count endpoints. No additional covariate was included in the analysis of % neutrophils, % macrophages and % eosinophils endpoints. Data for all cell count endpoints were provided by the site as number of cells, therefore values were

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divided by sample volume in mL. As the data showed a large amount of variability across treatment groups, the model fitted to the endpoints neutrophil count, total leukocyte count and % neutrophil data had been slightly altered to allow for a different variability in each treatment group, with a repeated statement added to the model code in Statistical Analysis Software (SAS).

The BAL biomarker endpoints were corrected for dilution using urea-corrected concentration in blood and BAL samples. A formal statistical analysis was carried out on loge-transformed IL-6, IL-8, MPO and TNF-α data using a fixed effects model adjusting for treatment. The loge-transformed 26 h post-dose post-saline reading was also included as a covariate to obtain a better fit of the model for all endpoints. As the IL-6 data showed a large amount of variability across treatment groups, the model was slightly altered to allow for a different variability in each treatment group, with a repeated statement added to the model code in SAS.

For the blood biomarker endpoints, a formal statistical analysis was carried out on loge- transformed SP-D and CC-16 data using a repeated measures model.

Following correction for dilution using urea in blood and BAL samples, the concentrations of GSK 256066 in the BAL pellet and supernatant were listed and summarised.

Relationships between corrected BAL GSK256066 concentration and BAL total neutrophils were explored graphically. No further PK/PD analysis was conducted.

Pharmacogenetic subject accountability data were summarised.

Changes in the Conduct of the Study or Planned Analyses

Data for all pharmacodynamic cell count endpoints was provided by the site as number of cells, therefore values were divided by sample volume in mL. The model fitted for the statistical analysis of total neutrophil count, total leukocyte count, % neutrophil and IL-6 data had been modified from the RAP as the data showed a large amount of variability across treatment groups. The following repeated statement was added to account for the different variability observed among the treatment groups.

REPEATED / SUBJECT= TYPE=vc GROUP=;

Some of the titles of the outputs planned in the RAP were slightly modified and some additional outputs were created although not originally listed in the RAP.

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SUMMARY

Pharmacodynamic Results

Bronchoalveolar Lavage Cell Count Data

Overall, there was an observed elevation in cell counts when comparing the 2 h and the 26 h saline compartments with the 26 h LPS compartment confirming sensitivity to LPS challenge. This was not formally analysed.

Bronchoalveolar lavage cell count is presented in Table 10.1. The data indicated there was a large variability across all treatment groups, as demonstrated in the between- subject coefficients of variation (CVb). Therefore, there was no evidence for a statistically significant treatment effect for any endpoint that was formally analysed because the confidence intervals either contained zero for the treatment differences or 1 for the treatment ratios. The mean square error (MSE) associated to the analysis of neutrophil count was 1.3519 compared with an approximate MSE of 0.2 quoted in the sample size calculation section from the roflumilast paper [Hohlfeld, 2008].

This made no difference to the analysis results and no difference to the variability as measured by the CVb values.

Neutrophils

There was no notable decrease in total neutrophil count between either GSK256066 dose QD or placebo. The total neutrophil count gave no evidence of a significant treatment effect as the confidence interval contained 1 for the treatment ratios. GSK256066 25 µg QD gave the greatest reduction in total neutrophil count (39%), but had the most variability as indicated by the wide confidence interval. An estimated 31% decrease in total neutrophil count was observed for GSK256066 87.5 µg QD compared with placebo. Results of statistical analysis of log-transformed total neutrophil count are summarised in Table 2.

Table 2 Summary of results of statistical analysis of log-transformed total neutrophils count data

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Neutrophil Placebo QD GSK256066 GSK256066 25 µg QD 87.5 µg QD parameter 25 µg QD 87.5 µg QD Count 0.95 0.58 0.65 0.614 0.691 (x106/mL) (0.67, 1.33) (0.21, 1.65) (0.34, 1.25) (0.210, 1.794) (0.343, 1.394) Source Data: Table 10.3 CI = confidence interval, LS = least squares, QD = once daily

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A summary of the individual values as well as the adjusted geometric means and 95% CI of BAL total number of neutrophils is presented in Figure 1.

Figure 1 Plot of adjusted geometric means (95% confidence intervals) of bronchoalveolar lavage total number of neutrophils (x106/mL) with individual values

Source: Figure 10.1

There was also no notable decrease in % neutrophils for either GSK256066 dose QD or placebo as the confidence interval contained zero for the treatment differences. Smaller differences were evident for the change in % neutrophils compared with total neutrophil count. The largest decrease in % neutrophils was observed when comparing GSK256066 87.5 µg QD with placebo (5%). An estimated 4% decrease in % neutrophils was observed when comparing GSK256066 25 µg QD with placebo. Results of statistical analysis of percentage neutrophils data are summarised in Table 3.

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Table 3 Summary of results of statistical analysis of percentage neutrophils data

LS means GSK256066 dose – placebo (95% CI) treatment difference (95% CI) Neutrophil Placebo QD GSK256066 GSK256066 25 µg QD 87.5 µg QD parameter 25 µg QD 87.5 µg QD 66.59 62.36 61.61 -4.23 -4.98 % Neutrophil (60.24, (47.42, (50.65, 72.57) (-19.97, (-17.09, 7.12) 72.94) 77.30) 11.50) Source Data: Table 10.4 CI = confidence interval, LS = least squares, QD = once daily

A plot of adjusted means of BAL percentage of neutrophils along with individual values is presented in Figure 2.

Figure 2 Plot of adjusted means (95% confidence intervals) of bronchoalveolar lavage percentage of neutrophils with individual values

Source: Figure 10.3

Leukocytes

There was no notable decrease in total leukocyte count across treatment groups, although the data were highly variable. GSK256066 25 µg QD demonstrated the greatest reduction

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in total leukocyte count, but had the most variability. There was no evidence of a statistically significant treatment effect as the confidence interval contained 1 for the treatment ratios. The largest decrease in total leukocyte count was observed when comparing GSK256066 25 µg QD with placebo (25%). An estimated 20% decrease in total leukocyte count was observed when comparing GSK256066 87.5 µg QD with placebo. Results of statistical analysis of log-transformed leukocyte data are summarised in Table 4.

Table 4 Summary of results of statistical analysis of log-transformed endpoints: leukocytes

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Analyte Placebo QD GSK256066 GSK256066 25 µg QD 87.5 µg QD 25 µg QD 87.5 µg QD Total leukocyte 1.43 1.07 1.14 0.747 0.800 count (x106/mL) (1.05, 1.95) (0.51, 2.25) (0.71, 1.84) (0.342, 1.633) (0.464, 1.378) Source Data: Table 10.3 CI = confidence interval, LS = least squares, QD = once daily

A plot of adjusted geometric means and 95% CIs of BAL total leukocyte count (x106/mL) along with individual values is presented in Figure 3.

Figure 3 Plot of adjusted geometric means and (95% confidence intervals) of bronchoalveolar lavage total leukocyte count (x106/mL) with individual values

Source: Figure 10.19

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Analysis of variability in neutrophils and leukocytes

The coefficient of variation was calculated as standard deviation / arithmetic mean in placebo and active treatment groups (GSK256066 25 µg QD and GSK256066 87.5 µg QD) for neutrophil count and total leukocyte count. It was compared with coefficients of variation in the placebo and active treatment groups from the roflumilast study [Hohlfeld, 2008]. A summary of the coefficient of variation in neutrophils and leukocytes is presented in Table 5.

Table 5 Coefficient of variation in neutrophils and leukocytes

Total leukocyte count Neutrophil count (x 106/mL) (x 106/mL) Roflumilast study Placebo Baseline / 2 h 0.500 1.408 Saline 0.545 1.938 LPS 0.558 0.692 Roflumilast Baseline / 2 h 0.500 1.328 Saline 1.143 2.679 LPS 0.375 0.375 IPC103711 study Placebo Baseline / 2 h 0.429 1.247 Saline 0.542 1.631 LPS 0.538 0.654 GSK256066 25 µg Baseline / 2 h 0.472 0.667 QD Saline 0.564 2.303 LPS 0.772 0.879 GSK256066 87.5 µg Baseline / 2 h 0.479 1.150 QD Saline 0.600 1.635 LPS 0.837 0.960 Source Data: Table 10.1 and Hohlfeld (2008) LPS = Lipopolysaccharide; QD = Once daily

The variability for all time points was very similar for placebo between the studies. It was also evident that the variability for the LPS time point was considerably lower in the roflumilast study compared to the LPS time point for both GSK256066 doses in the present study (IPC103711). The MSE associated with the analysis of neutrophil count was 1.3519 compared with an approximate MSE of 0.2 quoted in the sample size calculation section from the roflumilast paper [Hohlfeld 2008].

Macrophages

There was no notable change in total macrophage count across treatment groups. There was also a large degree of variability across the treatment groups, resulting in no evidence of a significant treatment effect, as the confidence interval contained 1 for the treatment ratios. For % macrophages, both GSK256066 doses showed an increase compared with placebo. This was an expected finding because the percentage of

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macrophages tends to increase with a reduction of the percentage of neutrophils. Results of statistical analysis of log-transformed macrophage data are summarised in Table 6.

Table 6 Summary of results of statistical analysis of log-transformed endpoints: macrophage

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Analyte Placebo GSK256066 GSK256066 25 µg QD 87.5 µg QD QD 25 µg QD 87.5 µg QD Macrophage 0.18 0.17 0.21 0.957 1.196 count (x106/mL) (0.12, 0.26) (0.12, 0.25) (0.14, 0.31) (0.553, 1.657) (0.686, 2.083) % Macrophages 12.73 16.10 18.09 1.265 1.420 (8.17, (10.32, (11.60, 28.20) (0.67, 2.37) (0.76, 2.66) 19.86) 25.12) Source Data: Table 10.3 CI = confidence interval, LS = least squares, QD = once daily

Eosinophils

There was no evidence of a statistical difference in eosinophil counts between either GSK256066 dose and placebo, as treatment differences included zero. A summary of eosinophil count and % eosinophils is presented in Table 7.

Table 7 Summary of results of statistical analysis of untransformed endpoints

LS means GSK256066 – placebo (95% CI) treatment difference (95% CI) Eosinophil Placebo GSK256066 GSK256066 25 µg QD 87.5 µg QD parameter QD 25 µg QD 87.5 µg QD Count (103/mL) 11 14.7 12 3.73 1.04 (1.9, 20.1) (5.5, 23.9) (2.9, 21.2) (-9.28, 16.74) (-11.87, 13.95 % Eosinophil 0.79 0.63 0.8 -0.16 0.004 (0.42, 1.16) (0.26, 1.00) (0.43, 1.17) (-0.68, 0.36) ( -0.52, 0.53) Source Data: Table 10.4 CI = confidence interval, LS = least squares, QD = once daily

Monocytes

GSK256066 25 µg and 87.5 µg doses QD resulted in a lower total monocyte count post- LPS than placebo. Values were 172.36 and 113.41 x 103/mL, respectively, versus 240.99 x 103/mL for placebo. Similar results were obtained for % monocytes. Percentages were 17.00 and 13.99% post-LPS exposure for GSK256066 25 µg and 87.5 µg QD respectively, compared with 19.47% for placebo.

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Bronchial epithelial cells

Both GSK256066 doses QD resulted in a lower % bronchial epithelial cells 24 h post- LPS exposure compared with placebo. No formal summary statistics were produced for bronchial epithelial cell count as over half the subjects had a value of zero for each treatment group 24 h post-LPS exposure.

Lymphocytes

Only the GSK256066 25 µg QD treatment group resulted in a lower lymphocyte count than placebo. For % lymphocytes, both doses demonstrated a higher count than placebo.

Flow Cytometry Bronchoalveolar Lavage Monocyte Data

There was no decrease in CD14+ monocyte count across treatment groups. There was a large amount of variability across the treatment groups. Treatment GSK256066 87.5 µg QD provided the greatest reduction in CD14+ monocyte count. These findings were also evident for % CD14+ monocytes. This was different from what was found with monocyte count and % monocytes which saw the GSK256066 25 µg QD treatment giving a larger reduction in count.

Biomarker Analyses

Bronchoalveolar Lavage

Overall, there was an observed elevation in BAL protein biomarkers when comparing the 2 h and the 26 h saline compartments with the 26 h LPS compartment. This confirmed sensitivity to LPS challenge, although the data were not formally analysed. This elevation, particularly for TNF-α, was not as large as seen in the cellular components.

As with the cell count data, the protein expression data showed a large amount of variability across all treatment groups. This resulted in no evidence of a statistically significant treatment effect for any BAL biomarker endpoints that were formally analysed, as the confidence intervals contained 1 for the treatment ratios.

Interleukin 6

There was no significant decrease in IL-6 across treatment groups and a large degree of variability was observed. There was no significant change when comparing GSK256066 87.5 µg QD with placebo (1%), but there was an estimated 11% increase when comparing GSK256066 25 µg QD with placebo.

Statistical analysis of log-transformed data for IL-6 is presented in Table 8.

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Table 8 Summary of results of statistical analysis of log-transformed data for interleukin 6

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Analyte Placebo QD GSK256066 GSK256066 25 µg 87.5µg 25 µg QD 87.5 µg QD IL-6 18839 20814 18613 1.105 0.988 (pg/mL) (14037, (14843, (9753, 35521) (0.726, 1.680) (0.498, 1.961) 25285) 29186) Source data: Table 10.5 CI = confidence intervals, IL-6 = Interleukin 6, LS = least squares, QD = once daily

A plot of adjusted geometric means and 95% CIs of BAL IL-6 data (pg/mL) along with individual values is presented in Figure 4.

Figure 4 Plot of adjusted geometric means (95% confidence intervals) of bronchoalveolar lavage interleukin 6 data (pg/mL) with individual values

Source data: Figure 11.1

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Interleukin 8

A reduction in IL-8 compared with placebo was observed after GSK256066 87.5 µg QD (21%), whereas an estimated 9% increase was observed when comparing GSK256066 25 µg QD with placebo. Statistical analysis of log-transformed data for IL-8 is presented in Table 9.

Table 9 Summary of results of statistical analysis of log-transformed data for interleukin 8

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Analyte Placebo QD GSK256066 GSK256066 25 µg 87.5µg 25 µg QD 87.5 µg QD 14598 IL-8 13457 10657 1.085 0.792 (10307, (pg/mL) (9551, 18959) (7544, 15055) (0.664, 1.772) (0.488, 1.286) 20675) Source data: Table 10.5 CI = confidence interval, IL-8 = interleukin 8, LS = least squares, QD = once daily

There was no decrease in IL-8 levels across treatment groups. A plot of adjusted geometric means and 95% CIs of BAL IL-8 data (pg/mL) is presented in Figure 5.

Figure 5 Plot of adjusted geometric means (95% confidence intervals) of bronchoalveolar lavage interleukin 8 data (pg/mL) with individual values

Source data: Figure 11.1

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Myeloperoxidase

The largest decrease in MPO levels was observed when comparing GSK256066 87.5 µg QD with placebo (23%). An estimated 10% decrease in MPO levels was observed when comparing GSK256066 25 µg QD with placebo. However, no statistical evidence of a treatment effect was observed. Statistical analysis of log-transformed data for MPO is presented in Table 10.

Table 10 Summary of results of statistical analysis of log-transformed data for myeloperoxidase

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Analyte Placebo QD GSK256066 GSK256066 25 µg 87.5µg 25 µg QD 87.5 µg QD MPO 2278936 2047426 1761626 0.898 0.773 (pg/mL) (1483894, (1334941, (1154178, (0.486, 1.659) (0.686, 2.083) 3499945) 3140178) 2688776) Source data: Table 10.5 CI = confidence interval, LS = least squares, MPO = myeloperoxidase, QD = once daily

A plot of adjusted geometric means and 95% confidence intervals of BAL myeloperoxidase data (pg/mL) is presented in Figure 6.

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Figure 6 Plot of adjusted geometric means (95% confidence intervals) of bronchoalveolar lavage myeloperoxidase data (pg/mL) with individual values

Source Data: Figure 11.1

Tumour necrosis factor alpha

A trend for increased levels of TNF-α in the BAL was observed in subjects treated with GSK256066 87.5 µg QD compared with placebo, although the confidence intervals of the treatment ratios included 1. Statistical analysis of log-transformed data for TNF-α is presented in Table 11.

Table 11 Summary of results of statistical analysis of log-transformed data for tumour necrosis factor alpha

LS means GSK256066 dose – placebo (95% CI) treatment ratio (95% CI) Analyte Placebo QD GSK256066 GSK256066 25 µg 87.5µg 25 µg QD 87.5 µg QD TNF-α (pg/mL) 3087 4603 5091 1.491 1.649 (1727, 5516) (2574, 8231) (2849, 9099) (0.655, 3.392) (0.726, 3.748) Source data: Table 10.5 CI = confidence interval, LS = least squares, QD = once daily, TNF-α = tumour necrosis factor alpha

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Serum

There was a minimal difference in CC-16 levels between either dose of GSK256066 and placebo on Day 7. There was only a small decrease for GSK256066 87.5 µg QD compared with placebo on Day 8 (7%).

There was a 6% decrease in SP-D levels when comparing GSK256066 25 µg QD with placebo on Day 7. There was an 8% decrease when comparing GSK256066 87.5 µg with placebo, with this result being the only statistical evidence for a treatment effect (p=0.017). There were no significant changes in SP-D levels between either GSK256066 doses and placebo on Day 8.

Overall, serum biomarker data suggested that CC-16 and SP-D were not sensitive to this model as there was no large increase in the serum in any treatment group following LPS challenge compared with baseline levels. This could be due to the LPS challenge being segmental and not in the whole lung.

Pharmacokinetics

The BAL fluid samples obtained for determination of the primary endpoints were also used to determine concentrations of GSK256066 and the active metabolite GSK614917 in the BAL pellet and the BAL supernatant. Eight of 13 subjects in 25 µg group and six of 12 subjects in 87.5 µg group did not provide data due to insufficient sample for analysis. The metabolite GSK614917 was not quantifiable in any sample from subjects providing sufficient sample for analysis.

In those subjects providing data, GSK256066 was quantifiable at both 2 h and 26 h post- dose in the BAL pellet, whereas GSK256066 was quantifiable in all subjects at 2 h post- dose but not at 26 h in most subjects. Urea-corrected GSK256066 concentrations were at least an order of magnitude greater in the pellet than in the supernatant. GSK256066 concentrations in both pellet and supernatant did not consistently increase between 25 µg and 87.5 µg. There was evidence for a more rapid decline over time in GSK256066 concentrations in BAL supernatant compared to BAL pellet. Concentrations dropped by approximately half from 2 h to 26 h in the pellet whereas the decrease was in excess of 6- fold for the supernatant.

Relationship between Pharmacokinetics and Pharmacodynamic Parameters

A scatter plot of BAL total neutrophils against GSK256066 corrected BAL pellet concentration on Day 7 at 24 h post-LPS exposure is presented in Figure 7. Although the data was limited there was no evidence for a relationship between GSK256066 concentration in BAL pellet and neutrophil count. There was insufficient data for GSK256066 in BAL supernatant to evaluate.

1921 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711

Figure 7 Scatter plot of bronchoalveolar lavage total neutrophils (x106/mL) versus GSK256066 corrected bronchoalveolar lavage concentration (pg/mL) on Day 7 at 26 h lipopolysaccharide exposure

Source Data: Figure 14.1

Safety

Twenty-four subjects reported 28 AEs, which were all judged to be of mild or moderate intensity by the Investigator. This was not felt to be drug related by the Investigator. Four subjects reported pyrexia (three received GSK256066 25 µg and one received GSK256066 87.5 µg). All cases were concurrent with bronchoscopy and/or instillation of LPS. No occurrence of fever was deemed related to administration of study medication by the Investigator

• •

•

There was no evidence of an increase in white blood cell count in any of the subjects with pyrexia. All of these continued with the GSK256066 QD treatment according to the protocol. All AEs were resolved during the study. A summary of all AEs irrespective of causality is presented in Table 12.

2022 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711

Table 12 Summary of all adverse events irrespective of causality

Adverse event Placebo GSK256066 Dose 25 µg 87.5 µg N=12 N=13 N=12 N (%) N (%) N (%) Any Event 6 (50) 9 (62) 9 (75) Headache 4 (33) 0 5 (42) Cough 0 2 (15) 5 (42) Pyrexia 0 3 (23) 1 (9) Pleuritic Pain 1 (9) 0 2 (17) Bradycardia 0 1 (9) 1 (9) Fatigue 0 1 (9) 1 (9) Pharyngolaryngeal pain 0 1 (9) 1 (9) Procedural pain 0 1 (9) 1 (9) Rhinitis 1 (9) 0 1 (9) Atrioventricular block first degree 1 (9) 0 0 Chest Pain 1 (9) 0 0 Eczema 1 (9) 0 0 Sinus bradycardia 1 (9) 0 0 Upper respiratory tract infection 1 (9) 0 0 Chills 0 1 (9) 0 Dysmenorrhoea 0 1 (9) 0 Influenza-like illness 0 1 (9) 0 Oral herpes 0 1 (9) 0 Painful respiration 0 1 (9) 0 Pulmonary function test decreased 0 1 (9) 0 Respiratory tract infection 0 1 (9) 0 Body temperature increase 0 0 1 (9) Intercostal neuralgia 0 0 1 (9) Myalgia 0 0 1 (9) Non-cardiac chest pain 0 0 1 (9) Ventricular tachycardia 0 0 1 (9) Vertigo 0 0 1 (9) Source Data: Table 12.1

Drug-Related Adverse Events

A summary of drug related adverse events as judged by the Investigator is presented in Table 13.

2123 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711

Table 13 Summary of drug-related adverse events

Adverse event Placebo GSK256066 Dose QD 25 µg 87.5 µg (N=12) (N=13) (N=12) n(%) n(%) n(%) Any Event 2 (17) 2 (15) 6 (50) Cough 0 2 (15) 5 (42) Atrioventricular block first degree 1 (8) 0 0 Sinus bradycardia 1 (8) 0 0 Bradycardia 0 0 1 (8) Source Data: Table 12.2

Ten subjects experienced drug-related adverse events.

There were no serious AEs or AEs leading to withdrawal during the study.

Twelve-Lead Electrocardiogram

Electrocardiography abnormalities of potential clinical importance were reported in six subjects (Table 12.11). QTcF and QTcB intervals >450 ms and PR intervals outside 120 – 200 ms are listed below:

•

• •

• A summary of maximum electrocardiogram values meeting or exceeding pre-specified individual changes from baseline of category and treatment is presented in Table 14.

2224 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711

Table 14 Summary of maximum electrocardiogram values meeting or exceeding pre-specified individual changes from baseline of category and treatment

Interval Range Placebo GSK256066 Dose QD 25 µg 87.5 µg (N=12) (N=13) (N=12) n(%) n(%) n(%) QTcB (msec) >30 to ≤60 0 2 (15) 5 (42) >60 0 0 0 QTcF (msec) >30 to ≤60 0 0 2 (17) >60 0 0 0 Source Data: Table 12.7 QD = Once daily

Clinical Chemistry

Clinical chemistry test abnormalities of potential clinical importance were reported in 13 subjects (Table 12.12):

•

All of these subjects had elevated bilirubin values at screening, but these did not worsen with treatment. • All subsequent values were within the normal range.

Pharmacogenetic Results

Pharmacogenetic subject accountability data was summarised.

CONCLUSIONS

• There was no evidence of a statistically significant treatment effect for the primary endpoint, total neutrophil count at 24 h post-LPS exposure in subjects treated with GSK256066 25 µg or 87.5 µg compared to placebo. There was a trend toward reduction in total neutrophil count for both doses compared with placebo. GSK256066 25 µg QD gave the largest reduction at 39%.

2325 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711

• There was no statistically significant decrease in differential cell counts in BAL at 24 h post-LPS exposure in subjects treated with GSK256066 25 µg or 87.5 µg compared to placebo. There was a trend towards a reduction in total leukocyte count and % neutrophils for both doses compared with placebo. GSK256066 25 µg QD gave the greatest reduction for these endpoints. • Large variability was observed across all treatment groups, resulting in no statistical evidence of a treatment effect for any endpoints that were formally analysed, as the confidence intervals either contained zero for the treatment differences or 1 for the treatment ratios. • There was no statistical difference in levels of inflammatory biomarkers in BAL in subjects treated with GSK256066 25 µg or 87.5 µg compared with placebo. A trend towards a decrease in MPO and IL-8 concentration was observed for at least one GSK256066 dose compared with placebo; GSK256066 87.5 µg QD gave the largest reduction for these endpoints. • There was no statistical difference in the levels of inflammatory biomarkers CC-16 and SP-D in the serum of subjects treated with GSK256066 25 µg or 87.5 µg compared with placebo. Data for CC-16 and SP-D were not sensitive to this model as there was no increase in the serum in any treatment group following LPS challenge compared to baseline values. • Outliers were investigated for the BAL endpoints neutrophil count, total leukocyte count and % neutrophils and BAL biomarker IL-6. This made no change in the analysis and to the data variability. No further investigation was performed as there were no consistent outliers for the endpoints in the cell count data or the BAL biomarker data. • Urea-corrected GSK256066 concentrations were at least an order of magnitude greater and declined slower over time in the pellet than in the supernatant. The metabolite GSK614917 was not quantifiable in any sample. • GSK256066 25 µg and 87.5 µg QD were generally well tolerated in this population of healthy subjects. All adverse events were judged to be mild or moderate in intensity and no serious adverse events were reported in the study.

REFERENCES

Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, Schaumann F, Mueller M, Bredenbroeker D, Krug N and Hermann R. Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial. Pulm Pharmacol Ther. 2008; 21:616-23.

DATE OF REPORT

October 2008

2426 CONFIDENTIAL GM2008/00234/00 IPC103711

Study Population Data Source Tables

Page Table 9.1 Summary of Subject Disposition (All Subjects Population) ...... 28 Table 9.2 Summary of Demographic Characteristics (All Subjects Population) ...... 29 Table 9.3 Summary of Race and Racial Combination Details (All Subjects Population) ...... 31

27 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 9.1 Summary of Subject Disposition

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------Completion Status Completed 12 (100%) 13 (100%) 12 (100%) Prematurely Withdrawn 0 0 0 CONFIDENTIAL 28 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 2 Population: All Subjects Table 9.2 Summary of Demographic Characteristics

Placebo 066 25mcg QD 066 87.5mcg QD Total (N=12) (N=13) (N=12) (N=37) ------Age (yrs) n 12 13 12 37 Mean 34.0 29.0 29.2 30.7 SD 11.09 7.22 7.85 8.90 Median 30.0 30.0 27.5 29.0 Min. 21 19 20 19 Max. 50 41 47 50

Sex n 12 13 12 37 Female 4 (33%) 6 (46%) 5 (42%) 15 (41%)

Male 8 (67%) 7 (54%) 7 (58%) 22 (59%) CONFIDENTIAL

Ethnicity n 12 13 12 37 Hispanic/Latino 1 (8%) 0 0 1 (3%) 29 Not Hispanic/Latino 11 (92%) 13 (100%) 12 (100%) 36 (97%)

Height (cm) n 12 13 12 37 Mean 176.3 176.7 176.9 176.6 SD 8.67 7.44 8.59 8.00 Median 175.0 173.0 178.0 175.0 Min. 162 166 164 162 Max. 191 188 192 192

Weight (kg) n 12 13 12 37 Mean 76.6 72.9 73.3 74.2 SD 11.67 11.25 10.02 10.83 Median 79.5 73.0 72.0 73.0 Min. 59 60 57 57 GM2008/00234/00 Max. 98 98 88 98 IPC103711 IPC103711 Protocol: IPC103711 Page 2 of 2 Population: All Subjects Table 9.2 Summary of Demographic Characteristics

Placebo 066 25mcg QD 066 87.5mcg QD Total (N=12) (N=13) (N=12) (N=37) ------Body mass index (kg/m^2) n 12 13 12 37 Mean 24.510 23.297 23.345 23.706 SD 2.1124 2.8103 1.8565 2.3170 Median 24.595 21.770 23.675 24.090 Min. 20.42 19.92 20.20 19.92 Max. 27.47 29.26 25.54 29.26 CONFIDENTIAL 30 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 9.3 Summary of Race and Racial Combination Details

Placebo 066 25mcg QD 066 87.5mcg QD Total Race (N=12) (N=13) (N=12) (N=37) ------n 12 13 12 37 African American/African Heritage 0 0 0 0 American Indian or Alaska Native 0 0 0 0 Asian - Central/South Asian Heritage 0 0 0 0 Asian - East Asian Heritage 0 0 0 0 Asian - Japanese Heritage 0 0 0 0 Asian - South East Asian Heritage 0 0 0 0 Asian - Mixed Race 0 0 0 0 Native Hawaiian or other Pacific 0 0 0 0

Islander CONFIDENTIAL White - Arabic/North African 0 1 (8%) 0 1 (3%) Heritage White - White/Caucasian/European 12 (100%) 12 (92%) 12 (100%) 36 (97%) 31 Heritage White - Mixed Race 0 0 0 0 Mixed Race 0 0 0 0 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 CONFIDENTIAL GM2008/00234/00 IPC103711

Pharmacodynamic Data Source Figures and Tables

Page Figure 10.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Total Number of Neutrophils (x10^6/mL) along with Individual Values...... 34 Figure 10.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Total Number of Neutrophils /mL ...... 35 Figure 10.3 Plot of Adjusted Means and 95% CIs of BAL Percentage of Neutrophils along with Individual values ...... 36 Figure 10.4 Plot of Adjusted Treatment Differences and 95% CIs of BAL Percentage of Neutrophils ...... 37 Figure 10.5 Plot of Adjusted Means and 95% CIs of BAL Total Number of Eosinophils (x10^6/mL) along with Individual Values ...... 38 Figure 10.6 Plot of Adjusted Treatment Differences and 95% CIs of BAL Total Number of Eosinophils /mL ...... 39 Figure 10.7 Plot of Adjusted Means and 95% CIs of BAL Percentage of Eosinophils ...... 40 Figure 10.8 Plot of Adjusted Treatment Differences and 95% CIs of BAL Percentage of Eosinophils ...... 41 Figure 10.9 Plot of Adjusted Geometric Means and 95% CIs of BAL Total Number of Macrophages (x10^6/mL) along with Individual Values . . . . . 42 Figure 10.10 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Total Number of Macrophages /mL ...... 43 Figure 10.11 Plot of Adjusted Means and 95% CIs of BAL Percentage of Macrophages ...... 44 Figure 10.12 Plot of Adjusted Treatment Differences and 95% CIs of BAL Percentage of Macrophages ...... 45 Figure 10.13 Plot of Individual BAL Total Number of Monocytes (x10^6/mL) . 46 Figure 10.14 Plot of Individual BAL Percentage of Monocytes ...... 47 Figure 10.15 Plot of Individual BAL Total Number of Lymphocytes (x10^6/mL) ...... 48 Figure 10.16 Plot of Individual BAL percentage of Lymphocytes ...... 49 Figure 10.17 Plot of Individual BAL Total Number of Bronchial Epithelial Cells (x10^6/mL) ...... 50

32 CONFIDENTIAL GM2008/00234/00 IPC103711

Figure 10.18 Plot of Individual BAL Percentage of Bronchial Epithelial cells . 51 Figure 10.19 Plot of Adjusted Geometric Means and 95% CIs of BAL Total Leukocyte Count (x10^6/mL) along with Individual Values ...... 52 Figure 10.20 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Total Leukocyte Count ...... 53 Figure 10.21 Mean Plots of BAL Total Number of Monocytes (x10^3/mL) by Flow Cytometry ...... 54 Figure 10.22 Mean Plots of BAL Percentage of Monocytes by Flow Cytometry ...... 55 Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type (Per-protocol Population) ...... 56 Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type (Per-protocol Population) ...... 62 Table 10.3 Summary of Results of Statistical Analysis of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type (Per-protocol Population) ...... 68 Table 10.4 Summary of Results of Statistical Analysis of BAL Percentage Cell Count Data by Inflammatory Cell Type (Per-protocol Population) . . . 72 Table 10.5 Summary of BAL Total Number of Monocytes (x10^3/mL) by Flow Cytometry (Per-protocol Population) ...... 76 Table 10.6 Summary of BAL Percentage of Monocytes by Flow Cytometry (Per-protocol Population) ...... 78

33 Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Total Number of Neutrophils (x10^6/mL) along with Individual Values

7.4

2.7 CONFIDENTIAL

1 34

0.368

0.135 Total Number of Neutrophils (log base e scale) 0.050 GM2008/00234/00 IPC103711 IPC103711 0.018 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Total Number of Neutrophils /mL

2.7 CONFIDENTIAL

1 35

0.368 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.135 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.3 Plot of Adjusted Means and 95% CIs of BAL Percentage of Neutrophils along with Individual values

100

80 CONFIDENTIAL

70 36 60

40 Percentage of Neutrophils 30

20 GM2008/00234/00 GM2008/00234/00

10 IPC103711 IPC103711 0 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.4 Plot of Adjusted Treatment Differences and 95% CIs of BAL Percentage of Neutrophils

12 10 8 6

4 CONFIDENTIAL 2

37 0 -2 -4 -6 -8 Treatment Difference -10 -12 -14 GM2008/00234/00 GM2008/00234/00 -16 -18 IPC103711 IPC103711 -20 066 25mcg QD - Placebo 066 87.5mcg QD - Placebo Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.5 Plot of Adjusted Means and 95% CIs of BAL Total Number of Eosinophils (x10^6/mL) along with Individual Values

0.10

0.09

0.08 CONFIDENTIAL 0.07

38 0.06

0.05

0.04

0.03 Total Number of Eosinophils (x10^6/mL) 0.02 GM2008/00234/00 GM2008/00234/00

0.01 IPC103711 IPC103711 0.00 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.6 Plot of Adjusted Treatment Differences and 95% CIs of BAL Total Number of Eosinophils /mL

0.03

0.02 CONFIDENTIAL

0.01 39

0.00 Treatment Difference -0.01

-0.02 GM2008/00234/00 IPC103711 IPC103711 -0.03 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.7 Plot of Adjusted Means and 95% CIs of BAL Percentage of Eosinophils

3.0

2.5 CONFIDENTIAL

2.0 40

1.5

1.0 Percentage of Eosinophils

0.5 GM2008/00234/00 IPC103711 IPC103711 0.0 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.8 Plot of Adjusted Treatment Differences and 95% CIs of BAL Percentage of Eosinophils

0.6

0.4

0.2 CONFIDENTIAL

41 0.0

-0.2

-0.4 Treatment Difference

-0.6 GM2008/00234/00 GM2008/00234/00 -0.8 IPC103711 IPC103711 -1.0 066 25mcg QD - Placebo 066 87.5mcg QD - Placebo Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.9 Plot of Adjusted Geometric Means and 95% CIs of BAL Total Number of Macrophages (x10^6/mL) along with Individual Values

0.368 CONFIDENTIAL 42

0.135

0.050 GM2008/00234/00 GM2008/00234/00 Total Number of Macrophages (log base e scale) IPC103711 IPC103711 0.018 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.10 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Total Number of Macrophages /mL

2.7 CONFIDENTIAL 43

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.11 Plot of Adjusted Means and 95% CIs of BAL Percentage of Macrophages

148

54.6 CONFIDENTIAL 44 20.1

7.4 Percentage of Macrophages

2.7 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 1 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.12 Plot of Adjusted Treatment Differences and 95% CIs of BAL Percentage of Macrophages

3.0

2.5 CONFIDENTIAL

45 2.0

1.5 Adjusted Treatment Differences

1.0 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.5 066 25mcg QD - Placebo 066 87.5mcg QD - Placebo Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.13 Plot of Individual BAL Total Number of Monocytes (x10^6/mL)

0.368 CONFIDENTIAL

0.135 46

0.050

0.018 Total Number of Monocytes (log base e scale) 0.0067 GM2008/00234/00 IPC103711 IPC103711 0.0025 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.14 Plot of Individual BAL Percentage of Monocytes

22 CONFIDENTIAL

20 47 18

Percentage of Monocytes 10

6 GM2008/00234/00 GM2008/00234/00 4

2 IPC103711 IPC103711 0 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.15 Plot of Individual BAL Total Number of Lymphocytes (x10^6/mL)

0.30

0.25 CONFIDENTIAL

0.20 48

0.15

0.10 Total Number of Lymphocytes (x10^6/mL)

0.05 GM2008/00234/00 IPC103711 IPC103711 0.00 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.16 Plot of Individual BAL percentage of Lymphocytes

18 CONFIDENTIAL 16

14 49

Percentage of Lymphocytes % 6

4 GM2008/00234/00

2 IPC103711 IPC103711 0 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.17 Plot of Individual BAL Total Number of Bronchial Epithelial Cells (x10^6/mL)

0.0250

0.0188 CONFIDENTIAL 50

0.0125

0.0063 GM2008/00234/00 GM2008/00234/00 Total Number of Bronchial Epithelial Cells (x10^6/mL) IPC103711 IPC103711 0.0000 Placebo 066 25mcg QD 066 87.5mcg QD Treatment NOTE: Values of zero were recorded by 8 subjects in Placebo, 7 subjects in 066 25mcg QD and 10 subjects in 066 87.5mcg QD Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.18 Plot of Individual BAL Percentage of Bronchial Epithelial cells

2.0

1.5 CONFIDENTIAL 51

1.0 Percentage of Epithelials %

0.5 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.0 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.19 Plot of Adjusted Geometric Means and 95% CIs of BAL Total Leukocyte Count (x10^6/mL) along with Individual Values

7.4

2.7 CONFIDENTIAL 52 1

0.368

Total Leukocyte Count (log base e scale) 0.135 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.050 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.20 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Total Leukocyte Count

2.7 CONFIDENTIAL

1 53

0.368 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.135 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 10.21 Mean Plots of BAL Total Number of Monocytes (x10^3/mL) by Flow Cytometry

1097

403 CONFIDENTIAL 148 54

54.6

20.1

7.4 CD14+ Monocyte Count (log base e scale) GM2008/00234/00 GM2008/00234/00 2.7 IPC103711 IPC103711 1 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 1 Population: All Subjects Figure 10.22 Mean Plots of BAL Percentage of Monocytes by Flow Cytometry

22 CONFIDENTIAL

20 55 18

6 Percentage of Percent CD14 pos. Monocytes GM2008/00234/00 GM2008/00234/00 4

2 IPC103711 IPC103711 0 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 6 Population: Per-protocol Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type

Planned Relative Arithmetic Analyte Treatment N Time n Mean SD Median Minimum Maximum ------

Lymphocyte Count Placebo 12 2 H 12 0.0053 0.00470 0.0036 0.0006 0.0165 26 H SALINE 12 0.0085 0.00663 0.0062 0.0005 0.0185 26 H LPS 12 0.0703 0.05184 0.0502 0.0089 0.1826

066 25mcg QD 12 2 H 12 0.0067 0.00562 0.0050 0.0012 0.0204 26 H SALINE 12 0.0068 0.00613 0.0055 0.0009 0.0211 26 H LPS 12 0.0517 0.04728 0.0402 0.0000 0.1538 CONFIDENTIAL 066 87.5mcg QD 12 2 H 12 0.0048 0.00726 0.0019 0.0005 0.0256 26 H SALINE 12 0.0074 0.00582 0.0058 0.0013 0.0213 26 H LPS 12 0.0807 0.07054 0.0566 0.0057 0.2519 56 Macrophage Count Placebo 12 2 H 12 0.0903 0.03829 0.1014 0.0244 0.1350 26 H SALINE 12 0.1025 0.04953 0.0975 0.0403 0.1800 26 H LPS 12 0.2249 0.15292 0.1882 0.0428 0.5065

066 25mcg QD 12 2 H 12 0.0897 0.04653 0.0762 0.0348 0.2085 26 H SALINE 12 0.0972 0.05576 0.0754 0.0388 0.2490 26 H LPS 12 0.1966 0.09809 0.1796 0.0515 0.3442

066 87.5mcg QD 12 2 H 12 0.0653 0.02883 0.0662 0.0251 0.0999 26 H SALINE 12 0.0855 0.04697 0.0712 0.0421 0.2051 26 H LPS 12 0.2499 0.15531 0.1895 0.0863 0.5633

Monocyte Count Placebo 12 2 H 12 0.0032 0.00231 0.0027 0.0002 0.0078 GM2008/00234/00 26 H SALINE 12 0.0052 0.00529 0.0036 0.0012 0.0204 26 H LPS 12 0.1811 0.12133 0.1905 0.0089 0.4363 IPC103711 IPC103711 066 25mcg QD 12 2 H 12 0.0030 0.00160 0.0031 0.0011 0.0063 26 H SALINE 12 0.0045 0.00305 0.0046 0.0010 0.0111

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 2 of 6 Population: Per-protocol Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type

Planned Relative Arithmetic Analyte Treatment N Time n Mean SD Median Minimum Maximum ------

Monocyte Count 066 25mcg QD 12 26 H LPS 12 0.1453 0.19578 0.0525 0.0074 0.6808

066 87.5mcg QD 12 2 H 12 0.0026 0.00386 0.0015 0.0005 0.0147 26 H SALINE 12 0.0036 0.00339 0.0025 0.0009 0.0133 26 H LPS 12 0.1500 0.18356 0.0720 0.0057 0.5704

Neutrophil Count Placebo 12 2 H 12 0.0017 0.00212 0.0010 0.0003 0.0075

26 H SALINE 12 0.0109 0.01778 0.0037 0.0008 0.0571 CONFIDENTIAL 26 H LPS 12 1.0819 0.70720 0.9566 0.4391 2.9838

066 25mcg QD 12 2 H 12 0.0009 0.00060 0.0008 0.0000 0.0020 57 26 H SALINE 12 0.0111 0.02556 0.0039 0.0014 0.0921 26 H LPS 12 1.2134 1.06654 1.0136 0.0229 2.9954

066 87.5mcg QD 12 2 H 12 0.0004 0.00046 0.0002 0.0000 0.0013 26 H SALINE 12 0.0075 0.01226 0.0021 0.0006 0.0417 26 H LPS 12 1.0698 1.02726 0.7682 0.0817 3.5795

Total Leukocyte Placebo 12 2 H 12 0.1011 0.04338 0.1127 0.0287 0.1525 Count 26 H SALINE 12 0.1276 0.06912 0.1162 0.0528 0.2721 26 H LPS 12 1.5711 0.84538 1.3252 0.6841 3.6928

066 25mcg QD 12 2 H 12 0.1009 0.04761 0.0891 0.0387 0.2206 26 H SALINE 12 0.1202 0.06780 0.0889 0.0663 0.2635 GM2008/00234/00 26 H LPS 12 1.6212 1.25127 1.3872 0.1131 3.8901

066 87.5mcg QD 12 2 H 12 0.0736 0.03526 0.0771 0.0269 0.1361 IPC103711 26 H SALINE 12 0.1053 0.06315 0.0983 0.0481 0.2779 26 H LPS 12 1.5608 1.30683 1.0865 0.3892 4.7536

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 3 of 6 Population: Per-protocol Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type

Planned Geometric 95% CI SD CVb(%) Analyte Treatment N Relative Time n Mean Geometric Mean logs [1] ------

Lymphocyte Count Placebo 12 2 H 12 0.0035 ( 0.0018, 0.0068) 1.046 140.8 26 H SALINE 12 0.0057 ( 0.0029, 0.0113) 1.071 146.7 26 H LPS 12 0.0535 ( 0.0317, 0.0903) 0.825 98.7

066 25mcg QD 12 2 H 12 0.0048 ( 0.0027, 0.0084) 0.877 107.6 26 H SALINE 12 0.0047 ( 0.0026, 0.0086) 0.944 120.0 26 H LPS 11 0.0383 ( 0.0192, 0.0763) 1.027 136.8

066 87.5mcg QD 12 2 H 12 0.0023 ( 0.0011, 0.0049) 1.200 179.6 CONFIDENTIAL 26 H SALINE 12 0.0055 ( 0.0032, 0.0095) 0.862 105.0 26 H LPS 12 0.0543 ( 0.0283, 0.1042) 1.025 136.3

58 Macrophage Count Placebo 12 2 H 12 0.0804 ( 0.0566, 0.1141) 0.551 59.6 26 H SALINE 12 0.0915 ( 0.0662, 0.1264) 0.509 54.4 26 H LPS 12 0.1782 ( 0.1109, 0.2864) 0.746 86.4

066 25mcg QD 12 2 H 12 0.0809 ( 0.0602, 0.1086) 0.464 49.0 26 H SALINE 12 0.0865 ( 0.0637, 0.1175) 0.481 51.1 26 H LPS 12 0.1703 ( 0.1163, 0.2494) 0.600 65.9

066 87.5mcg QD 12 2 H 12 0.0586 ( 0.0424, 0.0811) 0.511 54.6 26 H SALINE 12 0.0766 ( 0.0568, 0.1032) 0.469 49.6 26 H LPS 12 0.2123 ( 0.1459, 0.3088) 0.590 64.5

Monocyte Count Placebo 12 2 H 12 0.0022 ( 0.0011, 0.0044) 1.105 154.6 26 H SALINE 12 0.0037 ( 0.0023, 0.0062) 0.788 92.8 GM2008/00234/00 26 H LPS 12 0.1225 ( 0.0585, 0.2561) 1.161 168.9

066 25mcg QD 12 2 H 12 0.0027 ( 0.0019, 0.0038) 0.562 60.9 IPC103711 26 H SALINE 12 0.0035 ( 0.0021, 0.0059) 0.829 99.4 26 H LPS 12 0.0673 ( 0.0287, 0.1577) 1.340 224.2

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 4 of 6 Population: Per-protocol Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type

Planned Geometric 95% CI SD CVb(%) Analyte Treatment N Relative Time n Mean Geometric Mean logs [1] ------

Monocyte Count 066 87.5mcg QD 12 2 H 12 0.0017 ( 0.0010, 0.0029) 0.865 105.6 26 H SALINE 12 0.0027 ( 0.0017, 0.0044) 0.741 85.6 26 H LPS 12 0.0773 ( 0.0341, 0.1754) 1.290 206.8

Neutrophil Count Placebo 12 2 H 12 0.0010 ( 0.0005, 0.0019) 1.033 138.2 26 H SALINE 12 0.0044 ( 0.0020, 0.0101) 1.288 206.2 26 H LPS 12 0.9229 ( 0.6422, 1.3265) 0.571 62.1

066 25mcg QD 12 2 H 11 0.0009 ( 0.0006, 0.0013) 0.604 66.3 CONFIDENTIAL 26 H SALINE 12 0.0044 ( 0.0022, 0.0088) 1.076 147.7 26 H LPS 12 0.5673 ( 0.1968, 1.6353) 1.666 388.1

59 066 87.5mcg QD 12 2 H 7 0.0005 ( 0.0003, 0.0010) 0.717 81.9 26 H SALINE 12 0.0032 ( 0.0014, 0.0071) 1.260 197.4 26 H LPS 12 0.6863 ( 0.3508, 1.3430) 1.057 143.3

Total Leukocyte Placebo 12 2 H 12 0.0900 ( 0.0636, 0.1275) 0.548 59.2 Count 26 H SALINE 12 0.1112 ( 0.0783, 0.1580) 0.553 59.7 26 H LPS 12 1.4004 ( 1.0253, 1.9129) 0.491 52.2

066 25mcg QD 12 2 H 12 0.0921 ( 0.0694, 0.1222) 0.445 46.8 26 H SALINE 12 0.1072 ( 0.0795, 0.1446) 0.471 49.8 26 H LPS 12 1.0567 ( 0.5201, 2.1470) 1.116 157.3

066 87.5mcg QD 12 2 H 12 0.0650 ( 0.0459, 0.0919) 0.546 58.9 GM2008/00234/00 26 H SALINE 12 0.0932 ( 0.0684, 0.1269) 0.487 51.7 26 H LPS 12 1.1744 ( 0.7164, 1.9253) 0.778 91.2 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 5 of 6 Population: Per-protocol Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type

Planned Relative Arith 95% CI Analyte Treatment N Time n Mean Arith Mean SD Median Minimum Maximum ------

Eosinophil Placebo 12 2 H 12 0.000 ( -0.000, 0.000) 0.0004 0.000 0.00 0.00 Count 26 H SALINE 12 0.000 ( 0.000, 0.001) 0.0005 0.000 0.00 0.00 26 H LPS 12 0.011 ( 0.004, 0.019) 0.0119 0.006 0.00 0.04

066 25mcg QD 12 2 H 12 0.000 ( 0.000, 0.000) 0.0002 0.000 0.00 0.00 26 H SALINE 12 0.000 ( 0.000, 0.000) 0.0003 0.000 0.00 0.00

26 H LPS 12 0.014 ( 0.002, 0.027) 0.0199 0.010 0.00 0.07 CONFIDENTIAL

066 87.5mcg QD 12 2 H 12 0.000 ( 0.000, 0.000) 0.0003 0.000 0.00 0.00 26 H SALINE 12 0.000 ( -0.000, 0.001) 0.0008 0.000 0.00 0.00 60 26 H LPS 12 0.012 ( 0.004, 0.021) 0.0130 0.010 0.00 0.05 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 6 of 6 Population: Per-protocol Table 10.1 Summary of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type

Planned Relative Lower Upper Analyte Treatment N Time n Median Minimum Quartile Quartile Maximum ------

Bronchial Placebo 12 2 H 12 0.000 0.000 0.000 0.001 0.002 Epithelial Cell Count 26 H SALINE 12 0.000 0.000 0.000 0.000 0.001 26 H LPS 12 0.000 0.000 0.000 0.002 0.022

066 25mcg QD 12 2 H 12 0.000 0.000 0.000 0.001 0.002

26 H SALINE 12 0.000 0.000 0.000 0.001 0.001 CONFIDENTIAL 26 H LPS 12 0.000 0.000 0.000 0.004 0.012

066 87.5mcg QD 12 2 H 12 0.000 0.000 0.000 0.000 0.002 61 26 H SALINE 12 0.000 0.000 0.000 0.001 0.008 26 H LPS 12 0.000 0.000 0.000 0.000 0.003 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 1 of 6 Population: Per-protocol Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type

Planned 95% CI Relative Arith. Arithmetic Analyte Treatment N Time n Mean Mean SD Median Min. Max. ------

% Eosinophils Placebo 12 2 H 12 0.18 (-0.02, 0.37) 0.311 0.00 0.0 1.0 26 H SALINE 12 0.28 ( 0.12, 0.43) 0.249 0.30 0.0 0.8 26 H LPS 12 0.78 ( 0.34, 1.21) 0.680 0.65 0.0 1.8

066 25mcg QD 12 2 H 12 0.12 ( 0.00, 0.23) 0.180 0.00 0.0 0.5 26 H SALINE 12 0.25 ( 0.08, 0.42) 0.261 0.30 0.0 0.8 26 H LPS 12 0.59 ( 0.23, 0.95) 0.566 0.40 0.0 1.8 CONFIDENTIAL 066 87.5mcg 12 2 H 12 0.23 ( 0.05, 0.40) 0.270 0.15 0.0 0.8 QD 26 H SALINE 12 0.36 ( 0.05, 0.67) 0.491 0.30 0.0 1.8 62 26 H LPS 12 0.86 ( 0.33, 1.39) 0.839 0.80 0.0 2.8

% Epithelials Placebo 12 2 H 12 0.57 ( 0.24, 0.90) 0.521 0.50 0.0 1.5 26 H SALINE 12 0.16 (-0.04, 0.36) 0.312 0.00 0.0 0.8 26 H LPS 12 0.31 (-0.07, 0.69) 0.601 0.00 0.0 1.8

066 25mcg QD 12 2 H 12 0.69 ( 0.18, 1.21) 0.811 0.50 0.0 2.7 26 H SALINE 12 0.38 ( 0.16, 0.61) 0.359 0.40 0.0 1.0 26 H LPS 12 0.16 ( 0.03, 0.29) 0.207 0.00 0.0 0.5

066 87.5mcg 12 2 H 12 0.58 ( 0.13, 1.04) 0.721 0.40 0.0 2.3 QD 26 H SALINE 12 0.60 ( 0.01, 1.19) 0.931 0.00 0.0 2.8 26 H LPS 12 0.07 (-0.04, 0.17) 0.161 0.00 0.0 0.5 GM2008/00234/00

% Lymphocytes Placebo 12 2 H 12 5.43 ( 3.30, 7.56) 3.355 5.75 0.5 10.8

26 H SALINE 12 6.43 ( 4.03, 8.84) 3.784 6.40 0.8 13.8 IPC103711 26 H LPS 12 4.57 ( 2.78, 6.35) 2.806 4.15 1.3 10.8

066 25mcg QD 12 2 H 12 7.05 ( 3.28,10.82) 5.939 6.00 0.8 23.3 Protocol: IPC103711 Page 2 of 6 Population: Per-protocol Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type

Planned 95% CI Relative Arith. Arithmetic Analyte Treatment N Time n Mean Mean SD Median Min. Max. ------

% Lymphocytes 066 25mcg QD 12 26 H SALINE 12 6.80 ( 1.42,12.18) 8.467 3.90 1.3 31.8 26 H LPS 12 5.87 ( 1.92, 9.83) 6.223 4.00 0.0 20.3

066 87.5mcg 12 2 H 12 5.26 ( 1.74, 8.78) 5.543 3.15 1.3 18.8 QD 26 H SALINE 12 7.38 ( 4.19,10.58) 5.024 8.30 1.3 20.0 26 H LPS 12 5.58 ( 3.88, 7.29) 2.678 5.30 0.5 10.8 CONFIDENTIAL % Macrophages Placebo 12 2 H 12 89.37 (86.88,91.85) 3.907 88.90 85.0 94.8 26 H SALINE 12 83.01 (75.85,90.17) 11.264 86.00 59.5 94.8 26 H LPS 12 15.11 (10.17,20.05) 7.773 14.65 2.5 29.5 63 066 25mcg QD 12 2 H 12 88.14 (83.55,92.73) 7.223 88.90 68.3 95.5 26 H SALINE 12 81.96 (73.19,90.72) 13.795 87.90 51.3 94.8 26 H LPS 12 21.80 (10.66,32.94) 17.527 12.90 3.3 60.0

066 87.5mcg 12 2 H 12 90.57 (85.57,95.58) 7.874 92.55 69.5 96.8 QD 26 H SALINE 12 82.76 (76.60,88.92) 9.696 85.55 62.3 93.5 26 H LPS 12 22.47 (11.82,33.11) 16.755 17.50 4.8 66.3

% Monocytes Placebo 12 2 H 12 3.03 ( 1.96, 4.09) 1.673 2.80 0.3 5.8 26 H SALINE 12 3.63 ( 2.64, 4.62) 1.558 3.45 1.8 7.5 26 H LPS 12 12.79 ( 7.25,18.34) 8.725 14.25 1.0 25.8 GM2008/00234/00 GM2008/00234/00 066 25mcg QD 12 2 H 12 3.19 ( 2.23, 4.16) 1.521 2.65 1.3 6.3 26 H SALINE 12 3.73 ( 2.54, 4.93) 1.883 3.90 1.3 6.8

26 H LPS 12 9.36 ( 5.36,13.36) 6.300 9.15 0.8 20.3 IPC103711

066 87.5mcg 12 2 H 12 3.02 ( 1.42, 4.62) 2.520 2.40 1.5 10.8 QD Protocol: IPC103711 Page 3 of 6 Population: Per-protocol Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type

Planned 95% CI Relative Arith. Arithmetic Analyte Treatment N Time n Mean Mean SD Median Min. Max. ------

% Monocytes 066 87.5mcg 12 26 H SALINE 12 3.23 ( 2.30, 4.17) 1.474 2.65 1.8 6.0 QD 26 H LPS 12 9.56 ( 5.30,13.81) 6.699 9.00 0.5 24.3

% Neutrophils Placebo 12 2 H 12 1.57 ( 0.68, 2.45) 1.391 1.15 0.3 5.0 26 H SALINE 12 6.57 ( 1.71,11.42) 7.646 2.80 1.3 23.5 26 H LPS 12 66.59 (60.24,72.94) 9.996 67.50 50.3 84.8 CONFIDENTIAL 066 25mcg QD 12 2 H 12 0.92 ( 0.52, 1.31) 0.626 0.80 0.0 2.5 26 H SALINE 12 7.00 ( 0.71,13.29) 9.899 4.00 0.8 37.3 26 H LPS 12 62.36 (47.42,77.30) 23.515 69.00 6.3 88.3 64 066 87.5mcg 12 2 H 12 0.48 ( 0.16, 0.79) 0.496 0.50 0.0 1.3 QD 26 H SALINE 12 5.82 ( 1.33,10.30) 7.057 2.15 1.3 23.0 26 H LPS 12 61.61 (50.65,72.57) 17.248 65.15 21.0 80.0 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 4 of 6 Population: Per-protocol Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type

Planned Geometric 95% CI SD CVb(%) Analyte Treatment N Relative Time n Mean Geometric Mean logs [1] ------

% Eosinophils Placebo 12 2 H 4 0.46 ( 0.19, 1.14) 0.57 62.0 26 H SALINE 8 0.39 ( 0.28, 0.53) 0.37 38.8 26 H LPS 9 0.88 ( 0.54, 1.43) 0.64 71.1

066 25mcg QD 12 2 H 4 0.34 ( 0.23, 0.51) 0.26 26.0 26 H SALINE 7 0.40 ( 0.28, 0.57) 0.39 40.5 26 H LPS 9 0.65 ( 0.39, 1.09) 0.68 76.1

066 87.5mcg QD 12 2 H 6 0.42 ( 0.27, 0.64) 0.40 42.1 CONFIDENTIAL 26 H SALINE 8 0.43 ( 0.25, 0.72) 0.63 69.3 26 H LPS 9 0.94 ( 0.56, 1.58) 0.67 75.6

65 % Epithelials Placebo 12 2 H 8 0.76 ( 0.49, 1.19) 0.53 57.1 26 H SALINE 3 0.58 ( 0.14, 2.36) 0.57 61.5 26 H LPS 4 0.68 ( 0.15, 3.07) 0.95 121.0

066 25mcg QD 12 2 H 10 0.61 ( 0.36, 1.04) 0.74 84.7 26 H SALINE 8 0.52 ( 0.36, 0.77) 0.46 48.3 26 H LPS 5 0.37 ( 0.26, 0.52) 0.28 28.5

066 87.5mcg QD 12 2 H 9 0.58 ( 0.32, 1.03) 0.76 87.8 26 H SALINE 5 1.14 ( 0.40, 3.25) 0.84 101.5 26 H LPS 2 0.39 ( 0.02, 9.94) 0.36 37.3

% Lymphocytes Placebo 12 2 H 12 3.89 ( 2.00, 7.57) 1.05 141.3 26 H SALINE 12 5.14 ( 3.10, 8.53) 0.80 94.1 GM2008/00234/00 26 H LPS 12 3.82 ( 2.54, 5.74) 0.64 71.3

066 25mcg QD 12 2 H 12 5.20 ( 3.00, 9.00) 0.86 105.5 IPC103711 26 H SALINE 12 4.38 ( 2.47, 7.76) 0.90 111.9 26 H LPS 11 3.98 ( 1.83, 8.63) 1.15 166.7 Protocol: IPC103711 Page 5 of 6 Population: Per-protocol Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type

Planned Geometric 95% CI SD CVb(%) Analyte Treatment N Relative Time n Mean Geometric Mean logs [1] ------

% Lymphocytes 066 87.5mcg QD 12 2 H 12 3.53 ( 2.01, 6.20) 0.88 108.9 26 H SALINE 12 5.87 ( 3.64, 9.46) 0.75 87.2 26 H LPS 12 4.63 ( 2.80, 7.65) 0.79 93.4

% Macrophages Placebo 12 2 H 12 89.29 (86.85,91.79) 0.04 4.4 26 H SALINE 12 82.23 (74.87,90.31) 0.15 14.8 26 H LPS 12 12.73 ( 8.21,19.74) 0.69 78.2

066 25mcg QD 12 2 H 12 87.84 (83.01,92.95) 0.09 8.9 CONFIDENTIAL 26 H SALINE 12 80.69 (71.37,91.23) 0.19 19.5 26 H LPS 12 16.12 ( 9.46,27.47) 0.84 101.1

66 066 87.5mcg QD 12 2 H 12 90.22 (84.94,95.84) 0.10 9.5 26 H SALINE 12 82.20 (75.99,88.92) 0.12 12.4 26 H LPS 12 18.08 (11.64,28.07) 0.69 78.5

% Monocytes Placebo 12 2 H 12 2.44 ( 1.47, 4.07) 0.80 95.4 26 H SALINE 12 3.37 ( 2.61, 4.35) 0.40 42.0 26 H LPS 12 8.74 ( 4.36,17.52) 1.09 152.0

066 25mcg QD 12 2 H 12 2.89 ( 2.15, 3.88) 0.46 49.1 26 H SALINE 12 3.24 ( 2.24, 4.70) 0.58 63.5 26 H LPS 12 6.37 ( 3.15,12.86) 1.11 154.9

066 87.5mcg QD 12 2 H 12 2.54 ( 1.81, 3.56) 0.53 57.0 26 H SALINE 12 2.94 ( 2.21, 3.92) 0.45 47.2 GM2008/00234/00 26 H LPS 12 6.58 ( 3.26,13.30) 1.11 155.0

% Neutrophils Placebo 12 2 H 12 1.12 ( 0.64, 1.95) 0.87 106.6 IPC103711 26 H SALINE 12 3.99 ( 2.13, 7.47) 0.99 128.2 26 H LPS 12 65.90 (59.88,72.54) 0.15 15.2 Protocol: IPC103711 Page 6 of 6 Population: Per-protocol Table 10.2 Summary of BAL Percentage Cell Data by Inflammatory Cell Type

Planned Geometric 95% CI SD CVb(%) Analyte Treatment N Relative Time n Mean Geometric Mean logs [1] ------

% Neutrophils 066 25mcg QD 12 2 H 11 0.88 ( 0.61, 1.26) 0.54 58.4 26 H SALINE 12 4.13 ( 2.19, 7.80) 1.00 131.3 26 H LPS 12 53.69 (33.79,85.32) 0.73 83.7

066 87.5mcg QD 12 2 H 7 0.75 ( 0.51, 1.12) 0.43 45.0 26 H SALINE 12 3.43 ( 1.82, 6.44) 0.99 129.6 26 H LPS 12 58.44 (45.98,74.27) 0.38 39.1 CONFIDENTIAL 67 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 4 Population: Per-protocol Table 10.3 Summary of Results of Statistical Analysis of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type Adjusted Geometric Means

Adjusted Geometric 95% CI of Adjusted Analyte Treatment N n Mean (SE logs) Geometric Means ------

Macrophage Count Placebo 12 12 0.18 (0.191) ( 0.12, 0.26) 066 25mcg QD 12 12 0.17 (0.190) ( 0.12, 0.25) 066 87.5mcg QD 12 12 0.21 (0.192) ( 0.14, 0.31)

Neutrophil Count Placebo 12 12 0.95 (0.153) ( 0.67, 1.33) 066 25mcg QD 12 12 0.58 (0.473) ( 0.21, 1.65)

066 87.5mcg QD 12 12 0.65 (0.293) ( 0.34, 1.25) CONFIDENTIAL

Total Leukocyte Count Placebo 12 12 1.43 (0.140) ( 1.05, 1.95) 066 25mcg QD 12 12 1.07 (0.337) ( 0.51, 2.25) 68 066 87.5mcg QD 12 12 1.14 (0.216) ( 0.71, 1.84) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 2 of 4 Population: Per-protocol Table 10.3 Summary of Results of Statistical Analysis of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type Treatment Ratios

Ratio of Adjusted Geometric Means Analyte Treatment Comparison (SE logs) 95% CI of Ratio p-value ------

Macrophage Count 066 25mcg QD - Placebo 0.957 (0.2695) (0.553, 1.657) 0.871 066 87.5mcg QD - Placebo 1.196 (0.2725) (0.686, 2.083) 0.516

Neutrophil Count 066 25mcg QD - Placebo 0.614 (0.4970) (0.210, 1.794) 0.344 066 87.5mcg QD - Placebo 0.691 (0.3316) (0.343, 1.394) 0.282 CONFIDENTIAL Total Leukocyte Count 066 25mcg QD - Placebo 0.747 (0.3648) (0.342, 1.633) 0.438 066 87.5mcg QD - Placebo 0.800 (0.2592) (0.464, 1.378) 0.401 69 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 3 of 4 Population: Per-protocol Table 10.3 Summary of Results of Statistical Analysis of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type Adjusted Means

95% CI of Adjusted Analyte Treatment N n Adjusted Mean (SE) Means ------

Eosinophil Count Placebo 12 12 0.0110 (0.00448) (0.0019,0.0201) 066 25mcg QD 12 12 0.0147 (0.00452) (0.0055,0.0239) 066 87.5mcg QD 12 12 0.0120 (0.00450) (0.0029,0.0212) CONFIDENTIAL 70 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 4 of 4 Population: Per-protocol Table 10.3 Summary of Results of Statistical Analysis of BAL Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type Treatment Differences

95% CI of Analyte Treatment Comparison Difference (SE) Difference p-value ------

Eosinophil Count 066 25mcg QD - Placebo 0.00373 (0.006385) (-0.00928, 0.01674) 0.563 066 87.5mcg QD - Placebo 0.00104 (0.006337) (-0.01187, 0.01395) 0.871 CONFIDENTIAL 71 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 4 Population: Per-protocol Table 10.4 Summary of Results of Statistical Analysis of BAL Percentage Cell Count Data by Inflammatory Cell Type Adjusted Means

95% CI of Adjusted

Analyte Treatment N n Mean(SE ) Means ------

eosinophils % Placebo 12 12 0.79 (0.182) ( 0.42, 1.16)

066 25mcg QD 12 12 0.63 (0.182) ( 0.26, 1.00)

066 87.5mcg QD 12 12 0.80 (0.183) ( 0.43, 1.17) CONFIDENTIAL neutrophils % Placebo 12 12 66.59 (2.886) ( 60.24, 72.94)

066 25mcg QD 12 12 62.36 (6.788) ( 47.42, 77.30) 72 066 87.5mcg QD 12 12 61.61 (4.979) ( 50.65, 72.57) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 2 of 4 Population: Per-protocol Table 10.4 Summary of Results of Statistical Analysis of BAL Percentage Cell Count Data by Inflammatory Cell Type Treatment Differences

Treatment Analyte Comparison Difference (SE) 95% CI p-value ------

eosinophils % 066 25mcg QD - Placebo -0.160 (0.2569) ( -0.68, 0.36) 0.539

066 87.5mcg QD - Placebo 0.004 (0.2581) ( -0.52, 0.53) 0.988

neutrophils % 066 25mcg QD - Placebo -4.233 (7.3762) (-19.97, 11.50) 0.575

066 87.5mcg QD - Placebo -4.983 (5.7549) (-17.09, 7.12) 0.398 CONFIDENTIAL 73 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 3 of 4 Population: Per-protocol Table 10.4 Summary of Results of Statistical Analysis of BAL Percentage Cell Count Data by Inflammatory Cell Type Adjusted Geometric Means

95% CI of Adjusted Geometric Analyte Treatment N n Mean(SE logs ) Means ------

macrophages % Placebo 12 12 12.73 (0.218) ( 8.17, 19.86)

066 25mcg QD 12 12 16.10 (0.218) ( 10.32, 25.12)

066 87.5mcg QD 12 12 18.09 (0.218) ( 11.60, 28.20) CONFIDENTIAL 74 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 4 of 4 Population: Per-protocol Table 10.4 Summary of Results of Statistical Analysis of BAL Percentage Cell Count Data by Inflammatory Cell Type Treatment Ratios

Ratio of Adjusted Treatment Geometric Means Analyte Comparison (SE logs) 95% CI of Ratio p-value ------

macrophages % 066 25mcg QD - Placebo 1.265 (0.3088) ( 0.67, 2.37) 0.453

066 87.5mcg QD - Placebo 1.420 (0.3084) ( 0.76, 2.66) 0.264 CONFIDENTIAL 75 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Table 10.5 Summary of BAL Total Number of Monocytes (x10^3/mL) by Flow Cytometry

Planned Relative Arithmetic Analyte Treatment N Time n Mean SD Median Minimum Maximum ------

CD14+ Monocyte Count Placebo 12 2 H 12 1.57 0.970 1.70 0.3 3.4 26 H SALINE 12 8.26 18.508 2.49 0.3 66.4 26 H LPS 12 286.70 170.766 268.39 90.0 676.5

066 25mcg QD 12 2 H 12 1.51 0.994 1.26 0.2 3.6 26 H SALINE 12 4.37 6.479 2.22 0.2 24.3 26 H LPS 12 262.80 223.881 189.97 26.0 719.7 CONFIDENTIAL 066 87.5mcg QD 12 2 H 12 0.94 0.889 0.52 0.2 3.0 26 H SALINE 12 2.71 3.489 1.44 0.4 12.3 26 H LPS 12 205.90 188.368 112.45 2.4 545.1 76 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Table 10.5 Summary of BAL Total Number of Monocytes (x10^3/mL) by Flow Cytometry

Planned Geometric 95% CI SD CVb(%) Analyte Treatment N Relative Time n Mean Geometric Mean logs [1] ------

CD14+ Monocyte Count Placebo 12 2 H 12 1.19 ( 0.68, 2.09) 0.883 108.6 26 H SALINE 12 2.68 ( 1.13, 6.40) 1.367 234.2 26 H LPS 12 240.99 ( 160.73, 361.32) 0.637 70.8

066 25mcg QD 12 2 H 12 1.21 ( 0.75, 1.94) 0.745 86.2 26 H SALINE 12 2.36 ( 1.11, 5.01) 1.186 175.6 26 H LPS 12 172.36 ( 88.33, 336.33) 1.052 142.3

066 87.5mcg QD 12 2 H 12 0.65 ( 0.37, 1.14) 0.884 108.9 CONFIDENTIAL 26 H SALINE 12 1.62 ( 0.87, 3.03) 0.984 127.7 26 H LPS 12 113.41 ( 44.70, 287.75) 1.465 275.0 77 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Table 10.6 Summary of BAL Percentage of Monocytes by Flow Cytometry

Planned 95% CI Relative Arith. Arithmetic Analyte Treatment N Time n Mean Mean SD Median Min. Max. ------

% CD14 pos. Placebo 12 2 H 12 1.43 ( 1.09, 1.76) 0.523 1.37 0.7 2.3 Monocyte 26 H SALINE 12 4.17 ( 0.01, 8.33) 6.549 2.11 0.5 24.4 26 H LPS 12 18.47 (14.32,22.61) 6.524 19.44 7.3 29.3

066 25mcg QD 12 2 H 12 1.41 ( 1.05, 1.78) 0.572 1.35 0.6 2.6 26 H SALINE 12 3.09 ( 1.39, 4.80) 2.680 2.06 0.2 9.9

26 H LPS 12 17.00 (14.14,19.86) 4.505 17.60 7.1 23.0 CONFIDENTIAL

066 87.5mcg 12 2 H 12 1.17 ( 0.75, 1.59) 0.663 1.01 0.5 2.4 QD 78 26 H SALINE 12 2.25 ( 1.01, 3.48) 1.946 1.39 0.6 7.3 26 H LPS 12 13.99 ( 9.50,18.47) 7.054 13.82 0.2 27.6 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 CONFIDENTIAL GM2008/00234/00 IPC103711

Biomarker Data Source Figures and Tables

Page Figure 11.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Protein Expression Data (pg/mL) along with Individual Values ...... 80 Figure 11.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Protein Expression Data ...... 84 Figure 11.3 Individual Subject Profiles of Serum Protein Expression Data. . . 88 Figure 11.4 Plot of Adjusted Geometric Means and 95% CIs of Serum Protein Expression Data ...... 94 Figure 11.5 Plot of Adjusted Treatment Ratios and 95% CIs of Serum Protein Expression Data ...... 96 Table 11.1 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7 (Per-protocol Population) ...... 98 Table 11.2 Summary of Serum Protein Expression (ng/mL) Data by Protein and Day (Per-protocol Population) ...... 102 Table 11.3 Summary of Results of Statistical Analysis of BAL Protein Expression Data (pg/mL) (Per-protocol Population) ...... 104 Table 11.4 Summary of Results of Statistical Analysis of Serum Protein Expression Data (ng/mL) (Per-protocol Population) ...... 106 Table 11.101 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7 without Subject (Per-protocol Population) ...... 108

79 Protocol: IPC103711 Page 1 of 4 Population: Per-protocol Figure 11.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Protein Expression Data (pg/mL) along with Individual Values

Analyte=IL6

442413

162755 CONFIDENTIAL 80

59874

22026 IL6 Count (log base e scale)

8103 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 2981 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 2 of 4 Population: Per-protocol Figure 11.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Protein Expression Data (pg/mL) along with Individual Values

Analyte=IL8

162755 CONFIDENTIAL

59874 81

22026 IL8 Count (log base e scale) 8103 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 2981 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 3 of 4 Population: Per-protocol Figure 11.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Protein Expression Data (pg/mL) along with Individual Values

Analyte=MPO

24154953 CONFIDENTIAL

88861111 82

3269017 MPO Count (log base e scale) 1202604 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 442413 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 4 of 4 Population: Per-protocol Figure 11.1 Plot of Adjusted Geometric Means and 95% CIs of BAL Protein Expression Data (pg/mL) along with Individual Values

Analyte=TNFa

162755

59874 CONFIDENTIAL

22026 83

8103

2981

TNFa Count (log base e scale) 1097 GM2008/00234/00 GM2008/00234/00 403 IPC103711 IPC103711 148 Placebo 066 25mcg QD 066 87.5mcg QD Treatment Protocol: IPC103711 Page 1 of 4 Population: Per-protocol Figure 11.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Protein Expression Data

Analyte=IL-6

2.7 CONFIDENTIAL 84

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 2 of 4 Population: Per-protocol Figure 11.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Protein Expression Data

Analyte=IL-8

2.7 CONFIDENTIAL 85

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 3 of 4 Population: Per-protocol Figure 11.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Protein Expression Data

Analyte=MPO

2.7 CONFIDENTIAL 86

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 4 of 4 Population: Per-protocol Figure 11.2 Plot of Adjusted Treatment Ratios and 95% CIs of BAL Protein Expression Data

Analyte=TNFa

7.4 CONFIDENTIAL

87 2.7

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 066 25mcg QD vs. Placebo 066 87.5mcg QD vs. Placebo Treatment Comparison Protocol: IPC103711 Page 1 of 6 Population: Per-protocol Figure 11.3 Individual Subject Profiles of Serum Protein Expression Data

This section contained data from each individual patient, rather than in aggregate. They have been excluded 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 Sponsor Clinical Study Register. CONFIDENTIAL 88 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Figure 11.4 Plot of Adjusted Geometric Means and 95% CIs of Serum Protein Expression Data

Analyte=CC-16

20.1 CONFIDENTIAL

94 7.4

2.7 CC-16 Count (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 1 Plb 25 87.5 Plb 25 87.5 Day 7 Treatment (mcg QD) Day 8 Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Figure 11.4 Plot of Adjusted Geometric Means and 95% CIs of Serum Protein Expression Data

Analyte=SP-D

148 CONFIDENTIAL

95 54.6

20.1 SP-D Count (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 7.4 Plb 25 87.5 Plb 25 87.5 Day 7 Treatment (mcg QD) Day 8 Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Figure 11.5 Plot of Adjusted Treatment Ratios and 95% CIs of Serum Protein Expression Data

Analyte=CC-16

2.7 CONFIDENTIAL 96

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 25vPlb 87.5vPlb 25vPlb 87.5vPlb Day 7Treatment (mcg QD) Day 8 Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Figure 11.5 Plot of Adjusted Treatment Ratios and 95% CIs of Serum Protein Expression Data

Analyte=SP-D

2.7 CONFIDENTIAL 97

1 Treatment Ratio (log base e scale) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 0.368 25vPlb 87.5vPlb 25vPlb 87.5vPlb Day 7Treatment (mcg QD) Day 8 Protocol: IPC103711 Page 1 of 4 Population: Per-protocol Table 11.1 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7

Planned Relative Arithmetic Analyte Treatment N Time n Mean SD Median Minimum Maximum ------

IL-6 Placebo 12 2 H 12 789 465 655 402 2110 26 H SALINE 12 2075 1026 1964 814 4195 26 H LPS 12 20568 8167 22910 6838 30900

066 25mcg QD 12 2 H 12 655 342 509 309 1544 26 H SALINE 12 2544 2472 1529 720 8636 26 H LPS 12 23109 10682 20400 7767 41033 CONFIDENTIAL 066 87.5mcg QD 12 2 H 12 639 467 585 105 1544 26 H SALINE 12 2060 1196 1899 515 4209 26 H LPS 12 34811 57260 14282 5434 212006 98 IL-8 Placebo 12 2 H 12 6041 3631 5407 2031 14099 26 H SALINE 12 8198 2293 8896 3929 11085 26 H LPS 12 15081 7206 13872 4391 26693

066 25mcg QD 12 2 H 12 4923 2356 4342 1628 8754 26 H SALINE 12 12909 11458 7827 4496 41297 26 H LPS 12 21001 21571 12969 4856 84683

066 87.5mcg QD 12 2 H 12 3754 3280 3265 918 12956 26 H SALINE 12 7851 3296 6685 3856 14040 26 H LPS 12 11143 4907 10538 5610 20343

MPO Placebo 12 2 H 12 586084 386061 516015 129078 1385848 GM2008/00234/00 26 H SALINE 12 1191594 693050 1048071 428985 2581041 26 H LPS 12 2997550 2074681 2323265 969001 7002553 IPC103711 IPC103711 066 25mcg QD 12 2 H 12 275202 123205 273559 68747 564094 26 H SALINE 12 925047 765620 608112 226746 2973075

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 2 of 4 Population: Per-protocol Table 11.1 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7

Planned Relative Arithmetic Analyte Treatment N Time n Mean SD Median Minimum Maximum ------

MPO 066 25mcg QD 12 26 H LPS 12 2785056 2700548 1490006 657088 8787716

066 87.5mcg QD 12 2 H 12 328413 479853 194827 62360 1804250 26 H SALINE 12 1032241 684037 1006146 284341 2247436 26 H LPS 12 2359977 2557284 1718576 694026 10164641

TNFa Placebo 12 2 H 12 6764 16774 1477 155 59629

26 H SALINE 12 8330 13452 3540 97 47646 CONFIDENTIAL 26 H LPS 12 10589 17548 2643 205 52152

066 25mcg QD 12 2 H 12 932 924 553 191 3149 99 26 H SALINE 12 5268 7583 3017 101 27723 26 H LPS 12 11813 24436 4089 848 88101

066 87.5mcg QD 12 2 H 12 2200 2842 906 158 9335 26 H SALINE 12 4333 2936 4900 198 7958 26 H LPS 12 9150 10022 4201 965 34404 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 3 of 4 Population: Per-protocol Table 11.1 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7

Geometric 95% CI SD Analyte Treatment N Planned Time n Mean Geometric Mean logs CVb(%)[1] ------

IL-6 Placebo 12 2 H 12 705 ( 525, 946) 0.463 48.9 26 H SALINE 12 1848 ( 1335, 2558) 0.512 54.7 26 H LPS 12 18768 ( 13860, 25415) 0.477 50.6

066 25mcg QD 12 2 H 12 593 ( 448, 786) 0.443 46.5 26 H SALINE 12 1830 ( 1100, 3043) 0.801 94.8 26 H LPS 12 20761 ( 15096, 28553) 0.502 53.5

066 87.5mcg QD 12 2 H 12 483 ( 286, 818) 0.828 99.3 CONFIDENTIAL 26 H SALINE 12 1707 ( 1104, 2639) 0.686 77.5 26 H LPS 12 18730 ( 9874, 35529) 1.008 132.7

100 IL-8 Placebo 12 2 H 12 5180 ( 3591, 7472) 0.577 62.8 26 H SALINE 12 7852 ( 6399, 9636) 0.322 33.1 26 H LPS 12 13265 ( 9269, 18984) 0.564 61.2

066 25mcg QD 12 2 H 12 4371 ( 3122, 6120) 0.530 56.9 26 H SALINE 12 9623 ( 5923, 15633) 0.764 89.0 26 H LPS 12 15416 ( 9496, 25028) 0.763 88.8

066 87.5mcg QD 12 2 H 12 2849 ( 1756, 4623) 0.762 88.7 26 H SALINE 12 7276 ( 5631, 9401) 0.403 42.0 26 H LPS 12 10237 ( 7794, 13445) 0.429 45.0

MPO Placebo 12 2 H 12 462963 ( 284225, 754102) 0.768 89.6 26 H SALINE 12 1028057 ( 718282, 1471430) 0.564 61.2 GM2008/00234/00 26 H LPS 12 2454539 ( 1626884, 3703251) 0.647 72.1

066 25mcg QD 12 2 H 12 247171 ( 177271, 344634) 0.523 56.1 IPC103711 26 H SALINE 12 711224 ( 443048, 1141728) 0.745 86.1 26 H LPS 12 1917124 ( 1103379, 3331010) 0.869 106.3

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 4 of 4 Population: Per-protocol Table 11.1 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7

Geometric 95% CI SD Analyte Treatment N Planned Time n Mean Geometric Mean logs CVb(%)[1] ------

MPO 066 87.5mcg QD 12 2 H 12 191718 ( 102658, 358042) 0.983 127.6 26 H SALINE 12 826959 ( 523100, 1307324) 0.721 82.5 26 H LPS 12 1746762 ( 1099951, 2773922) 0.728 83.6

TNFa Placebo 12 2 H 12 1351 ( 436, 4187) 1.780 477.0 26 H SALINE 12 2396 ( 703, 8166) 1.930 636.1 26 H LPS 12 3201 ( 1112, 9213) 1.664 386.3

066 25mcg QD 12 2 H 12 578 ( 299, 1121) 1.041 139.8 CONFIDENTIAL 26 H SALINE 12 1938 ( 634, 5921) 1.758 458.2 26 H LPS 12 4225 ( 1798, 9929) 1.345 225.9

101 066 87.5mcg QD 12 2 H 12 981 ( 407, 2367) 1.386 241.5 26 H SALINE 12 2450 ( 970, 6188) 1.458 271.6 26 H LPS 12 5349 ( 2657, 10765) 1.101 153.6 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Table 11.2 Summary of Serum Protein Expression (ng/mL) Data by Protein and Day

Planned Relative Arith Analyte Treatment N Visit Time n Mean SD Median Minimum Maximum ------

CC-16 Placebo 12 DAY 1 PRE-DOSE 12 6.04 1.668 5.68 3.8 10.1 DAY 7 PRE-DOSE 12 6.28 1.695 5.79 4.0 10.0 DAY 8 PRE-BRONCHOSCOPY 12 6.63 2.034 6.20 4.5 10.8

066 25mcg QD 12 DAY 1 PRE-DOSE 12 6.86 2.599 6.13 4.0 12.6 DAY 7 PRE-DOSE 12 7.01 2.577 6.43 3.8 13.6 DAY 8 PRE-BRONCHOSCOPY 12 7.28 2.556 6.53 3.8 13.5

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 6.98 2.667 6.25 2.0 10.9 CONFIDENTIAL DAY 7 PRE-DOSE 12 7.04 2.427 6.44 1.9 10.5 DAY 8 PRE-BRONCHOSCOPY 12 7.10 2.745 6.32 1.8 10.5

102 SP-D Placebo 12 DAY 1 PRE-DOSE 12 66.51 28.296 63.32 30.0 106.3 DAY 7 PRE-DOSE 12 69.62 31.249 60.63 33.7 113.7 DAY 8 PRE-BRONCHOSCOPY 12 64.42 25.023 61.14 31.4 103.3

066 25mcg QD 12 DAY 1 PRE-DOSE 12 69.76 35.517 80.03 18.1 112.9 DAY 7 PRE-DOSE 12 68.99 36.696 76.01 17.6 125.5 DAY 8 PRE-BRONCHOSCOPY 12 71.21 35.765 79.22 17.5 113.7

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 63.98 36.299 51.97 27.9 143.8 DAY 7 PRE-DOSE 12 60.13 30.985 50.79 24.8 129.9 DAY 8 PRE-BRONCHOSCOPY 12 60.90 31.532 51.59 27.2 143.5 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Table 11.2 Summary of Serum Protein Expression (ng/mL) Data by Protein and Day

Geometric 95% CI SD CVb(%) Analyte Treatment N Visit Planned Time n Mean Geometric Mean logs [1] ------

CC-16 Placebo 12 DAY 1 PRE-DOSE 12 5.85 ( 4.96, 6.90) 0.259 26.4 DAY 7 PRE-DOSE 12 6.08 ( 5.16, 7.18) 0.260 26.4 DAY 8 PRE-BRONCHOSCOPY 12 6.36 ( 5.28, 7.67) 0.295 30.1

066 25mcg QD 12 DAY 1 PRE-DOSE 12 6.47 ( 5.19, 8.08) 0.348 35.9 DAY 7 PRE-DOSE 12 6.64 ( 5.37, 8.21) 0.334 34.3 DAY 8 PRE-BRONCHOSCOPY 12 6.91 ( 5.59, 8.54) 0.333 34.2

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 6.43 ( 4.81, 8.60) 0.457 48.2 CONFIDENTIAL DAY 7 PRE-DOSE 12 6.53 ( 4.90, 8.70) 0.451 47.5 DAY 8 PRE-BRONCHOSCOPY 12 6.47 ( 4.70, 8.89) 0.501 53.5

103 SP-D Placebo 12 DAY 1 PRE-DOSE 12 60.55 ( 45.01, 81.46) 0.467 49.3 DAY 7 PRE-DOSE 12 63.04 ( 46.66, 85.18) 0.474 50.1 DAY 8 PRE-BRONCHOSCOPY 12 59.93 ( 46.42, 77.36) 0.402 41.9

066 25mcg QD 12 DAY 1 PRE-DOSE 12 58.74 ( 38.24, 90.22) 0.676 76.1 DAY 7 PRE-DOSE 12 57.81 ( 37.65, 88.75) 0.675 75.9 DAY 8 PRE-BRONCHOSCOPY 12 60.59 ( 40.13, 91.49) 0.649 72.3

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 56.69 ( 41.47, 77.52) 0.492 52.4 DAY 7 PRE-DOSE 12 54.23 ( 40.44, 72.73) 0.462 48.8 DAY 8 PRE-BRONCHOSCOPY 12 55.27 ( 41.79, 73.10) 0.440 46.2 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Table 11.3 Summary of Results of Statistical Analysis of BAL Protein Expression Data (pg/mL)

Geometric Means

Adjusted Geometric 95% CI of Adjusted Analyte Treatment N n Mean (SE logs) Geometric Means ------

IL6 Placebo 12 12 18839 (0.132) ( 14037, 25285) 066 25mcg QD 12 12 20814 (0.152) ( 14843, 29186) 066 87.5mcg QD 12 12 18613 (0.294) ( 9753, 35521)

IL8 Placebo 12 12 13457 (0.168) ( 9551, 18959) 066 25mcg QD 12 12 14598 (0.171) ( 10307, 20675)

066 87.5mcg QD 12 12 10657 (0.170) ( 7544, 15055) CONFIDENTIAL

MPO Placebo 12 12 2278936 (0.211) ( 1483894, 3499945) 066 25mcg QD 12 12 2047426 (0.210) ( 1334941, 3140178) 104 066 87.5mcg QD 12 12 1761626 (0.208) ( 1154178, 2688776)

TNFa Placebo 12 12 3087 (0.285) ( 1727, 5516) 066 25mcg QD 12 12 4603 (0.285) ( 2574, 8231) 066 87.5mcg QD 12 12 5091 (0.285) ( 2849, 9099) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Table 11.3 Summary of Results of Statistical Analysis of BAL Protein Expression Data (pg/mL)

Treatment Ratios

Ratio of Adjusted Geometric Means Analyte Treatment Comparison (SE logs) 95% CI of Ratio p-value ------

IL-6 066 25mcg QD - Placebo 1.105 (0.2015) ( 0.726, 1.680) 0.626 066 87.5mcg QD - Placebo 0.988 (0.3222) ( 0.498, 1.961) 0.970

IL-8 066 25mcg QD - Placebo 1.085 (0.2409) ( 0.664, 1.772) 0.738 066 87.5mcg QD - Placebo 0.792 (0.2382) ( 0.488, 1.286) 0.335 CONFIDENTIAL MPO 066 25mcg QD - Placebo 0.898 (0.3012) ( 0.486, 1.659) 0.724 066 87.5mcg QD - Placebo 0.773 (0.2962) ( 0.423, 1.413) 0.391

105 TNFa 066 25mcg QD - Placebo 1.491 (0.4035) ( 0.655, 3.392) 0.330 066 87.5mcg QD - Placebo 1.649 (0.4030) ( 0.726, 3.748) 0.223 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Table 11.4 Summary of Results of Statistical Analysis of Serum Protein Expression Data (ng/mL)

Geometric Means

Adjusted Geometric 95% CI of Adjusted Analyte Treatment N Visit n Mean (SE logs) Geometric Means ------

CC-16 Placebo 12 DAY 7 12 6.48 (0.033) ( 6.05, 6.93) DAY 8 12 6.77 (0.038) ( 6.27, 7.31) 066 25mcg QD 12 DAY 7 12 6.42 (0.033) ( 6.00, 6.86) DAY 8 12 6.68 (0.038) ( 6.18, 7.21) 066 87.5mcg QD 12 DAY 7 12 6.35 (0.033) ( 5.93, 6.79) DAY 8 12 6.29 (0.038) ( 5.82, 6.79) CONFIDENTIAL SP-D Placebo 12 DAY 7 12 61.11 (0.024) (58.15, 64.22) DAY 8 12 58.09 (0.046) (52.92, 63.77) 066 25mcg QD 12 DAY 7 12 57.72 (0.024) (54.92, 60.65) 106 DAY 8 12 60.49 (0.046) (55.11, 66.40) 066 87.5mcg QD 12 DAY 7 12 56.03 (0.024) (53.32, 58.88) DAY 8 12 57.11 (0.046) (52.02, 62.69) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Table 11.4 Summary of Results of Statistical Analysis of Serum Protein Expression Data (ng/mL)

Treatment Ratios

Ratio of Adjusted Geometric Means Analyte Treatment Comparison Visit (SE logs) 95% CI of Ratio p-value ------

CC-16 066 25mcg QD - Placebo DAY 7 0.991 (0.0471) ( 0.900, 1.091) 0.849 DAY 8 0.986 (0.0534) ( 0.884, 1.099) 0.792 066 87.5mcg QD - Placebo DAY 7 0.980 (0.0471) ( 0.891, 1.079) 0.675 DAY 8 0.928 (0.0534) ( 0.832, 1.035) 0.172

SP-D 066 25mcg QD - Placebo DAY 7 0.944 (0.0344) ( 0.880, 1.013) 0.107 CONFIDENTIAL DAY 8 1.041 (0.0647) ( 0.913, 1.188) 0.536 066 87.5mcg QD - Placebo DAY 7 0.917 (0.0345) ( 0.855, 0.984) 0.017 DAY 8 0.983 (0.0647) ( 0.862, 1.122) 0.793 107 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 2 Population: Per-protocol Table 11.101 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7 without Subject

Planned Relative Arithmetic Analyte Treatment N Time n Mean SD Median Minimum Maximum ------

IL8 Placebo 12 2 H 12 6041 3631 5407 2031 14099 26 H SALINE 12 8198 2293 8896 3929 11085 26 H LPS 12 15081 7206 13872 4391 26693

066 25mcg QD 12 2 H 11 4575 2122 4196 1628 8196 26 H SALINE 11 12157 11702 7371 4496 41297

26 H LPS 11 15212 8333 12171 4856 30668 CONFIDENTIAL

066 87.5mcg QD 12 2 H 12 3754 3280 3265 918 12956 26 H SALINE 12 7851 3296 6685 3856 14040 108 26 H LPS 12 11143 4907 10538 5610 20343 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). Protocol: IPC103711 Page 2 of 2 Population: Per-protocol Table 11.101 Summary of BAL Protein Expression Data (pg/mL) by Protein on Day 7 without Subject

Geometric 95% CI SD Analyte Treatment N Planned Time n Mean Geometric Mean logs CVb(%)[1] ------

IL8 Placebo 12 2 H 12 5180 ( 3591, 7472) 0.577 62.8 26 H SALINE 12 7852 ( 6399, 9636) 0.322 33.1 26 H LPS 12 13265 ( 9269, 18984) 0.564 61.2

066 25mcg QD 12 2 H 11 4104 ( 2921, 5764) 0.506 54.0 26 H SALINE 11 8956 ( 5384, 14899) 0.758 88.0 26 H LPS 11 13204 ( 9012, 19347) 0.569 61.8 CONFIDENTIAL 066 87.5mcg QD 12 2 H 12 2849 ( 1756, 4623) 0.762 88.7 26 H SALINE 12 7276 ( 5631, 9401) 0.403 42.0 26 H LPS 12 10237 ( 7794, 13445) 0.429 45.0 109 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]: CVb(%)=100*sqrt(exp(logSD^2)-1). CONFIDENTIAL GM2008/00234/00 IPC103711

Safety Data Source Tables

Page Table 12.1 Summary of All Adverse Events (All Subjects Population) ...... 111 Table 12.2 Summary of Drug-Related Adverse Events (All Subjects Population) ...... 114 Table 12.3 Summary of ECG Findings (All Subjects Population) ...... 115 Table 12.4 Summary of ECG Values (All Subjects Population) ...... 118 Table 12.5 Summary of Maximum Change from Baseline ECG Values (All Subjects Population) ...... 124 Table 12.6 Summary of Number of Subjects with Maximum ECG Values meeting or exceeding Pre-specified Ranges of concern by Category and Treatment (All Subjects Population) ...... 126 Table 12.7 Summary of Number of Subjects with Maximum ECG Values meeting or exceeding Pre-specified Individual Changes from Baseline of Category and Treatment (All Subjects Population) ...... 127 Table 12.8 Summary of Urinalysis Dipstick Results (All Subjects Population) 128 Table 12.9 Summary of Troponin Data (All Subjects Population) ...... 131 Table 12.10 Summary of Holter Interpretations (All Subjects Population) . . . 132 Table 12.11 Listing of ECG Values of Potential Clinical Importance (All Subjects Population) ...... 133 Table 12.12 Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance (All Subjects Population) ...... 137

110 Protocol: IPC103711 Page 1 of 3 Population: All Subjects Table 12.1 Summary of All Adverse Events

System Organ Class Placebo 066 25mcg QD 066 87.5mcg QD Preferred Term (N=12) (N=13) (N=12) ------ANY EVENT 6 (50%) 8 (62%) 9 (75%)

Respiratory, thoracic and mediastinal disorders Any event 1 (8%) 3 (23%) 7 (58%) Cough 0 2 (15%) 5 (42%) Pleuritic pain 1 (8%) 0 2 (17%) Pharyngolaryngeal pain 0 1 (8%) 1 (8%) Painful respiration 0 1 (8%) 0 CONFIDENTIAL General disorders and administration site conditions Any event 1 (8%) 5 (38%) 3 (25%) 111 Pyrexia 0 3 (23%) 1 (8%) Fatigue 0 1 (8%) 1 (8%) Chest pain 1 (8%) 0 0 Chills 0 1 (8%) 0 Influenza like illness 0 1 (8%) 0 Non-cardiac chest pain 0 0 1 (8%)

Nervous system disorders Any event 4 (33%) 0 5 (42%) Headache 4 (33%) 0 5 (42%) Intercostal neuralgia 0 0 1 (8%)

Cardiac disorders Any event 2 (17%) 1 (8%) 2 (17%) GM2008/00234/00 Bradycardia 0 1 (8%) 1 (8%) Atrioventricular block first 1 (8%) 0 0

degree IPC103711 Sinus bradycardia 1 (8%) 0 0 Ventricular tachycardia 0 0 1 (8%) Protocol: IPC103711 Page 2 of 3 Population: All Subjects Table 12.1 Summary of All Adverse Events

System Organ Class Placebo 066 25mcg QD 066 87.5mcg QD Preferred Term (N=12) (N=13) (N=12) ------Infections and infestations Any event 2 (17%) 2 (15%) 1 (8%) Rhinitis 1 (8%) 0 1 (8%) Oral herpes 0 1 (8%) 0 Respiratory tract infection 0 1 (8%) 0 Upper respiratory tract 1 (8%) 0 0 infection

Injury, poisoning and

procedural complications CONFIDENTIAL Any event 0 1 (8%) 1 (8%) Procedural pain 0 1 (8%) 1 (8%)

112 Investigations Any event 0 1 (8%) 1 (8%) Body temperature increased 0 0 1 (8%) Pulmonary function test 0 1 (8%) 0 decreased

Reproductive system and breast disorders Any event 0 1 (8%) 1 (8%) Dysmenorrhoea 0 1 (8%) 1 (8%)

Ear and labyrinth disorders Any event 0 0 1 (8%) Vertigo 0 0 1 (8%) GM2008/00234/00

Musculoskeletal and connective

tissue disorders IPC103711 Any event 0 0 1 (8%) Myalgia 0 0 1 (8%) Protocol: IPC103711 Page 3 of 3 Population: All Subjects Table 12.1 Summary of All Adverse Events

System Organ Class Placebo 066 25mcg QD 066 87.5mcg QD Preferred Term (N=12) (N=13) (N=12) ------Skin and subcutaneous tissue disorders Any event 1 (8%) 0 0 Eczema 1 (8%) 0 0 CONFIDENTIAL 113 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 12.2 Summary of Drug-Related Adverse Events

System Organ Class Placebo 066 25mcg QD 066 87.5mcg QD Preferred Term (N=12) (N=13) (N=12) ------ANY EVENT 2 (17%) 2 (15%) 6 (50%)

Respiratory, thoracic and mediastinal disorders Any event 0 2 (15%) 5 (42%) Cough 0 2 (15%) 5 (42%)

Cardiac disorders Any event 2 (17%) 0 1 (8%)

Atrioventricular block first 1 (8%) 0 0 CONFIDENTIAL degree Bradycardia 0 0 1 (8%) Sinus bradycardia 1 (8%) 0 0 114 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 3 Population: All Subjects Table 12.3 Summary of ECG Findings

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------DAY 1 PRE-DOSE n 12 13 12 Normal 9 (75%) 9 (69%) 7 (58%) Abnormal - not clinically significant 3 (25%) 4 (31%) 5 (42%) Abnormal - clinically significant 0 0 0

0.5 H n 12 13 12

Normal 5 (42%) 4 (31%) 7 (58%) CONFIDENTIAL Abnormal - not clinically significant 7 (58%) 9 (69%) 5 (42%) Abnormal - clinically significant 0 0 0

115 1 H n 12 13 12 Normal 4 (33%) 3 (23%) 8 (67%) Abnormal - not clinically significant 8 (67%) 10 (77%) 4 (33%) Abnormal - clinically significant 0 0 0

2 H n 12 13 12 Normal 6 (50%) 4 (31%) 8 (67%) Abnormal - not clinically significant 6 (50%) 9 (69%) 3 (25%) Abnormal - clinically significant 0 0 1 (8%)

4 H n 0 0 0 GM2008/00234/00 Normal 0 0 0 Abnormal - not clinically significant 0 0 0

Abnormal - clinically significant 0 0 0 IPC103711 Protocol: IPC103711 Page 2 of 3 Population: All Subjects Table 12.3 Summary of ECG Findings

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------24 H n 0 0 0 Normal 0 0 0 Abnormal - not clinically significant 0 0 0 Abnormal - clinically significant 0 0 0

DAY 7 PRE-DOSE n 12 13 12

Normal 8 (67%) 7 (54%) 8 (67%) CONFIDENTIAL Abnormal - not clinically significant 4 (33%) 6 (46%) 4 (33%) Abnormal - clinically significant 0 0 0

116 0.5 H n 0 0 0 Normal 0 0 0 Abnormal - not clinically significant 0 0 0 Abnormal - clinically significant 0 0 0

1 H n 0 0 0 Normal 0 0 0 Abnormal - not clinically significant 0 0 0 Abnormal - clinically significant 0 0 0

2 H n 0 0 0 GM2008/00234/00 Normal 0 0 0 Abnormal - not clinically significant 0 0 0

Abnormal - clinically significant 0 0 0 IPC103711 Protocol: IPC103711 Page 3 of 3 Population: All Subjects Table 12.3 Summary of ECG Findings

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------4 H n 12 13 12 Normal 5 (42%) 7 (54%) 8 (67%) Abnormal - not clinically significant 7 (58%) 6 (46%) 4 (33%) Abnormal - clinically significant 0 0 0

24 H n 12 13 12 Normal 8 (67%) 7 (54%) 8 (67%)

Abnormal - not clinically significant 4 (33%) 6 (46%) 4 (33%) CONFIDENTIAL Abnormal - clinically significant 0 0 0 117 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 6 Population: All Subjects Table 12.4 Summary of ECG Values

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. ------Heart rate (BPM) Placebo 12 DAY 1 PRE-DOSE 12 66.9 15.72 63.0 54 112 0.5 H 12 58.8 7.14 61.0 46 69 1 H 12 57.8 6.61 59.0 45 68 2 H 12 59.9 6.49 58.5 52 74 DAY 7 PRE-DOSE 12 57.8 7.00 59.0 45 69 4 H 12 60.5 6.04 59.5 53 73 24 H 12 59.9 9.27 57.0 49 79

066 25mcg QD 13 DAY 1 PRE-DOSE 13 63.3 9.04 61.0 50 81 CONFIDENTIAL 0.5 H 13 58.4 8.26 57.0 47 72 1 H 13 58.4 8.23 58.0 45 72 2 H 13 59.5 7.28 60.0 50 69 118 DAY 7 PRE-DOSE 13 61.2 9.64 59.0 51 87 4 H 13 62.8 8.79 62.0 48 76 24 H 13 64.7 8.98 63.0 54 87

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 65.2 7.99 64.5 55 78 0.5 H 12 60.8 5.63 61.5 51 72 1 H 12 62.2 5.86 60.0 55 72 2 H 12 64.0 7.78 65.5 49 79 DAY 7 PRE-DOSE 12 64.8 6.03 65.5 55 75 4 H 12 64.2 5.47 65.5 53 70 24 H 12 65.9 6.63 65.5 57 79

RR Interval (MSEC) Placebo 12 DAY 1 PRE-DOSE 12 930.3 160.85 953.0 536 1111 GM2008/00234/00 0.5 H 12 1036.0 131.88 984.0 870 1304 1 H 12 1052.3 129.59 1017.0 882 1333

2 H 12 1011.4 100.74 1026.5 811 1154 IPC103711 DAY 7 PRE-DOSE 12 1053.6 133.59 1017.0 870 1333 4 H 12 1000.5 95.82 1008.5 822 1132 24 H 12 1022.2 148.34 1055.5 759 1224 Protocol: IPC103711 Page 2 of 6 Population: All Subjects Table 12.4 Summary of ECG Values

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. ------RR Interval (MSEC) 066 25mcg QD 13 DAY 1 PRE-DOSE 13 965.2 134.42 984.0 741 1200 0.5 H 13 1046.2 143.75 1053.0 833 1277 1 H 13 1047.2 152.94 1034.0 833 1333 2 H 13 1023.4 126.02 1000.0 870 1200 DAY 7 PRE-DOSE 13 1000.2 132.38 1017.0 690 1176 4 H 13 972.9 142.24 968.0 789 1250 24 H 13 942.1 115.89 952.0 690 1111

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 933.2 112.02 930.5 769 1091 CONFIDENTIAL 0.5 H 12 995.5 92.58 976.0 833 1176 1 H 12 973.0 88.52 1000.5 833 1091 2 H 12 950.9 122.89 916.0 759 1224 119 DAY 7 PRE-DOSE 12 933.2 88.22 917.0 800 1091 4 H 12 941.8 87.12 916.0 857 1132 24 H 12 918.6 91.12 916.0 759 1053

QT Interval (MSEC) Placebo 12 DAY 1 PRE-DOSE 12 397.5 24.84 390.0 368 442 0.5 H 12 408.8 25.55 405.0 374 448 1 H 12 408.3 26.35 405.0 374 454 2 H 12 406.7 22.19 405.0 380 440 DAY 7 PRE-DOSE 12 413.3 24.22 410.0 364 448 4 H 12 411.5 19.17 408.0 370 442 24 H 12 407.2 27.10 405.0 350 452

066 25mcg QD 13 DAY 1 PRE-DOSE 13 400.9 25.23 404.0 354 444 GM2008/00234/00 0.5 H 13 410.2 32.49 424.0 350 468 1 H 13 415.8 31.42 418.0 368 470

2 H 13 413.1 27.55 416.0 368 456 IPC103711 DAY 7 PRE-DOSE 13 407.8 24.03 404.0 368 444 4 H 13 406.9 34.66 408.0 352 458 24 H 13 401.2 26.84 404.0 356 452 Protocol: IPC103711 Page 3 of 6 Population: All Subjects Table 12.4 Summary of ECG Values

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. ------QT Interval (MSEC) 066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 397.8 16.66 401.0 372 424 0.5 H 12 403.8 14.13 399.0 390 436 1 H 12 402.5 12.12 402.0 384 428 2 H 12 399.7 12.82 400.0 380 424 DAY 7 PRE-DOSE 12 398.8 18.67 399.0 372 426 4 H 12 403.3 16.85 410.0 370 422 24 H 12 395.5 19.80 400.0 356 426 CONFIDENTIAL QTcF (MSEC) Placebo 12 DAY 1 PRE-DOSE 12 409.7 31.24 407.5 361 488 0.5 H 12 404.4 14.80 405.0 376 427 1 H 12 402.2 19.71 406.0 372 432 120 2 H 12 405.7 17.78 407.0 374 430 DAY 7 PRE-DOSE 12 406.8 17.18 409.5 381 439 4 H 12 411.9 18.00 415.5 384 443 24 H 12 405.0 15.89 405.5 379 431

066 25mcg QD 13 DAY 1 PRE-DOSE 13 406.3 13.97 410.0 386 429 0.5 H 13 404.4 17.20 404.0 372 431 1 H 13 410.2 19.97 413.0 378 441 2 H 13 410.4 17.18 412.0 386 435 DAY 7 PRE-DOSE 13 408.8 18.28 410.0 382 431 4 H 13 411.2 24.64 410.0 378 442 24 H 13 409.6 18.32 411.0 385 436

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 407.9 15.16 408.0 380 431 GM2008/00234/00 0.5 H 12 404.8 11.21 405.0 384 421 1 H 12 406.8 17.02 405.5 385 440

2 H 12 407.3 14.96 410.0 378 435 IPC103711 DAY 7 PRE-DOSE 12 408.6 15.14 408.0 390 438 4 H 12 412.0 20.06 415.5 383 440 24 H 12 407.3 17.18 407.0 384 434 Protocol: IPC103711 Page 4 of 6 Population: All Subjects Table 12.4 Summary of ECG Values

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. ------QTcB (MSEC) Placebo 12 DAY 1 PRE-DOSE 12 404.9 20.29 405.5 356 430 0.5 H 12 405.1 14.98 409.5 376 424 1 H 12 400.4 21.28 407.0 366 432 2 H 12 406.3 18.77 411.5 374 426 DAY 7 PRE-DOSE 12 413.6 22.88 413.5 380 468 4 H 12 415.0 20.96 417.5 384 447 24 H 12 406.0 16.83 408.5 373 432

066 25mcg QD 13 DAY 1 PRE-DOSE 13 411.5 15.53 411.0 386 439 CONFIDENTIAL 0.5 H 13 402.2 15.57 399.0 382 428 1 H 13 410.2 20.00 417.0 382 452 2 H 13 410.8 17.31 406.0 389 440 121 DAY 7 PRE-DOSE 13 411.8 22.55 415.0 375 457 4 H 13 414.1 24.19 405.0 379 447 24 H 13 415.8 22.14 416.0 381 461

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 415.6 20.77 416.0 385 451 0.5 H 12 404.5 16.56 404.5 371 436 1 H 12 411.5 21.31 407.0 384 456 2 H 12 413.5 21.68 415.0 367 443 DAY 7 PRE-DOSE 12 415.8 17.09 416.5 391 450 4 H 12 416.9 25.48 423.0 380 451 24 H 12 414.4 19.11 411.5 384 449

PR Interval (MSEC) Placebo 12 DAY 1 PRE-DOSE 12 155.8 20.76 160.0 122 184 GM2008/00234/00 0.5 H 12 157.2 31.13 156.0 114 240 1 H 12 153.0 25.94 156.0 110 204

2 H 12 156.2 22.31 161.0 112 186 IPC103711 DAY 7 PRE-DOSE 12 164.0 31.62 163.0 130 250 4 H 12 157.2 19.60 163.0 116 186 24 H 12 159.5 28.08 163.0 120 220 Protocol: IPC103711 Page 5 of 6 Population: All Subjects Table 12.4 Summary of ECG Values

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. ------PR Interval (MSEC) 066 25mcg QD 13 DAY 1 PRE-DOSE 13 156.8 20.40 152.0 132 196 0.5 H 13 154.5 18.41 154.0 130 186 1 H 13 157.2 25.28 146.0 130 204 2 H 13 154.0 18.15 146.0 130 192 DAY 7 PRE-DOSE 13 154.6 18.57 152.0 128 190 4 H 13 156.8 16.50 154.0 132 184 24 H 13 152.5 16.41 146.0 130 186

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 157.0 27.88 169.0 116 192 CONFIDENTIAL 0.5 H 12 152.8 23.76 156.0 114 190 1 H 12 151.5 27.36 158.0 100 184 2 H 12 152.7 23.14 152.0 122 186 122 DAY 7 PRE-DOSE 12 161.5 28.21 172.0 120 198 4 H 12 161.6 29.58 172.0 116 195 24 H 12 159.8 24.66 168.0 122 188

QRS Duration Placebo 12 DAY 1 PRE-DOSE 12 93.8 3.56 94.0 88 100 (MSEC) 0.5 H 12 94.0 3.62 94.0 88 102 1 H 12 94.0 3.30 94.0 90 100 2 H 12 93.3 4.29 92.0 88 102 DAY 7 PRE-DOSE 12 94.3 4.33 93.0 88 100 4 H 12 94.5 4.98 95.0 86 102 24 H 12 93.7 4.89 93.0 86 102 GM2008/00234/00 GM2008/00234/00 066 25mcg QD 13 DAY 1 PRE-DOSE 13 91.4 5.19 90.0 84 100 0.5 H 13 92.0 6.43 90.0 82 104

1 H 13 91.4 5.06 90.0 86 100 IPC103711 2 H 13 94.3 6.87 92.0 86 108 DAY 7 PRE-DOSE 13 90.8 6.86 88.0 82 106 4 H 13 91.2 5.13 90.0 82 98 Protocol: IPC103711 Page 6 of 6 Population: All Subjects Table 12.4 Summary of ECG Values

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. ------QRS Duration 066 25mcg QD 13 DAY 7 24 H 13 91.7 6.97 92.0 80 100 (MSEC)

066 87.5mcg QD 12 DAY 1 PRE-DOSE 12 90.7 7.25 90.0 80 100 0.5 H 12 90.2 6.79 90.0 80 100 1 H 12 90.8 6.85 90.0 80 100 2 H 12 89.8 8.11 91.0 80 102 DAY 7 PRE-DOSE 12 90.2 8.20 90.0 78 100

4 H 12 90.8 7.93 93.0 76 100 CONFIDENTIAL 24 H 12 89.7 7.38 91.0 76 98 123 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 2 Population: All Subjects Table 12.5 Summary of Maximum Change from Baseline ECG Values

Mean Treatment N Baseline n Mean SD Median Min. Max. ------PR Interval (MSEC) Placebo 12 155.8 24 2.5 12.12 1.0 -16 38

066 25mcg QD 13 156.8 26 -2.2 9.99 -1.0 -24 18

066 87.5mcg QD 12 157.0 24 3.7 14.15 0.0 -18 45

QRS Duration (MSEC) Placebo 12 93.8 24 0.3 3.35 2.0 -8 4

066 25mcg QD 13 91.4 26 0.1 4.06 0.0 -8 12 CONFIDENTIAL 066 87.5mcg QD 12 90.7 24 -0.4 4.25 -1.0 -10 10

QT Interval (MSEC) Placebo 12 397.5 24 11.8 14.84 14.0 -24 32 124 066 25mcg QD 13 400.9 26 3.2 22.94 3.0 -36 68

066 87.5mcg QD 12 397.8 24 1.6 20.74 4.0 -54 38

QTcB (MSEC) Placebo 12 404.9 24 5.6 15.83 8.0 -22 33

066 25mcg QD 13 411.5 26 3.4 16.51 3.5 -28 35

066 87.5mcg QD 12 415.6 24 0.1 17.26 -2.0 -35 39

QTcF (MSEC) Placebo 12 409.7 24 -1.2 26.04 2.0 -84 27

066 25mcg QD 13 406.3 26 4.1 12.45 4.5 -28 28 GM2008/00234/00

066 87.5mcg QD 12 407.9 24 1.8 16.54 3.0 -40 34 IPC103711 IPC103711 Protocol: IPC103711 Page 2 of 2 Population: All Subjects Table 12.5 Summary of Maximum Change from Baseline ECG Values

Mean Treatment N Baseline n Mean SD Median Min. Max. ------RR Interval (MSEC) Placebo 12 930.3 24 81.1 167.27 46.0 -137 575

066 25mcg QD 13 965.2 26 -7.7 132.42 -5.5 -236 428

066 87.5mcg QD 12 933.2 24 -3.0 94.35 6.0 -168 119 CONFIDENTIAL 125 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 12.6 Summary of Number of Subjects with Maximum ECG Values meeting or exceeding Pre-specified Ranges of concern by Category and Treatment

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------

QTCB n 12 13 12 >450 to <480 1 (8%) 4 (31%) 6 (50%) >=480 to <500 0 0 0 >=500 0 0 0

QTCF

n 12 13 12 CONFIDENTIAL >450 to <480 0 0 0 >=480 to <500 1 (8%) 0 0 >=500 0 0 0 126 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 12.7 Summary of Number of Subjects with Maximum ECG Values meeting or exceeding Pre-specified Individual Changes from Baseline of Category and Treatment

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------

QTCB n 12 13 12 >30 to <60 1 (8%) 2 (15%) 4 (33%) >=60 1 (8%) 0 0

QTCF

n 12 13 12 CONFIDENTIAL >30 to <60 0 0 2 (17%) >=60 0 0 0 127 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 3 Population: All Subjects Table 12.8 Summary of Urinalysis Dipstick Results

Planned Relative Placebo 066 25mcg QD 066 87.5mcg QD Visit Time Test (N=12) (N=13) (N=12) ------DAY 1 PRE-DOSE Urine Bilirubin Negative 12 (100%) 13 (100%) 12 (100%) (dipstick)

Urine Occult Blood Positive 1 (8%) 1 (8%) 2 (17%) (dipstick) Negative 11 (92%) 12 (92%) 10 (83%)

Urine General Positive 1 (8%) 1 (8%) 2 (17%)

Dipstick CONFIDENTIAL Negative 11 (92%) 12 (92%) 10 (83%)

Urine Glucose Negative 12 (100%) 13 (100%) 12 (100%) 128 (dipstick)

Urine Ketones Negative 12 (100%) 13 (100%) 12 (100%) (dipstick)

Urine Leukocyte Positive 0 1 (8%) 0 Esterase (dipstick) Negative 12 (100%) 12 (92%) 12 (100%)

Urine Nitrite Negative 12 (100%) 13 (100%) 12 (100%) (dipstick)

Urine pH 7 3 (25%) 2 (15%) 3 (25%) 6 4 (33%) 5 (38%) 8 (67%) GM2008/00234/00 5 5 (42%) 6 (46%) 1 (8%)

Urine Protein Negative 12 (100%) 13 (100%) 12 (100%) IPC103711 (dipstick) Protocol: IPC103711 Page 2 of 3 Population: All Subjects Table 12.8 Summary of Urinalysis Dipstick Results

Planned Relative Placebo 066 25mcg QD 066 87.5mcg QD Visit Time Test (N=12) (N=13) (N=12) ------DAY 1 PRE-DOSE Urine Specific 1.05 0 1 (8%) 0 Gravity 1.025 3 (25%) 3 (23%) 1 (8%) 1.02 5 (42%) 4 (31%) 4 (33%) 1.015 1 (8%) 2 (15%) 5 (42%) 1.01 1 (8%) 3 (23%) 0 1.005 2 (17%) 0 1 (8%) 1 0 0 1 (8%) CONFIDENTIAL Urine Urobilinogen Negative 12 (100%) 13 (100%) 12 (100%) (dipstick) 129

DAY 7 PRE-DOSE Urine Bilirubin Negative 12 (100%) 13 (100%) 12 (100%) (dipstick)

Urine Occult Blood Positive 2 (17%) 0 0 (dipstick) Negative 10 (83%) 13 (100%) 12 (100%)

Urine General Positive 3 (25%) 0 1 (8%) Dipstick Negative 9 (75%) 13 (100%) 11 (92%)

Urine Glucose Negative 12 (100%) 13 (100%) 12 (100%) GM2008/00234/00 (dipstick)

Urine Ketones Negative 12 (100%) 13 (100%) 12 (100%) IPC103711 (dipstick) Protocol: IPC103711 Page 3 of 3 Population: All Subjects Table 12.8 Summary of Urinalysis Dipstick Results

Planned Relative Placebo 066 25mcg QD 066 87.5mcg QD Visit Time Test (N=12) (N=13) (N=12) ------DAY 7 PRE-DOSE Urine Leukocyte Positive 1 (8%) 0 0 Esterase (dipstick) Negative 11 (92%) 13 (100%) 12 (100%)

Urine Nitrite Negative 12 (100%) 13 (100%) 12 (100%) (dipstick)

Urine pH 8 0 0 1 (8%)

7 2 (17%) 1 (8%) 3 (25%) CONFIDENTIAL 6 5 (42%) 6 (46%) 4 (33%) 5 5 (42%) 6 (46%) 4 (33%)

130 Urine Protein Positive 0 0 1 (8%) (dipstick) Negative 12 (100%) 13 (100%) 11 (92%)

Urine Specific 1.025 2 (17%) 4 (31%) 3 (25%) Gravity 1.02 5 (42%) 3 (23%) 3 (25%) 1.015 1 (8%) 2 (15%) 6 (50%) 1.01 1 (8%) 4 (31%) 0 1.005 3 (25%) 0 0

Urine Urobilinogen Negative 12 (100%) 13 (100%) 12 (100%) (dipstick) GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 12.9 Summary of Troponin Data

Planned Study Relative Result Placebo 066 25mcg QD 066 87.5mcg QD Day Time (UG/L) (N=12) (N=13) (N=12) ------7 PRE-DOSE 0 7 (64%) 8 (62%) 7 (58%) 0.01 1 (9%) 2 (15%) 3 (25%) <0.01 3 (27%) 3 (23%) 2 (17%) CONFIDENTIAL 131 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 12.10 Summary of Holter Interpretations

Placebo 066 25mcg QD 066 87.5mcg QD (N=12) (N=13) (N=12) ------DAY 1 0-6 H n 12 13 12 Normal 9 (75%) 7 (54%) 10 (83%) Abnormal - Not clinically significant 3 (25%) 6 (46%) 2 (17%) Abnormal - Clinically significant 0 0 0 CONFIDENTIAL 132 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 4 Population: All Subjects Table 12.11 Listing of ECG Values of Potential Clinical Importance

Treatment: Placebo Age(y)/ Planned Heart PR QRS RR QT Sex/ Study Relative ECG Rate Int. Dur. Int. Int. QTcB QTcF Subj. Race Day Time Date/Time (bpm) (msec) (msec) (msec) (msec) (msec) (msec) This section contained data from each individual patient, rather than in aggregate. They have been excluded 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 Sponsor Clinical Study Register.

CONFIDENTIAL

133

GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

Note: L=Low, H=High Protocol: IPC103711 Page 1 of 6 Population: All Subjects Table 12.12 Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance

Treatment: Placebo Age(y)/ Planned Sex/ Study Relative _____Converted Data______Flag[1] Subj. Race Lab Test (Units) Day Time Date/Time Value Normal Range NR CC BL This section contained data from each individual patient, rather than in aggregate. They have been excluded 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 Sponsor Clinical Study Register. CONFIDENTIAL 137 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

[1]NR for Normal Range flag, CC for Clinical Importance flag; BL for Change from Baseline H=Above range, L=Below range CONFIDENTIAL GM2008/00234/00 IPC103711

Pharmacokinetic Data Source Figure and Tables

Page Figure 13.1 Individual and Median Subject BAL GSK256066 Urea-Corrected Concentration-Time Plots - by Treatment Group ...... 144 Table 13.1 Summary of Urea-Corrected BAL GSK256066 (Supernatant) Pharmacokinetic Concentration-Time Data (pg/ml) (PK Concentration Population) ...... 146 Table 13.2 Summary of Urea-Corrected BAL GSK256066 (Pellet) Pharmacokinetic Concentration-Time Data (pg/ml) (PK Concentration Population) ...... 147 Table 13.3 Summary of Urea-Corrected BAL GSK614917 (Supernatant) Pharmacokinetic Concentration-Time Data (pg/ml) (PK Concentration Population) ...... 148 Table 13.4 Summary of Urea-Corrected BAL GSK614917 (Pellet) Pharmacokinetic Concentration-Time Data (pg/ml) (PK Concentration Population) ...... 149

143 Protocol: IPC103711 Page 1 of 2 Population: PK Concentration Figure 13.1 Individual and Median Subject BAL GSK256066 Urea-Corrected Concentration-Time Plots - by Treatment Group

Specimen Type=BAL Pellet 700000

600000 CONFIDENTIAL

500000 144

400000

300000

200000 GM2008/00234/00 GM2008/00234/00 100000 BAL GSK256066 Urea-Corrected Concentration (pg/mL) IPC103711 IPC103711 0 2H 26H Sal 26H LPS 2H 26H Sal 26H LPS 066 25mcg QDTimepoint 066 87.5mcg QD NOTE: For BAL Supernatant the median for the 26H timepoints are zero due to majority of the values being assigned as NQ. Protocol: IPC103711 Page 2 of 2 Population: PK Concentration Figure 13.1 Individual and Median Subject BAL GSK256066 Urea-Corrected Concentration-Time Plots - by Treatment Group

Specimen Type=BAL Supernatant 50000

40000 CONFIDENTIAL 145

30000

20000

10000 GM2008/00234/00 BAL GSK256066 Urea-Corrected Concentration (pg/mL) IPC103711 IPC103711 0 2H 26H Sal 26H LPS 2H 26H Sal 26H LPS 066 25mcg QDTimepoint 066 87.5mcg QD NOTE: For BAL Supernatant the median for the 26H timepoints are zero due to majority of the values being assigned as NQ. Protocol: IPC103711 Page 1 of 1 Population: PK Concentration Table 13.1 Summary of Urea-Corrected BAL GSK256066 (Supernatant) Pharmacokinetic Concentration-Time Data (pg/ml)

Planned Relative No. Treatment N Visit Time n Imputed Mean SD Median Min. Max. ------066 25mcg QD 12 DAY 7 2 H 8 0 4083.1 2955.33 3121.1 1453 8637 26 H SALINE 8 3 294.6 226.6 NQ 725 26 H LPS 8 4 723.2 NQ NQ 2893

066 87.5mcg QD 12 DAY 7 2 H 12 0 14034.3 16963.34 6555.0 2036 48875 26 H SALINE 12 4 1175.5 NQ NQ 6799 26 H LPS 12 5 369.3 NQ NQ 2216 CONFIDENTIAL 146 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

Note: LLQ = 5 ng/mL, NQ = Not Quantifiable Protocol: IPC103711 Page 1 of 1 Population: PK Concentration Table 13.2 Summary of Urea-Corrected BAL GSK256066 (Pellet) Pharmacokinetic Concentration-Time Data (pg/ml)

Planned Relative No. Treatment N Visit Time n Imputed Mean SD Median Min. Max. ------066 25mcg QD 12 DAY 7 2 H 8 0 118717.1 48468.99 128803.0 46355 170907 26 H SALINE 8 0 55940.7 18680.78 48364.3 41953 85081 26 H LPS 8 0 51760.3 23040.21 52693.4 26302 75353

066 87.5mcg QD 12 DAY 7 2 H 12 0 268687.6 193653.20 172576.1 116272 653121 26 H SALINE 12 0 178974.5 100454.00 139634.9 83052 333108 26 H LPS 12 0 101511.4 91482.81 58975.5 2466 240309 CONFIDENTIAL 147 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: PK Concentration Table 13.3 Summary of Urea-Corrected BAL GSK614917 (Supernatant) Pharmacokinetic Concentration-Time Data (pg/ml)

No data to report CONFIDENTIAL 148 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 Protocol: IPC103711 Page 1 of 1 Population: PK Concentration Table 13.4 Summary of Urea-Corrected BAL GSK614917 (Pellet) Pharmacokinetic Concentration-Time Data (pg/ml)

No data to report CONFIDENTIAL 149 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 CONFIDENTIAL GM2008/00234/00 IPC103711

Pharmacokinetic / Pharmacodynamic Data Source Figure

Page Figure 14.1 Scatter Plot of BAL Total Neutrophils (x10^6/mL) versus GSK256066 Corrected BAL Concentration (pg/mL) on Day 7 at 26H LPS ...... 151

150 Protocol: IPC103711 Page 1 of 1 Population: Per-protocol Figure 14.1 Scatter Plot of BAL Total Neutrophils (x10^6/mL) versus GSK256066 Corrected BAL Concentration (pg/mL) on Day 7 at 26H LPS

Specimen Type=BAL Pellet

7.4

2.7 CONFIDENTIAL

151 1

0.368

0.135

Total Neutrophil Count (log base e scale) 0.050 GM2008/00234/00 GM2008/00234/00

0.018 IPC103711 IPC103711 1097 2981 8103 22026 59874 162755 442413 GSK256066 Corrected BAL Concentration (log base e scale) 066 25mcg QD 066 87.5mcg QD CONFIDENTIAL GM2008/00234/00 IPC103711

Pharmacogenetic Data Source Table

Page Table 15.1 Summary of Genetics Subject Accountability (All Subjects Population) ...... 153

152 Protocol: IPC103711 Page 1 of 1 Population: All Subjects Table 15.1 Summary of Genetics Subject Accountability

Placebo 066 25mcg QD 066 87.5mcg QD Total (N=12) (N=13) (N=12) (N=37) ------Genotype consent Obtained 9 (75%) 12 (92%) 7 (58%) 28 (76%) Not obtained 3 (25%) 1 (8%) 5 (42%) 9 (24%)

Genotype sample status Collected and evaluated 9/9 (100%) 12/12 (100%) 7/7 (100%) 28/28 (100%) CONFIDENTIAL 153 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711

Attachment 1: Time and Events Table

Assessment Screening Day Early Follow- With- up drawal1 Visit 1 Visit Visit 3 Visit 4 Visit 5 2 Time relative to baseline 1 2 3 4 5 6 7 8 18-22 (Days) Informed consent x Medical & surgical history x Physical examination 2 x x x Height and weight x measurement Clinical Laboratory testing x3,16 x14 x14,16 x 7 x Urinalysis x x14 x14 x Tests for DoA, alcohol, x x14 X14 cotinine Pregnancy test x x14 x Unit visits x x x x x x Dosing x x x x x x x Vital signs (blood pressure, x4 x5 x6 x7 x x pulse, temp) in supine position Holter monitoring X15 Resting 12-lead ECG x4 x5 X13 x7 x x Spirometry x4,8 x8 x8 x8 x Bronchoscopy x x LPS instillation x BAL fluid collection x 11 x11 Blood sample for x9 Pharmacogenetics Blood Biomarkers X10 x10 x10 x Blood sample for x12 x12 measurement of urea AE/Con Med questioning x x x x x x x x x x Continued

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Attachment 1: Time and Events Table (Continued)

1. Subjects who stopped taking study medication prior to Day 7 attended an early withdrawal visit within 24h 2. Included a chest exam 3. Included serology (hepatitis and HIV) 4. In triplicate at screening only 5. Pre-dose and 30min, 1h, 2h post-dose 6. Pre-dose, 3h, 4h post dose 7. 24 hours after dosing on Day 7 8. FVC was performed at screening only. FEV1 pre-dose on Day 1 and 7, and after bronchoscopy (on Day 7 & Day 8) if required. 9. Blood sample for PGx were collected at any time post-dose (although preferably during Visit 2) once informed consent had been signed 10. Blood for biomarkers were collected pre-dose Day 1 and 7, and pre-bronchoscopy on Day 8 11. BAL samples were collected for baseline at 2 hours post dose and following LPS instillation and saline control challenge at 26 hours post-dose on Day 7. BAL concentrations of GSK25066 and GSK614917 were also determined at these time points 12. Where possible, blood sampling was taken simultaneously to BAL sample collection 13. Pre-dose and 3h 14. Pre-dose 15. Continuous Holter monitoring for 6hrs post dose 16. Included Troponin testing NB: where multiple assessments were scheduled at the same timepoints, assessments were conducted in the following order: vital signs, 12 Lead-ECG, Spirometry or, Biomarker blood sample, Bronchoscopy, BAL fluid collection,

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Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Reporting and Analysis Plan

Title: Clinical Pharmacology Reporting and Analysis Plan for a double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers

Compound Number: GSK256066

Effective Date: 02-JUN-2008

Description:

The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses and output to be included in the Clinical Pharmacology Study Report for Protocol [GlaxoSmithKline Document Number GM2007/00126/01]. This RAP is intended to describe the bronchoalveolar lavage (BAL), safety, tolerability and biomarker analyses required for the study. This document will be provided to the study team members to convey the content of the Statistical Analysis Complete (SAC) deliverable.

Identifier/Version Number: GM2007/00400/00

Subject: COPD, GSK256066, lipopolysaccharide (LPS), healthy volunteers

Author’s Name and Functional Area:

Discovery Biometrics, Respiratory

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Approved by: E-mail approval obtained

Centre for Excellence in Drug Discovery Medicine, Respiratory Clinical Science & Study Operations Clinical Pharmacokinetics Modelling & Simulation Clinical Pharmacology Data Sciences Discovery Biometrics, Respiratory Discovery Biometrics, Respiratory Interesource (Programmer, Ruislip)

The Discovery Biometrics Director (or designee) will give final approval

Discovery Biometrics (Director) 02-JUN-2008

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TABLE OF CONTENTS

PAGE

1. INTRODUCTION...... 7

2. STUDY OBJECTIVES AND ENDPOINTS...... 7 2.1. Study Objectives...... 7 2.1.1. Primary Objective ...... 7 2.1.2. Secondary Objectives...... 7 2.2. Study Endpoints...... 8 2.2.1. Primary Endpoints ...... 8 2.2.2. Secondary Endpoints...... 8

3. STUDY DESIGN ...... 8

4. PLANNED ANALYSES ...... 9 4.1. Interim Analyses ...... 9 4.2. Final Analyses ...... 9

5. ANALYSIS POPULATIONS ...... 10

6. HYPOTHESES AND TREATMENT COMPARISONS ...... 10

7. TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS...... 11

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ...... 11 8.1. Reporting Conventions ...... 11 8.2. Data Management ...... 16 8.3. Premature Withdrawal and Missing Data ...... 16 8.4. Baseline Definition...... 17 8.5. Derived and Transformed Data...... 17 8.5.1. Multiple Measurements at One Timepoint...... 17 8.5.2. Calculation of QTc(B) and QTc(F) ...... 18 8.5.3. Calculation of Spirometry Screening Parameters...... 18 8.5.4. Derivation of BAL Cell Counts and Concentrations ...... 18 8.5.5. Values Below the Limit of Quantfication...... 19 8.6. Values of Potential Clinical Importance...... 19

9. STUDY POPULATION ...... 21

10. PHARMACODYNAMIC AND BIOMARKER ANALYSES ...... 21 10.1. Pharmacodynamic Analyses...... 22 10.1.1. Bronchoalveolar Lavage (BAL) Cell Count Data ...... 22 10.1.2. BAL Flow Cytometry Monocyte Data ...... 23 10.2. Biomarker Analyses...... 23 10.2.1. BAL Biomarkers...... 23 10.2.2. Blood Biomarkers ...... 24

11. SAFETY ANALYSES ...... 24 11.1. Extent of Exposure ...... 24

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11.2. Other Safety Measures...... 25 11.2.1. Adverse Events of Special Interest ...... 25 11.2.2. Clinical Laboratory Evaluations...... 25 11.2.2.1. Troponin...... 25 11.2.3. ECG Data ...... 25 11.2.4. Holter monitoring ...... 25 11.2.5. Vital Signs Data ...... 25

12. PHARMACOKINETIC ANALYSES...... 26 12.1. Drug Concentration Measures ...... 26

13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...... 26

14. PHARMACOGENETIC ANALYSES ...... 27 14.1. Pharmacogenetic Analyses ...... 27

15. REFERENCES...... 28

16. ATTACHMENTS ...... 29 16.1. Table of Contents for Data Display Specifications...... 29 16.1.1. Study Population Tables...... 29 16.1.2. Pharmacodynamic Figures and Tables...... 29 16.1.3. Biomarker Figures and Tables ...... 35 16.1.4. Safety Tables...... 37 16.1.5. Pharmacokinetic Figures and Tables...... 38 16.1.6. Pharmacokinetic/Pharmacodynamic Figures ...... 39 16.1.7. Pharmacogenetic Tables ...... 39 16.1.8. ICH Listings ...... 40 16.1.9. Other Listings ...... 42 16.2. Data Display Specifications ...... 46

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LIST OF ABBREVIATIONS

A&R Analysis & Reporting AE Adverse Event ALT Alanine aminotransferase (SGPT) AST Aspartate aminotransferase (SGOT) BAL Bronchoalveolar lavage BP Blood pressure BPM Beat Per Minute CI Confidence Interval CPSR Clinical Pharmacology Study Report CRF Case Report Form CV Coefficient of variance DB Discovery Biometrics dp Decimal place DMPK Discovery Medicine Pharmacokinetics ECG Electrocardiograph eCRF Electronic case report form FEV1 Forced Expiratory Volume in One Second FVC Forced vital capacity h Hour HARP Harmonisation of Analysis and Reporting Program HR Heart rate ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use IDSL Integrated Data Standards Library L Litre LPS Lipopolysaccharide LQ Limit of Quantification µg Microgram MedDRA Medical dictionary for regulatory applications mL Milliliter msec Millisecond NQ Non-quantifiable concentration measured as below LLQ PCI Potential Clinical Importance PD Pharmacodynamics PDF Portable Document Format PK Pharmacokinetics QD Once daily RAP Reporting and Analysis Plan SAC Statistical Analysis Complete SAS Statistical Analysis Software SD Standard deviation SDb Between-subject standard deviation se Standard error sf Significant figures SI System Independent TST Therapeutic Standards Team

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ULN Upper limit of normal WBC White blood cells

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies ACCUHALER SAS UNIX

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1. INTRODUCTION

The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in the Clinical Pharmacology Study Report for Protocol:

Revision Chronology:

Original Document Number: 2007-APR-23 Original [GlaxoSmithKline Document Number GM2007/00126/01]

Revised Document Number: 2007-AUG-14 Amendment 1 [GlaxoSmithKline Document Number GM2007/00126/02]

The statistical analyses, data listings, summary tables and graphs will be produced by, or under the direct auspices of, Discovery Biometrics (DB), GlaxoSmithKline. The results of the analyses will be provided for inclusion in the final study report.

All decisions regarding final analysis, as defined in this RAP document, have been made prior to Database Freeze (unblinding) of the study data. Interim analyses are detailed within Section 4.1 where applicable.

2. STUDY OBJECTIVES AND ENDPOINTS

2.1. Study Objectives

2.1.1. Primary Objective

• To investigate the effects of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) on lung inflammation following segmental LPS challenge in healthy volunteers.

2.1.2. Secondary Objectives

• To investigate the safety and tolerability of 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) in healthy volunteers. • To investigate the response of systemic markers of inflammation following 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) in healthy volunteers.

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2.2. Study Endpoints

2.2.1. Primary Endpoints

• Bronchoalveolar lavage (BAL): • Absolute BAL neutrophils at 24 h post LPS exposure • The total and differential cell count (total and percentage cell counts) in BAL at 24 h post LPS exposure Note: Cell types include neutrophils, eosinophils, macrophages, lymphocytes and bronchial epithelial cells from cytospins and CD14+ monocytes from flow cytometry. For clarification purposes, the main primary endpoint of interest is total number of BAL neutrophils/mL at 24 h post LPS exposure. Please refer to Section 8.5.4 for derivation.

2.2.2. Secondary Endpoints

• Safety and tolerability: • Vital Signs: systolic and diastolic blood pressure (BP), heart rate (HR) • Holter monitoring • 12-lead ECG including QTc(B), QT, QRS, PR, and ventricular rate (VR) • Lung function (FEV1 and FVC) • Laboratory safety tests (haematology, clinical chemistry, urinalysis) • Adverse Events • Serum concentration of protein inflammatory biomarkers (e.g. surfactant protein D (SP-D), clara cell protein (CC-16)) Note: The final list of serum protein inflammatory biomarkers is SP-D, CC-16.

• BAL concentrations of protein inflammatory biomarkers (e.g. interleukin 8 (IL-8), tumour necrosis factor alpha (TNFα), interleukin 6 (IL-6), myeloperoxidase (MPO)) Note: The final list of BAL protein inflammatory biomarkers is IL-8, TNFα, IL-6, MPO.

• BAL concentrations of GSK256066 and metabolite GSK614917

3. STUDY DESIGN

This is a single centre, randomised, double-blind, parallel-group, 7 day repeat dose study in healthy volunteers.

All subjects will attend the unit for screening within 28 days of their first dosing occasion.

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Eligible subjects will be randomised (1:1:1) to receive one of the following treatments, as a single, once daily inhaled dose for 7 days (via an ACCUHALER™ device):

• GSK256066 (25µg) • GSK256066 (87.5µg) • Placebo Following dosing on Day 7 subjects will undergo bronchoscopy, bronchoalveolar lavage (BAL) and segmental LPS challenge. Repeat bronchoscopy and BAL will be performed 24 hours later; (subjects may have only two bronchososcopies conducted within a 7 day period).

All subjects will attend the unit for a follow up visit within 7-10 days following their final dose.

The overall duration (screening to follow up), for participating subjects, will not exceed 45 days.

4. PLANNED ANALYSES

Data will be analysed when all eCRF and external data has been brought in house, cleaned, released, frozen and unblinded.

4.1. Interim Analyses

No interim analyses are planned. However, if there is a delay in receiving the biomarker results, all other data will be processed and a partial database release will be conducted to allow for the reporting of all other data collected in this study. Unblinding will occur at this time. Although the data at time of database release will be as near to final as possible, it is not possible to guarantee that this data will not change until the database is frozen. Database freeze will occur once all data including the urea analysis results are in- house.

4.2. Final Analyses

The final planned analyses will be performed after all subjects have completed the study and after database freeze/unblinding. See Section 9 to Section 14 for all final planned analyses for this study.

The final analysis will occur in two stages. See Section 16.1 for details of output to be included in headline results (stage 1).

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5. ANALYSIS POPULATIONS

All Subjects Population

The ‘All Subjects Population’ is defined as all subjects who receive at least one dose of study medication/treatment (including placebo). This population will be used for all study population, safety and pharmacogenetic outputs.

Per-Protocol (PP) Population

The subject complained about systemic LPS side effect (fever) and the site noticed elevated leukocyte count and CRP. With local LPS challenge, the site had never seen such a systemic reaction and a neutrophilic inflammation in the post saline segment. The ‘Per-Protocol’ population is defined as the ‘All Subjects’ population with this subject excluded and will be used for all pharmacodynamic and biomarker outputs.

Pharmacokinetic (PK) Population

The ‘PK Population' is defined as subjects in the ‘All Subjects’ population for whom a pharmacokinetic sample was obtained and analysed. This population will be used for all PK outputs.

All analyses will be based on the actual treatment each subject received. Any departures from the planned treatment according to the randomisation schedule will be documented in the study report.

6. HYPOTHESES AND TREATMENT COMPARISONS

Precision Estimation

This study is designed to estimate the effect of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) relative to placebo on lung inflammation following segmental LPS challenge in healthy volunteers. No formal hypothesis will be tested. Point estimates and corresponding 95% confidence intervals will be constructed for the difference between the mean of the test treatment and the mean of the reference treatment, µ(test) - µ(reference).

Primary Comparisons of Interest

The primary treatment comparisons are:

• GSK256066 25µg versus placebo for the total number of BAL neutrophils/mL at 24 hours post LPS exposure. • GSK256066 87.5µg versus placebo for the total number of BAL neutrophils/mL at 24 hours post LPS exposure.

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Other Comparisons of Interest

The secondary treatment comparisons are:

• GSK256066 25µg versus placebo • GSK256066 87.5µg versus placebo For the following endpoints:

• The total and differential cell count in BAL • The concentration of BAL inflammatory biomarkers (IL-8, TNFα, IL-6, MPO) • The concentration of serum inflammatory biomarkers (SP-D, CC-16) No adjustments will be made for multiplicity.

7. TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS

Randomisation Final Data Display (i.e. HARP / other) Code Treatment Description Treatment Description A GSK256066 25µg 066 25mcg QD B GSK256066 87.5µg 066 87.5mcg QD C Placebo Placebo

In accordance with IDSL, treatments will appear in the displays with placebo first, followed by GSK256066 in dose ascending order.

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING

8.1. Reporting Conventions

Statistical analyses will be performed by, or under the direct auspices of, Discovery Biometrics, GlaxoSmithKline. All data displays will be presented according to the IDSL statistical display principles and all approved IDSL TST standards. All figures, tables and listings will be produced in HARP which utilises the currently supported version of SAS on a UNIX platform.

Any changes from the analyses described within this RAP will be detailed in Section 8.2.4 of the study report, together with the reason for such changes.

The following conventions will be applied to the figures, tables, listings and analyses described in this RAP:

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• Any unplanned or unscheduled data will be presented in the subject listings. • Data collected at screening, at unscheduled time points and at follow-up will be listed however it will not be included in the summary tables, summary figures, statistical analyses or derivation of derived parameters, except where otherwise stated. • All listings and summaries will be based on the actual treatment each subject received rather than the intended randomised treatment. • In all tables/listings (except where otherwise stated), planned and actual relative times will be relative to the last study drug dosing start time. • In all listings and tables, the PTM (planned timepoint description) variable needs to be reformatted without ‘1’ when there is only one measurement at the given visit, e.g. ‘SCREENING 1’ should be reformatted to ‘SCREENING’ if there is no ‘SCREENING 2’.

General Considerations for the Creation of PKCNC and PDCNC Datasets

• Creation of Analysis & Reporting (A&R) PKCNC dataset: 1. PK System Independent (SI) dataset and PK SMS file should be merged by the variable PKSMPID to create a temporary PKCNC dataset. 2. The temporary PKCNC dataset and PDCNC2 SI dataset, containing BAL and serum urea data should be merged by the variables SUBJID and PTMNUM to create the PKCNC A&R dataset. Note: See Section 8.5.4 for details about urea correction.

• Creation of Analysis & Reporting (A&R) PDCNC1 dataset: 1. PD SI dataset and PDCNC1 SI dataset should be merged to create the A&R PDCNC1 dataset. 2. PD SI dataset and PDCNC2 SI dataset should be merged to create the A&R PDCNC2 dataset. 3. The A&R PDCNC1 and PDCNC2 datasets should be merged by the variables SUBJID and PTMNUM to create the D_PDCNC1 A&R dataset containing the urea dilution factor, the raw BAL corrected concentration and the BAL corrected concentration. Note: See Section 8.5.4 for details about urea correction.

• Creation of Analysis & Reporting (A&R) PDCNC3 dataset: 1. PD SI dataset and PDCNC3 SI dataset should be merged to create the A&R PDCNC3 dataset. 2. PD SI dataset and PDCNC2 SI dataset should be merged to create the A&R PDCNC2 dataset.

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3. The A&R PDCNC2 and PDCNC3 datasets should be merged by the variables SUBJID and PTMNUM to create the D_PDCNC3 A&R dataset containing the urea dilution factor, the raw BAL corrected concentration and the BAL corrected concentration. Note: See Section 8.5.4 for details about urea correction.

• Creation of Analysis & Reporting (A&R) PDCNC4 dataset: 1. PD SI dataset and PDCNC4 SI dataset should be merged to create the A&R PDCNC4 dataset.

General Considerations for Listings

Listings will be sorted by treatment (in chronological order), subject number, and where applicable, day and planned relative time.

Raw data will generally be presented in the listings to the same number of decimal places as the data was collected. Any derived parameters will generally be presented to 1 additional decimal place than the raw data. However, the maximum number of decimal places will be to 3 significant figures.

General Considerations for Summary Tables

Summaries will be provided by treatment and where applicable, day and planned relative time.

The following basic descriptive statistics will be included in each summary table of continuous data: n, mean, standard deviation (sd), median, minimum (min) and maximum (max). Additional summary statistics will be included where stated in the relevant analysis section.

N and n will be presented to 0 decimal places, minimum and maximum will be presented to the same number of decimal places as in the listings, mean, median and confidence intervals will be presented to 1 additional decimal place, SD will be presented to 2 additional decimal places, CV% will be presented to 1 d.p. In the case where the number of decimal places is so great that no additional information is being added, reporting will be to the number of decimal places considered appropriate. For data log-normally distributed the following statistics will be presented: geometric mean, standard deviation of the log-transformed data, 95% confidence interval and coefficient of variation.

The between-subject coefficient of variation expressed as a percentage (CV%) will only be presented on summary tables for log-transformed endpoints. For loge-transformed SD**2 data the CV% will be calculated as 100*sqrt(e – 1), with SD of loge-transformed data.

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The between-subject standard deviation (SDb) should not be presented within the analysis tables. a. Use actual, rather than planned, sampling times in the individual concentration-time plots. Use nominal time in the descriptive summaries and in mean and median plots. List concentration-time data according to actual sampling times relative to dosing time. Any subjects excluded from the summaries and/or statistical analyses will be documented along with the reason for exclusion in the study report.

The largest possible font size should be used for the axis text and the legend on pdf plots, in order to obtain a good resolution.

Plots performed on log-transformed data should use a log scale.

As a minimum, the variables listed in Table 1 will be included in the presentation of Adjusted (Geometric) Means.

Table 1 List of Variables for Inclusion in the Presentation of Adjusted (Geometric) Means

If Data untransformed If Data Log-transformed No. of decimal places (dp) more than raw data Label Description Label Description Parameter Where applicable Parameter Where applicable e.g. total N/A cell count Treatment Treatment group e.g. Placebo, Treatment Treatment group e.g. N/A 066 Placebo, 066 N (number of subjects in the N (number of subjects in the N/A treatment group for the treatment group for the respective populations) respective populations) Planned Where applicable e.g. 1h Planned Time Where applicable e.g. 1h N/A Time n (number of subjects with non- N (number of subjects with non- N/A missing values) missing values) Adjusted Adjusted mean for each Adjusted Geo. Adjusted geometric mean for 1 dp more Mean treatment group Mean each treatment group SE Standard errors of data for SE logs Standard errors of log Always each treatment group transformed data for each present to 3 sf. treatment group 95%1 CI of 95% confidence interval around 95%1 CI of Geo. 95% confidence interval 1 dp more Means adjusted treatment mean Means around adjusted geometric treatment mean 1. A two-sided t-test with α=0.05

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• As a minimum, the variables listed in Table 2 will be included in the presentation of pairwise comparisons. Table 2 List of Variables for Inclusion in the Presentation of Pairwise Comparisons

If Data untransformed If Data Log-transformed No. of decimal places (dp) more than raw data

Label Description Label Description

Comparison Treatment Comparison Treatment comparison N/A Test-Ref. comparison e.g. 066 Test/Ref. e.g. 066 25mcg vs. 25mcg vs. placebo placebo

Planned Time Where applicable Planned Time Where applicable e.g. N/A e.g. 24 h 24 h

Difference in Treatment Ratio of Adjusted Treatment ratio of 1 dp more Adjusted difference of Geo. Means adjusted geometric (untransformed)/always to 3 Means adjusted means means (Test/Ref.) dp (log-transformed) (Test-Ref.)

SE Standard error of SE logs Standard error of ratio 2 dp more difference (untransformed)/always to 3 dp (log-transformed)

95%1 CI of Diff. 95% confidence 95%1 CI of Ratio 95% confidence 1 dp more interval of difference interval of the ratio of (untransformed)/always to 3 in treatment means treatment means dp (log-transformed) P-Value P-Value for P-Value P-Value for Always present to 3dp comparison comparison 1. A two-sided t-test with α=0.05

For each analysis, the variables in Table 1 and Table 2 will be included in the same table but presented on separate pages.

General Considerations for Statistical Analyses

Distributional assumptions underlying the model used for analysis will be examined by obtaining a normal probability plot of the residuals, a plot of the residuals versus the predicted values and a plot of the residuals versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the model respectively) to gain confidence that the model assumptions are reasonable. If the assumptions are not valid alternative analyses will be performed. All summaries and plots checking underlying assumptions of the model will be included in the appropriate raw SAS output.

The Kenward and Roger method for approximating the denominator degrees of freedom and correcting for bias in the estimated variance-covariance of the fixed effects will be used in mixed models analyses.

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In all repeated measures models (i.e. serial timepoint analyses), an unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on the REPEATED line.

If there is a memory problem, there is an option in HARP to change the SAS memsize which allows use of more memory. The default is 96 MB, and HARP allows you to increase the memory from 97 MB to 300MB.

For each statistical analysis, two lsmeans statements will be used. These will be the same in terms of the lsmeans specified, but one will include the OM option. Standard least squares means give equal weighting across the levels of a covariate. The OM option changes these weights to be proportional to those found in the input dataset. When the number of subjects in each level of a covariate differs greatly, using the OM option would result in the least squares means being close to the average value for the data set, rather than being shifted to be a value for an average across the classes. The OM option has not been used enough in previous studies to choose it as default. If the treatment difference is the same whether using the OM option or not, and if the adjusted means are closer to the raw means using the OM option, the estimates obtained using the OM option will be used. Otherwise, estimates from the LSMEANS obtained in the model using the OM option will be investigated.

8.2. Data Management

Data Type Source Format of Planned Date Responsibility Data of Final File1 All data Inform database IDSL – SI DBR : CPDS except datasets 29MAY08 PDCNC, PK DBF : and Lab 02JUN08 LAB, PDCNC External IDSL – SI DBR : CPDS datasets 29MAY08 DBF : 02JUN08 PK SMS 2000 PK HARP DBR : DMPK concentration 29MAY08 DBF : 02JUN08 1. This is for study teams to determine upfront if there is a possibility of not meeting the completion of the CPSR within 6 months of LSLV (i.e. novel data that may not be available until several months after LSLV).

8.3. Premature Withdrawal and Missing Data

Data for any subjects who were recruited but withdrew prior to receiving study drug will not be databased and will therefore not be included in any of the listings, summaries, analyses or figures.

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All subjects who withdraw prematurely from the study/study drug will be documented and the reason for their withdrawal recorded in the final Clinical Pharmacology Study Report (CPSR). All available data from subjects who withdraw will be listed and all available planned data will be included in the summaries according to the populations defined in Section 5.

If a subject completes a session but has missing data (e.g. a missing safety, pharmacokinetic, pharmacodynamic measurement) these data will be indicated by the use of a “blank” or “dot” in subject listings.

8.4. Baseline Definition

The following table indicates the baseline day to be used in the analysis:

Parameter Baseline (Predose) Days Collected Day 1 Day 7 Safety : Urinalysis X Vital Signs X ECG X Holter Monitoring X

Spirometry (FEV1) X Blood Biomarkers X BAL Cell Count X (2h Post Dose)

8.5. Derived and Transformed Data

Details regarding any other deviations or data transformations are given in the relevant analyses sections.

8.5.1. Multiple Measurements at One Timepoint

Where multiple measurements are recorded for a particular time point, the mean of the measurements will be calculated and used in any derivation of summary statistics, unless for FEV1 and FVC where it will be the maximum. However all available data will be listed.

Where more than the specified number of measurements has been taken, the most recently recorded values will be used in the derivation of the appropriate summary measure (i.e. mean or maximum).

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8.5.2. Calculation of QTc(B) and QTc(F)

QTc(B) and QTc(F) will be derived as follows (assuming that QT value is available):

Firstly the RR interval (msec) will be calculated as

RR interval = 1/ ((EGHR/60)/1000)

Bazett’s correction (msec) will be calculated as

1/2 QTc(B) =QT/(RR/1000)

And then Fridericia's correction (msec) will be calculated as

1/3 QTc(F) =QT/(RR/1000)

8.5.3. Calculation of Spirometry Screening Parameters

Derived parameters at screening for spirometry data will be calculated as follows:

• Males : Predicted Normal FEV1 = [(4.301x(Height/100))–(0.029xAge) – 2.492]. • Females : Predicted Normal FEV1 = [(3.953x(Height/100))–(0.025xAge)–2.604]. Where age=25 if subject aged 18-25. Note, this is the appropriate formula for subjects aged >18yrs as per inclusion criteria.

• % Predicted Normal FEV1 = (Max. FEV1/Predicted Normal FEV1)*100. • FEV1/FVC ratio = Max FEV1 / Max FVC.

8.5.4. Derivation of BAL Cell Counts and Concentrations

Total Number of Cells/mL

The total Number of Inflammatory Cells (cells/mL) is calculated as:

Total ofnumber ofe(percentag inflammato cells)ry = x (total leukocyte count) inflammato cells/mLry 100

BAL Concentrations

BAL concentrations will be first correct for dilution. Corrected concentrations will be calculated as follows: Corrected concentration = ConcentrationBAL x dilution factor,

Where dilution factor = UREAserum / UREABAL

Only corrected concentrations will be used for summaries and analyses.

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8.5.5. Values Below the Limit of Quantfication

For pharmacodynamic and biomarker endpoints, values that are below the limit of quantification (LQ) will be substituted with half the limit of quantification prior to the analysis (multiply the LQ value by the dilution factor for BAL concentrations). If there are more than 25% of these values a sensitivity analyses (i.e. using 0 or LQ instead of half LQ) may be used in order to determine the effect of such substitutions on the results of the analyses. If there are over 75% values BLQ no analyses will be performed and the data will only be summarised.

8.6. Values of Potential Clinical Importance

Laboratory Values of Potential Clinical Importance (Healthy Volunteers)

Haematology Analyte Effect Potential Clinical Importance (PCI) Range Unit White Blood Cell Count Low < 3 x109/ L (WBC) High > 20 x109/ L Haemoglobin Low > 25 Change from baseline g/L High > 180 g/L Haematocrit Low > 0.075 Change from baseline Ratio of 1 High > 0.54 Ratio of 1 Platelet Count Low < 100 x109/ L High > 550 x109/ L Red Blood Cell Count (RBC) Low Male < 4.185 x1012/ L Female < 3.72 x1012/ L High Male > 6.313 x1012/ L Female > 5.564 x1012/ L MCV Low < 19 FL High > 192 FL MCH Low Male < 23.8 pg Female < 22.95 pg High Male > 39.6 pg Female > 38.4 pg MCHC Low < 272 g/L High > 396 g/L Reticulocytes Low < 2 % High > 18 % Basophilis Low 0 % High > 10 % Eosinophils Low 0 % High > 10 % Lymphocytes Low < 16 % High > 80 % Monocytes Low < 0.5 % High > 20 % Neutrophils Low < 32 % High > 90 %

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Chemistry Analyte Effect Potential Clinical Importance (PCI) Unit Range/Value Albumin Low < 45 % High > 85 % Calcium Low < 2.0 mmol/L High > 2.75 mmol/L Creatinine High > 1.3x ULN mmol/L High > 27 Change from baseline µmol/L Glucose Low < 3.0 mmol/L High > 9 mmol/L Phosphate Low 0 mmol/L High > 3.2 mmol/L Potassium Low < 2.63 mmol/L High > 6.16 mmol/L Sodium Low < 130 mmol/L High > 155 mmol/L Blood Urea Low 0 mmol/L High > 14.3 mmol/L Creatine Kinase Low 0 U/L High > 510 U/L Creatine Kinase-MB High > 25 U/L Uric Acid Low Male < 123.9 µmol/L Female < 118 µmol/L High Male > 501.5 µmol/L Female > 413 µmol/L Total Protein Low 0 g/L High > 100 g/L Gamma GT Low Male 0 U/L Female 0 U/L High Male > 120 U/L Female > 80 U/L Chloride Low < 85.5 mmol/L High > 121 mmol/L LDH Low 0 U/L High > 486 U/L CRP Low 0 U/L High > 15 U/L Troponin T Low 0 ng/mL High > 0.1 ng/mL Gamma Globulin Low < 7 % High > 30 %

Liver Function Test Analyte Effect Potential Clinical Importance (PCI) Range Unit ALT/SGPT High ≥ 2x ULN U/L AST/SGOT High ≥ 2x ULN U/L AlkPhos High ≥ 2x ULN U/L T Bilirubin High ≥ 1.5xULN µmol/L

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ECG Values of Potential Clinical Importance (Healthy Volunteers)

All ranges for QTc intervals apply to both QTc(b) and QTc(F):

ECG Parameter Potential Clinical Importance Range (PCI) Unit Absolute QTc interval >450 msec Increase from baseline QTc >60 msec PR interval <110 and >220 msec QRS interval <75 and >110 msec

Further subdivision of ECG data for analysis (see Section 11.2.3) for more details:

ECG Parameter Potential Clinical Importance Range (PCI) Unit Absolute QTc interval >450 to ≤479 msec Absolute QTc interval ≥480 to ≤499 msec Absolute QTc interval ≥500 msec Increase from baseline QTc >30 to ≤59 msec Increase from baseline QTc ≥60 msec

Vital Sign Values of Potential Clinical Importance (Healthy Volunteers)

Vital Sign Parameter Potential Clinical Importance Range (PCI) Unit Systolic Blood Pressure < 85 and > 160 mmHg Diastolic Blood Pressure < 45 and > 100 mmHg Heart Rate < 40 and > 110 bpm

9. STUDY POPULATION

Study population data will be summarised by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The precise format and content of Study Population tables are shown in Section 16.1.1 of the RAP.

The tables will use the “All subjects” population unless otherwise specified.

10. PHARMACODYNAMIC AND BIOMARKER ANALYSES

Pharmacodynamic and biomarker data will be summarised by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The precise format and content of pharmacodynamic and biomarker figures and tables are shown in Section 16.1.2 and Section 16.1.3 of the RAP.

The figures and tables will use the “All subjects” population unless otherwise specified.

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10.1. Pharmacodynamic Analyses

10.1.1. Bronchoalveolar Lavage (BAL) Cell Count Data

BAL cell count data will be collected on Day 7 at three timepoints: 2 hours post-dose, and following saline instillation and LPS instillation at 26 hours post-dose.

The total number of inflammatory cells in cells/mL (neutrophils, eosinophils, macrophages, lymphocytes, bronchial epithelial cells) will be derived according to the formula displayed in Section 8.5.4.

The percentage of inflammatory cell type (neutrophils, eosinophils, macrophages, lymphocytes, bronchial epithelial cells) will be listed alongside the total leukocyte count and the total number of inflammatory cells in cells/mL (neutrophils, eosinophils, macrophages, lymphocytes, bronchial epithelial cells).

For each inflammatory cell, total number cells/mL and percentage of cells will be summarised by treatment using appropriate statistics depending on the data distribution.

Statistical Analysis of Sputum Inflammatory Cells

The primary analysis will be the comparison of total number of BAL neutrophils/mL at 24 h post LPS exposure between each dose of GSK256066 and placebo on Day 7. Loge- transformed data will be analysed using a fixed effects analysis of variance model adjusting for treatment effect. No sample has been taken pre-treatment (a ‘true’ baseline) for the subjects are limited to two bronchoscopies over a week. Inclusion of loge- transformed total number of neutrophils/mL at 2h post-dose (baseline1) and post-saline at 26h post-dose (baseline2) on Day 7 will be considered. The impact of these baseline effects in the model will be investigated and baseline may be removed from the model.

The following statements will be specified in the PROC MIXED procedure in SAS:

CLASS ;

MODEL = / DDFM = kenwardroger;

LSMEANS / DIFF CL ALPHA=0.05;

RUN;

Adjusted geometric means for each treatment group will be presented, along with corresponding 95% confidence intervals. Pairwise comparisons between each dose (25µg and 87.5µg) and placebo will be calculated by exponentiating the difference between the adjusted arithmetic means of the loge transformed data. Corresponding 95% confidence intervals of these ratios will also be constructed, using the residual variance from the fixed effects model. Corresponding plots of adjusted treatment geometric means and treatment ratios will be produced.

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Similarly, the same fixed effects model will be fitted for the untransformed percentage total neutrophils/mL at 26 h post-dose and post-LPS exposure. If diagnostic checks suggest that a loge transformation is appropriate, then the fixed effects model will be fitted to loge-transformed data. The summaries will clearly state whether analysis was performed on untransformed or loge-transformed data.

Using the same approach, the following inflammatory cells will also be analysed: total number of macrophages/mL, %eosinophils, total number of eosinophils/mL, %macrophages, total cell count. The summaries will clearly state whether the analysis was performed on untransformed or loge transformed data for each individual endpoint.

10.1.2. BAL Flow Cytometry Monocyte Data

BAL total number of monocytes/mL and percentage of monocytes from flow cytometry will be listed, summarised and plotted in the form of mean plots, including individual values.

10.2. Biomarker Analyses

10.2.1. BAL Biomarkers

BAL concentrations will be corrected for dilution (refer to Section 8.5.4 for more details), only the corrected concentrations will be used for analysis, the uncorrected ‘raw’ concentrations will be included in the listings.

Raw and corrected concentration BAL biomarker data and dilution factor will be listed by treatment and planned time relative to dosing (i.e. Day 7, 2 hours or 26 hours post- dose, post-saline and post-LPS instillation), however only corrected concentration BAL biomarker data will be summarised.

Corrected concentration will be loge-transformed and analysed using a fixed effects model adjusting for treatment. As explained in Section 10.1.1, the impact of the baseline effect in the model will be investigated and baseline may be removed from the model.

Refer to Section 10.1.1 for details about the model.

From the above analysis, adjusted geometric means for each treatment group on Day 7 26 hours post-LPS instillation will be presented, along with corresponding 95% confidence intervals. Estimates of treatment ratios for both the doses of GSK256066 compared to placebo will be calculated by exponentiating the difference between the adjusted means. Corresponding 95% confidence intervals of these ratios will also be presented. Plots of adjusted treatment geometric means and treatment ratios will be produced.

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10.2.2. Blood Biomarkers

The following statements will be specified in the PROC MIXED procedure in SAS:

CLASS ;

MODEL = / DDFM = kenwardroger;

REPEATED / subject=subjid type=UN R CORR;

LSMEANS / DIFF CL ALPHA=0.05;

RUN;

Adjusted geometric means for each treatment group on Day 7 pre-dose and 26 hours post-dose will be presented, along with the corresponding 95% confidence intervals. Estimate of treatment ratios for both doses of GSK256066 compared to placebo will be calculated by exponentiating the difference between the adjusted means. The corresponding 95% confidence intervals of these ratios will also be presented. Plots of adjusted treatment geometric means and treatment ratios will be produced.

11. SAFETY ANALYSES

Safety data will be graphically presented, summarised and listed by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The precise format and content of Safety tables and listings are shown in Section 16.1.3 of the RAP.

The tables will use the “All subjects” population unless otherwise specified. No formal statistical analysis will be carried out on the safety endpoints.

11.1. Extent of Exposure

Treatment exposure data will be listed. The data listing will include treatment, subject number, day, the date and time of dose. The daily dose received (in terms of µg), cumulative dose (in terms of µg) received and time on study drug will be summarised for GSK256066.

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11.2. Other Safety Measures

11.2.1. Adverse Events of Special Interest

Listings showing safety data for subjects with AEs of interest will be added in Section 11.2.2, Section 11.2.3 and Section 11.2.5, to monitor any renal and cardiac events following the pre-clinical renal and cardiac findings.

A list of AEs of interest by preferred term will be sent by the programmer and agreed by the medical monitor and the safety review team leader when final data is available.

11.2.2. Clinical Laboratory Evaluations

A listing of clinical chemistry data for subjects with AE’s of interest (see Section 11.2.1 for more details) will be provided.

11.2.2.1. Troponin

Troponin data will be summarised categorically by treatment group and day.

11.2.3. ECG Data

A listing of ECG data for subjects with AE’s of interest (see Section 11.2.1 for more details) will be provided.

Summaries of ECG values and maximum increase from baseline in ECG values will be created to monitor cardiac events.

Subject data fulfilling the ECG criteria given in Section 8.6 will be summarised by category and treatment to monitor cardiac events.

Summaries will consist of number and percentage of subjects fulfilling the criteria across all of the planned relative time points.

11.2.4. Holter monitoring

Holter monitoring data will be listed and summarised.

11.2.5. Vital Signs Data

A listing of vital signs data for subjects with AE’s of interest (see Section 11.2.1 for more details) will be provided.

Pulmonary Lung Function Tests: FEV1 and FVC

FEV1, % predicted FEV1 (only at screening) and FVC (only at screening) will be listed.

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12. PHARMACOKINETIC ANALYSES

The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be performed by, or under the direct auspices of, Clinical Pharmacology Data Sciences (CPDS), GlaxoSmithKline.

The merge of PK concentration data, randomisation and CRF data will be performed by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The figures and tables will use the PK population unless otherwise specified.

The precise format and content of PK figures and tables are shown in Section 16.1.5 of the RAP.

12.1. Drug Concentration Measures

Individual raw and urea corrected BAL concentrations of GSK256066 and metabolite GSK614917 will be listed by nominal time and treatment.

Corrected concentrations of GSK256066 and its metabolite GSK614917 in BAL will be summarised by treatment group and nominal time. Standard summary statistics will be calculated (i.e. mean, standard deviation, median, minimum and maximum). Corrected BAL concentrations below the assay’s lower limit of quantification (NQ) should be set to zero for calculation of summary statistics.

Individual and median BAL concentration-time data profiles and median/mean profiles by treatment group will be plotted. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot).

13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES

PK/PD data will be summarised by, or under the direct auspices of, Discovery Biometrics (Statistician), GlaxoSmithKline.

The precise format and content of PK/PD figures are shown in Section 16.1.6 of the RAP.

The figures will use the PK population unless otherwise specified.

If the summary statistics indicates a correlation between dose and the primary endpoints, exploratory data-driven analysis many be conducted to investigate the relationship between dose, urea-corrected BAL concentration of GSK256066 and active metabolite GSK614917, and the primary endpoints. If data permit, spaghetti-type plots of individuals will be produced. Urea-corrected BAL concentration data will only be used at time points where PD endpoints have been collected.

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14. PHARMACOGENETIC ANALYSES

14.1. Pharmacogenetic Analyses

Pharmacogenetic data will be summarised by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The precise format and content of the pharmacogenetic table are shown in Section 16.1.7 of the RAP.

The table will use the “All subjects” population unless otherwise specified.

If any pharmacogenetic data analysis is to be carried out, it will be described in a separate analysis plan.

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15. REFERENCES

GlaxoSmithKline Document Number GM2007/00126/01 Study ID IPC103711. A double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers. Report Date 23-Apr-2007.

GlaxoSmithKline Document Number GM2007/00126/02 Study ID IPC103711. A double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers. Report Date 14-Aug-2007.

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16. ATTACHMENTS

16.1. Table of Contents for Data Display Specifications

16.1.1. Study Population Tables

Table Population IDSL No. / Title Additional Programming Responsibility Deliverable No. Example Shell Notes Priority 9.1 All Subjects ES1 (Core) Summary of Subject Disposition DB (Prog) Headline

9.2 All Subjects DM1 (Core) Summary of Demographic Characteristics DB (Prog) Headline CONFIDENTIAL

9.3 All Subjects DM6 (Core) Summary of Race and Racial Combination Details DB (Prog)

184 16.1.2. Pharmacodynamic Figures and Tables

Figures

Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Plot of Adjusted Geometric Means and 95% CIs 10.1 All Subjects With individual raw values DB (Stats) Headline of BAL Total Number of Neutrophils /mL

Plot of Adjusted Treatment Ratios and 95% CIs of GM2008/00234/00 10.2 All Subjects DB (Stats) Headline BAL Total Number of Neutrophils /mL Continued IPC103711

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Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Plot of Adjusted Means and 95% CIs of BAL 10.3 All Subjects With individual raw values DB (Stats) Headline Percentage of Neutrophils

Plot of Adjusted Treatment Differences and 95% 10.4 All Subjects DB (Stats) Headline CIs of BAL Percentage of Neutrophils

Plot of Adjusted Geometric Means and 95% CIs 10.5 All Subjects With individual raw values DB (Stats) of BAL Total Number of Eosinophils /mL

Plot of Adjusted Treatment Ratios and 95% CIs of CONFIDENTIAL 10.6 All Subjects DB (Stats) BAL Total Number of Eosinophils /mL

185 Plot of Adjusted Means and 95% CIs of BAL 10.7 All Subjects With individual raw values DB (Stats) Percentage of Eosinophils

Plot of Adjusted Treatment Differences and 95% 10.8 All Subjects DB (Stats) CIs of BAL Percentage of Eosinophils

Plot of Adjusted Means and 95% CIs of BAL Total 10.9 All Subjects With individual raw values DB (Stats) Number of Macrophages /mL

Plot of Adjusted Treatment Ratios and 95% CIs of 10.10 All Subjects DB (Stats) BAL Total Number of Macrophages /mL

Plot of Adjusted Means and 95% CIs of BAL GM2008/00234/00 10.11 All Subjects With individual raw values DB (Stats) Percentage of Macrophages Continued IPC103711

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Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Plot of Adjusted Treatment Differences and 95% 10.12 All Subjects DB (Stats) CIs of BAL Percentage of Macrophages

Plot of Individual BAL Total Number of Monocytes 10.13 All Subjects only individual raw values DB (Stats) /mL

10.14 All Subjects Plot of Individual BAL Percentage of Monocytes only individual raw values DB (Stats)

Plot of Individual BAL Total Number of

10.15 All Subjects only individual raw values DB (Stats) CONFIDENTIAL Lymphocytes /mL

10.16 All Subjects Plot of Individual BAL Percentage of Lymphocytes only individual raw values DB (Stats) 186 Plot of Individual BAL Total Number of Bronchial 10.17 All Subjects only individual raw values DB (Stats) Epithelial Cells /mL

Plot of Individual BAL Percentage of Bronchial 10.18 All Subjects only individual raw values DB (Stats) Epithelial Cells

Plot of Adjusted Geometric Means and 95% CIs 10.19 All Subjects only individual raw values DB (Stats) Headline of BAL Total Number of Total Leukocyte Count

Plot of Adjusted Treatment Ratios and 95% CIs of 10.20 All Subjects DB (Stats) Headline BAL Total Number of Total Leukocyte Count GM2008/00234/00 Continued IPC103711

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Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Means with 95% CI along with individual values. All Mean Plots of BAL Total Number of 10.21 All Subjects treatments and all DB (Stats) Monocytes/mL timepoints on the same page.

Means with 95% CI along with individual values. All 10.22 All Subjects Mean Plots of BAL Percentage of Monocytes treatments and all DB (Stats) timepoints on the same CONFIDENTIAL page.

187 Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell First page: N, n, mean, SD, median, min, max Summary of BAL Total Cell Count Data /mL by 10.1 All Subjects PD1 DB (Stats) Headline Inflammatory Cell Type Second page: N, n, geo mean, 95% CI geo mean, SD logs, CVb(%) GM2008/00234/00 Continued IPC103711

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Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell N, n, mean, 95% CI Summary of BAL Percentage Cell Data by 10.2 All Subjects PD1 mean, SD, median, min, DB (Stats) Headline Inflammatory Cell Type max

First page: N, n, adj (geo) mean, SD/SE logs, 95% CI (geo) mean

Second page: N, n,

PD6A/PD6B Summary of Results of Statistical Analysis of BAL CONFIDENTIAL diff/ratio, SD/SE logs, 10.3 All Subjects or Total Cell Count Data /mL by Inflammatory Cell DB (Stats) Headline 95% CI diff/ratio, p-value PD7A/PD7B Type 188 1st and 2nd pages for untransformed cell types and 3rd and 4th pages for transformed cell types.

First page: N, n, adj mean, SD logs, 95% CI Summary of Results of Statistical Analysis of BAL 10.4 All Subjects PD6A/PD6B Percentage Cell Count Data by Inflammatory Cell Second page: N, n, diff, DB (Stats) Headline Type SD logs, 95% CI diff, p- value Continued GM2008/00234/00 IPC103711

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Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell First page: N, n, mean, SD, median, min, max Summary of BAL Total Number of Monocytes/mL 10.5 All Subjects PD1 DB (Stats) by Flow Cytometry Second page: N, n, geo mean, 95% CI geo mean, SD logs, CVb(%)

N, n, mean, 95% CI Summary of BAL Percentage of Monocytes by Flow 10.6 All Subjects PD1 mean, SD, median, min, DB (Stats)

Cytometry CONFIDENTIAL max

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16.1.3. Biomarker Figures and Tables

Figures

Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Plot of Adjusted Geometric Means and 95% CIs Headline (IL-8 11.1 All Subjects With individual raw values DB (Stats) of BAL Protein Expression Data only)

Plot of Adjusted Treatment Ratios and 95% CIs of Headline (IL-8 11.2 All Subjects DB (Stats) BAL Protein Expression Data only) CONFIDENTIAL All treatments on the same page. All time

190 Individual Subject Profiles of Serum Protein 11.3 All Subjects points on the x-axis: Day DB (Stats) Expression Data 1 pre-dose, Day 7 predose and Day 7 26h.

Plot of Adjusted Geometric Means and 95% CIs 11.4 All Subjects DB (Stats) of Serum Protein Expression Data

Plot of Adjusted Treatment Ratios and 95% CIs of 11.5 All Subjects DB (Stats) Serum Protein Expression Data

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Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority First page: N, n, mean, SD, median, min, max Summary of BAL Protein Expression Data by Headline (IL-8 11.1 All Subjects PD1 DB (Stats) Protein and Day Second page: N, n, geo only) mean, 95% CI geo mean, SD logs, CVb(%)

First page: N, n, mean, SD, median, min, max CONFIDENTIAL Summary of Serum Protein Expression Data by 11.2 All Subjects PD1 DB (Stats) Protein and Day Second page: N, n, geo 191 mean, 95% CI geo mean, SD logs, CVb(%)

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16.1.4. Safety Tables

Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority 12.1 All Subjects AE1 (Core) Summary of All Adverse Events DB (Prog)

12.2 All Subjects AE1 (Core) Summary of Drug-Related Adverse Events DB (Prog)

12.3 All Subjects EG1 (Core) Summary of ECG Findings DB (Prog)

12.4 All Subjects EG2 (Core) Summary of ECG Values DB (Prog) CONFIDENTIAL

Summary of Maximum Increase from Baseline

192 12.5 All Subjects EG10 (CP) DB (Prog) ECG Values

Summary of Number of Subjects with Maximum 12.6 All Subjects EG11 (CP) ECG Values meeting or exceeding Pre-specified DB (Prog) Ranges of Concern by Category and Treatment

Summary of Number of Subjects with Maximum ECG Values meeting or exceeding Pre-specified 12.7 All Subjects EG12 (CP) DB (Prog) Individual Changes from Baseline of Concern by Category and Treatment

12.8 All Subjects UR3 (Core) Summary of Urinalysis Dipstick Results DB (Prog) Continued GM2008/00234/00 IPC103711

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Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority To be summarised categorically by visit and 12.9 All Subjects Summary of Troponin Data DB (Prog) troponin value across all treatment groups

12.10 All Subjects HM1 Summary of Holter Interpretations DB (Prog)

16.1.5. Pharmacokinetic Figures and Tables

Figures CONFIDENTIAL

Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable 193 No. Example Shell Priority Scatter plot (using S-Plus Individual and Median Subject BAL GSK256066 toolkit) of individual data 13.1 PK Urea-Corrected Concentration-Time Plots – by with median as bar. Both DB (Stats) Treatment Group (Linear) treatments and times on same plot.

Scatter plot (using S-Plus Individual and Median Subject BAL GSK614917 toolkit) of individual data 13.2 PK Urea-Corrected Concentration-Time Plots – by with median as bar. Both DB (Stats) Treatment Group (Linear and Semi-log) treatments and times on

same plot. GM2008/00234/00

IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority This must be the urea- Summary of Urea-Corrected BAL GSK256066 13.1 PK PKCT1 (PK) corrected concentrations DB (Prog) Pharmacokinetic Concentration-Time Data not the raw.

This must be the urea- Summary of Urea-Corrected BAL GSK614917 13.2 PK PKCT1 (PK) corrected concentrations DB (Prog) Pharmacokinetic Concentration-Time Data not the raw.

CONFIDENTIAL 16.1.6. Pharmacokinetic/Pharmacodynamic Figures

194 Figures

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority Scatter Plot of BAL Total Neutrophils /mL versus 14.1 PK DB (Stats) GSK256066 BAL Concentration

16.1.7. Pharmacogenetic Tables

Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable GM2008/00234/00 No. Example Shell Priority 15.1 All Subjects GN1 (Core) Summary of Genetics Subject Accountability DB (Prog) IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

16.1.8. ICH Listings

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell 1 All Subjects ES2 (Core) Listing of Reasons for Withdrawal DB (Prog) Headline

Listing of Subjects With Inclusion/Exclusion Headline 2 All Subjects IE3 (Core) DB (Prog) Criteria Deviations

Listing of Subjects for Whom the Treatment Blind Headline 3 All Subjects BL1 (Core) DB (Prog) CONFIDENTIAL was Broken

195 4 All Subjects DM2 (Core) Listing of Demographic Characteristics DB (Prog) Headline

Listing of Concomitant Medications by Generic 5 All Subjects CM3 (Core) DB (Prog) Term

6 All Subjects CP_RA1 Listing of Actual and Planned Treatments DB (Prog) Headline

7 All Subjects EX3 (Core) Listing of Exposure Data DB (Prog) Headline

8 All Subjects AE8 (Core) Listing of All Adverse Events DB (Prog)

Listing of Subject Numbers for Individual Adverse 9 All Subjects AE7 (Core) DB (Prog) Events GM2008/00234/00 10 All Subjects AE8 (Core) Listing of Serious Adverse Events DB (Prog) Continued IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Listing of Adverse Events Leading to Withdrawal 11 All Subjects AE8 (Core) DB (Prog) from Study

Listing of All ECG Values for Subjects with a Value 12 All Subjects EG15a (CP) DB (Prog) of Potential Clinical Importance

Listing of ECG Values of Potential Clinical 13 All Subjects EG5 (Core) DB (Prog) Importance

14 All Subjects EG15b (CP) Listing of Abnormal ECG Findings DB (Prog) CONFIDENTIAL

Listing of Clinical Chemistry Abnormalities of

196 15 All Subjects LB5 (Core) DB (Prog) Potential Clinical Importance

Listing of All Clinical Chemistry Laboratory Data for Same as Listing 15, 16 All Subjects LB5 (Core) Subjects with Abnormalities of Potential Clinical using a subset of the DB (Prog) Importance population

Listing of Haematology Abnormalities of Potential No conversion needed 17 All Subjects LB5 (Core) DB (Prog) Clinical Importance for Haematology values

No conversion needed Listing of All Haematology Laboratory Data for for Haematology values. 18 All Subjects LB5 (Core) Subjects with Abnormalities of Potential Clinical Same as Listing 17, DB (Prog) Importance using a subset of the GM2008/00234/00 population Continued IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Abnormal data 19 All Subjects UR2a (Core) Listing of Abnormal Urinalysis Data corresponds to positive DB (Prog) dipstick results.

CP_VS4 Listing of Vital Signs of Potential Clinical 20 All Subjects DB (Prog) (Core) Importance

CP_VS4 Listing of All Vital Signs for Subjects with Values of 21 All Subjects DB (Prog) (Core) Potential Clinical Importance CONFIDENTIAL

16.1.9. Other Listings 197

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Listing will include the three FEV1 values, max Listing of % Predicted FEV and FEV /FVC Ratio FEV , the three FVC 1 All Subjects PFT8 1 1 1 DB (Prog) Data at Screening values, max FVC, % pred FEV1 and FEV1/FVC ratio

Relationship between ATC Level 1, Ingredient and 2 All Subjects CM6 (Core) DB (Prog) GM2008/00234/00 Verbatim Text Continued IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Listing of BAL Inflammatory Cell Data: Total Cell Headline 3 All Subjects Example 1 DB (Stats) Count /mL and Percentage

Raw Statistical Analysis SAS Output of Total Cell Headline 4 All Subjects DB (Stats) Count Data /mL by Inflammatory Cell Type

Raw SAS Output for the Statistical Analysis of Headline 5 All Subjects Percentage Cell Count Data by Inflammatory Cell DB (Stats) Type CONFIDENTIAL 6 All Subjects Listing of BAL Monocyte Data DB (Stats)

198 7 All Subjects Listing of BAL Protein Expression Data DB (Stats) Headline

Raw SAS Output for the Statistical Analysis of BAL Headline 8 All Subjects DB (Stats) Protein Expression Data

9 All Subjects Listing of Serum Protein Expression Data DB (Stats)

Raw SAS Output for the Statistical Analysis of 10 All Subjects DB (Stats) Serum Protein Expression Data

11 All Subjects HM10 Listing of Clinically Significant Holter Abnormalities DB (Prog)

Relationship between System Organ Class and GM2008/00234/00 12 All Subjects AE2 (Core) DB (Prog) Verbatim Text Continued IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Merge with the MedDRA dictionary located under Similar to Listing of All Clinical Chemistry Laboratory Data for 13 All Subjects /local/apps/dictionaries DB (Prog) LB5 (CP) Subjects with AEs of Interest to obtain MedDRA high level terms

Merge with the MedDRA dictionary located under Listing of All ECG Values for Subjects with 14 All Subjects EG15a (CP) /local/apps/dictionaries DB (Prog)

Adverse Events of Interest CONFIDENTIAL to obtain MedDRA high level terms 199 See Listing 27 15 All Subjects Listing of Laboratory Reference Ranges DB (Prog) IPR107498

Merge with the MedDRA dictionary located under Listing of All Vital Signs for Subjects with AEs of 16 All Subjects CP_VS4 (CP) /local/apps/dictionaries DB (Prog) interest to obtain MedDRA high level terms Continued GM2008/00234/00 IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Listing will include the three FEV1 readings (all visits), max FEV1 (all visits), % pred FEV 17 All Subjects PFT8 Listing of Spirometry Data 1 DB (Prog) (only at screening), the three FVC readings (only at screening), max FVC (only at screening)

Listing of Raw and Urea-Corrected GSK256066 CONFIDENTIAL 18 PK PKCL1p(PK) DB (Prog) BAL Pharmacokinetic Concentration-Time Data 200 Listing of Raw and Urea-Corrected GSK614917 19 PK PKCL1p(PK) DB (Prog) BAL Pharmacokinetic Concentration-Time Data GM2008/00234/00 IPC103711

CONFIDENTIAL GM2008/00234/00 IPC103711

CONFIDENTIAL GM2007/00400/00 IPC103711

16.2. Data Display Specifications

Available on request

201 GM2007/00126/02 CONFIDENTIAL GM2008/00234/00GM2007/00126/02 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies IPC103711IPC103711

Division: Worldwide Development Retention Category: GRS019 Information Type: Protocol Amendment

Title: A double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers

Compound Number: GSK256066

Effective Date: 15-AUG-2007 Protocol Amendment Number: 01

Description: This is a double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental lipopolysaccharide (LPS) challenge in healthy volunteers. Subjects will be randomized using a 1:1:1 ratio to receive either GSK256066 (25 mcg or 87.5 mcg) or placebo once daily for 7 days.

Key assessments: safety, tolerability will be assessed by measurement of blood pressure, heart rate, holter monitoring, 12-lead ECG, spirometry measurements, clinical laboratory safety tests, collection of adverse events; pharmacodynamics will be assessed by measurement of blood biomarkers and BAL biomarkers.

Subject: GSK256066, cellobiose octaacetate (COA), lipopolysaccharide (LPS), healthy volunteers.

Author(s): (CPDM), (CPDM), (CPSP), (CPKMS), (CPDM), (CPDM)

Revision Chronology:

GM2007/00126/01 2007-APR-23 Original

GM2007/00126/02 2007-AUG-15 Amendment No.1: In response to guidance from the regulatory authority (BfArm) to further enhance subject cardiac safety; the stopping criteria for 12-Lead ECG has been made more stringent and holter monitoring and troponin analysis have been added to the planned study assessments. As a result of this, subjects will now be required to reside in the unit for a total of 6 hours on Day 1.

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INVESTIGATOR AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

Investigator Name: ______

Investigator Signature Date

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SPONSOR INFORMATION PAGE

Clinical Study Identifier: IPC103711

GlaxoSmithKline Greenford Road Greenford, Middlesex, UB6 0HE, UK Telephone:

Sponsor Contact Information:

If there are any urgent queries concerning this study, or if any adverse events need to be reported immediately, the Physician Responsible (Dr. may be contacted by telephoning:

Work: Mobile: Email: Facsimile:

Direct fax to GCSP:

If for any reason you are unable to contact the medical monitor and the matter is urgent please contact:

Alternative GSK medical contact: Dr.

Telephone Number: Mobile Number: Email: Facsimile:

In the event that neither the Primary or Secondary Medical Monitor can be reached, the following number should be contacted:

Sponsor Serious Adverse Events (SAE) Contact Information:

Case Management Group, GCSP - Greenford,

UK Fax:

E-mail:

The Medical Monitor must also be informed (see contact details above).

Regulatory Agency Identifying Number(s): 2007-001935-75

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TABLE OF CONTENTS

Page ABBREVIATIONS ...... 8 PROTOCOL SUMMARY ...... 10 1. INTRODUCTION ...... 12 1.1. Background ...... 12 1.1.1. GSK256066 ...... 12 1.2. Rationale ...... 12 2. OBJECTIVE(S) ...... 13 2.1. Primary ...... 13 2.2. Secondary ...... 13 3. ENDPOINT(S) ...... 13 3.1. Primary ...... 13 3.2. Secondary ...... 13 4. STUDY DESIGN ...... 14 5. STUDY POPULATION ...... 14 5.1. Number of Subjects ...... 14 5.2. Eligibility Criteria...... 15 5.2.1. Inclusion Criteria ...... 15 5.2.2. Exclusion Criteria ...... 17 5.2.3. Other Eligibility Criteria Considerations ...... 18 6. STUDY ASSESSMENTS AND PROCEDURES ...... 18 6.1. Demographic and Baseline Assessments ...... 18 6.2. Treatment Phase ...... 19 6.3. Post Study visit...... 19 6.4. Safety ...... 19 6.4.1. Adverse Events ...... 19 6.4.2. Safety Laboratory Tests ...... 20 6.4.3. Vital Signs ...... 20 6.4.4. Holter Monitoring ...... 20 6.4.5. 12-Lead ECG ...... 20 6.4.6. Lung Function Tests...... 21 6.4.7. Pregnancy ...... 22 6.5. Pharmacodynamics ...... 23 6.6. Pharmacogenetics ...... 24

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7. LIFESTYLE AND/OR DIETARY RESTRICTIONS ...... 25 7.1. Contraception for females: ...... 25 7.2. Dietary ...... 25 7.3. Alcohol ...... 25 8. INVESTIGATIONAL PRODUCTS ...... 26 8.1. Description of Investigational Product ...... 26 8.2. Dosage and Administration ...... 26 8.3. Dose Rationale...... 26 8.4. Blinding ...... 29 8.5. Treatment Assignment ...... 29 8.6. Packaging and Labeling ...... 30 8.7. Preparation...... 30 8.8. Handling and Storage ...... 30 8.9. Product Accountability ...... 30 8.10. Assessment of Compliance ...... 30 8.11. Treatment of Investigational Product Overdose...... 30 8.12. Occupational Safety ...... 31 9. CHALLENGE AGENTS ...... 31 10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES...... 32 10.1. Permitted Medications ...... 32 10.2. Prohibited Medications ...... 32 11. SUBJECT COMPLETION AND WITHDRAWAL ...... 33 11.1. Subject Completion ...... 33 11.2. Subject Withdrawal ...... 33 11.2.1. Subject Withdrawal from Study ...... 33 11.2.2. Subject Withdrawal from Investigational Product...... 34 11.3. Treatment After the End of the Study ...... 35 11.4. Screen and Baseline Failures ...... 35 12. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) . . 35 12.1. Definition of an AE ...... 35 12.2. Definition of a SAE ...... 35 12.2.1. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs ...... 36 12.3. Time Period, and Frequency of Detecting AEs and SAEs ...... 38 12.4. Prompt Reporting of SAEs to GSK ...... 38 12.4.1. Timeframes for Submitting SAE Reports to GSK ...... 38

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12.5. AE and SAE Documentation and Follow-up Procedures ...... 38 13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ...... 39 13.1. Hypotheses ...... 39 13.2. Study Design Considerations...... 39 13.2.1. Sample Size Assumptions ...... 39 13.2.2. Sample Size Sensitivity ...... 39 13.2.3. Sample Size Re-estimation ...... 39 13.3. Data Analysis Considerations ...... 39 13.3.1. Analysis Populations ...... 39 13.3.2. Analysis Data Sets ...... 40 13.3.3. Treatment Comparisons...... 40 13.3.4. Interim Analysis ...... 41 13.3.5. Key Elements of Analysis Plan ...... 41 14. STUDY CONDUCT CONSIDERATIONS ...... 44 14.1. Regulatory and Ethical Considerations, Including the Informed Consent Process ...... 44 14.2. Quality Control (Study Monitoring) ...... 44 14.3. Quality Assurance ...... 45 14.4. Study and Site Closure ...... 45 14.5. Records Retention ...... 46 14.6. Provision of Study Results and Information to Investigators ...... 46 14.7. Data Management ...... 46 15. REFERENCES ...... 47 Appendices ...... 48 Appendix 1: General Time and Events Table ...... 48 Appendix 2: Study Schematic Figure ...... 50 Appendix 3: PGx ...... 51 Appendix 4: Country Specific Requirements ...... 57 Appendix 5: Protocol Changes ...... 58

7 GM2007/00126/02 CONFIDENTIAL GM2008/00234/00GM2007/00126/02 IPC103711IPC103711

ABBREVIATIONS

AE Adverse Event ALT Alanine aminotransferase AMP Adenosine monophosphate ANOVA Analysis of Variance (F-test) AST Aspartate aminotransferase AUC Area under curve AUC0-last Area under the plasma drug concentration versus time curve BAL Bronchoalveolar lavage BD Twice daily BP Blood pressure bpm Beats per minute cAMP Cyclic adenosine monophosphate CK MB Creatine Kinase-Myocardial Band Cmax Maximum concentration COPD Chronic Obstructive Pulmonary Disease CPDM Clinical Pharmacology and Discovery Medicine CPK Clinical Pharmacokinetics CPSP Clinical Pharmacology Statistics and Programming CRF Case Report Form DMPK Drug metabolism and pharmacokinetics DNA Deoxyribonucleic acid DOA Drugs of Abuse EC50 Median Effective Concentration ECG Electrocardiograph eCRF Electronic case report form EDTA Ethylenediaminetetraacetic acid FC Fold change FEV1 Forced Expiratory Volume in One Second FP Fluticasone propionate FVC Forced vital capacity g/day Gram per day GCP Good clinical practice GCSP Global Clinical Safety and Pharmacovigilance GPS Genomics & Proteomics Sciences GSK GlaxoSmithKline h Hour hCG Human chorionic gonadotrophin HIV Human Immunodeficiency Virus HLA Human leukocyte antigen HR Heart rate IB Investigator Brochure LDH Lactate dehydrogenase IEC Independent Ethics Committee IgM Immunoglobin M

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IRB Institutional Review Board IUD Intrauterine device IUS Intrauterine system kg Kilogram kg/m2 Kilogram per meter squared LDH Lactate dehydrogenase LPS lipopolysaccharide mcg Micrograms mg/dL Milligram per decilitre mg/mL Milligram per milllitre mL millilitre mm millimeter mRNA Messenger ribonucleic acid MedDRA Medical dictionary for regulatory applications MSDS Material Safety Data Sheet msec millisecond NCS Not clinically significant PD Pharmacodynamics PDE4 Phosphodiesterase-4 PGx Pharmacogenetics PK Pharmacokinetics RAST Radioallergosorbent Test RAP Reporting and Analysis Plan RNA Ribonucleic acid RT-PCR Reverse transcriptase- polymerase chain reaction SAE Serious Adverse Event SNP Single nucleotide polymorphisms SOC System Organ Class SRM Study reference manual T1/2 Half-life Tlast Time to last observed plasma drug concentration Tmax Time to reach maximum concentration ULN Upper limit normal VASP Vasodilator-stimulated phosphoprotein

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies ACCUHALER Roflumilast

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PROTOCOL SUMMARY

Rationale

GSK256066 is a potent and selective inhibitor of PDE4 that is being developed as an orally inhaled treatment for asthma and COPD.

The proposed study will examine the effect of pre-treatment with inhaled GSK256066 (25 µg or 87.5 µg once daily) using a lung inflammation model induced by bronchoscopic instillation of bacterial endotoxin (lipopolysaccharide, LPS) in healthy volunteers. In healthy subjects, inhalation of pure LPS produces both a systemic and a bronchial inflammatory response. This response is short-lived (6-8 hours) and is dose- related [Michel, 1997]. Segmental LPS challenge by bronchoscopic instillation of LPS into the airway also produces a systemic and bronchial inflammatory response. A cellular response starts at 2-6 hours, peaks at 24 hours, and resolves at 48-72 hours [O'Grady, 2001]. Roflumilast, an oral PDE4 inhibitor was shown using this challenge model to inhibit airway inflammation [Hohlfeld, 2006], and doses that were effective in the LPS challenge model were subsequently demonstrated to be clinically efficacious in patients with COPD [Rabe, 2005].

Data from this study will be used to support GSK256066 dose selection for future studies in COPD patients.

Objective(s)

Primary

To investigate the effects of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) on lung inflammation following segmental LPS challenge in healthy volunteers.

Secondary

To investigate the safety and tolerability of 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) in healthy volunteers.

To investigate the response of systemic markers of inflammation following 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) in healthy volunteers.

Endpoint(s)

Primary

• Bronchoalveolar lavage (BAL): • Absolute BAL neutrophils at 24 h post LPS exposure • The total and differential cell count (absolute and percentage cell counts) in BAL at 24 h post LPS exposure

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Secondary

• Safety and tolerability: • Vital Signs: systolic and diastolic blood pressure (BP), heart rate (HR) • Holter monitoring • 12-lead ECG including QTc(B), QT, QRS, PR, and ventricular rate (VR). • Lung function (FEV1 and FVC) • Laboratory safety tests (haematology, clinical chemistry, urinalysis) • Adverse Events • Serum concentration of protein inflammatory biomarkers (e.g. SP-D, CC-16). • BAL concentrations of protein inflammatory biomarkers (e.g. IL-8, TNFα, IL-6, MPO) • BAL concentrations of GSK256066 and metabolite GSK614917

Study Design

This is a randomised, double-blind, parallel-group study in healthy volunteers. This study will be conducted in a single centre.

Study Population

An estimated total of 42 healthy male and female subjects will be recruited into the study to allow for completion of 36 evaluable subjects.

Study Assessments

Safety

Demographic details, including a medical history, will be recorded and a physical examination conducted. Vital signs (HR and BP), holter monitoring, 12-lead ECG, spirometry assessments including a chest examination, and laboratory tests for haematology, clinical chemistry and urinalysis and Hepatitis B and C and HIV screens will also be performed. Furthermore, pregnancy tests will also be conducted for all female subjects. Subjects will be trained on use of the ACCUHALER™ device (using placebo) to assess their ability to use the device.,

Pharmacodynamics

Bronchoscopy will be performed on Day 7 and Day 8.

Bronchoalveolar lavage (BAL) will be performed on Day 7 and Day 8 for analysis of biomarkers related to pulmonary inflammation.

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1. INTRODUCTION

1.1. Background

1.1.1. GSK256066

GSK256066 is a potent and selective inhibitor of PDE4 that is being developed as an orally inhaled treatment for asthma and COPD. One of the key challenges in developing oral PDE4 inhibitors is that the threshold for induction of adverse effects, such as nausea and emesis, is close to the dose level required for therapeutic activity. It is hypothesized that topical administration may improve the therapeutic index of this class. The first proof of pharmacology for topical administration of PDE4 inhibitors was recently attained in Study IPR101987 in subjects with allergic rhinitis that demonstrated the effects of intranasal GSK256066 on allergen-induced nasal symptoms and nasal biomarkers (SNFL1LK). The data provided confidence in progressing this topical PDE4 inhibitor in COPD.

Current therapies available for such inflammatory disorders comprise of acute symptom relievers (bronchodilators for asthma and COPD) and topical corticosteroids, which ameliorate the underlying inflammation. However, steroids are non-selective and concerns remain over the long-term sequelae of steroid use. Despite the availability of existing therapies, both diseases are inadequately treated with consequent health impairment. As a result, a range of novel anti-inflammatory agents are under development, including GSK256066.

Selective PDE4 inhibitors offer an appealing molecular basis for anti-inflammatory activity in airway disease. The PDE4 isoenzyme is responsible for the degradation of intracellular cyclic 3’-5’adenosine monophosphate (cAMP), a second messenger that is selectively expressed in smooth muscle, epithelial cells and many inflammatory cells (including eosinophils, neutrophils, T-lymphocytes, mast cells, monocytes and basophils). cAMP mediates the broad suppression of immune and inflammatory cell activity, and inhibition of its breakdown increases intracellular levels, which leads to reduced synthesis and/or release of inflammatory mediators. This in turn induces airway smooth muscle relaxation, suppresses smooth muscle mitogenesis and modulates the activity of pulmonary nerves [Barnette, 1999]. Inhibition of PDE4 should thus suppress the activation and migration of immuno-competent cells and attenuate many of the pathophysiologic features of COPD [Torphy, 1998].

1.2. Rationale

GSK256066 is a potent and selective inhibitor of PDE4 that is being developed as an orally inhaled treatment for asthma and COPD.

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volunteers. In healthy subjects, inhalation of pure LPS produces both a systemic and a bronchial inflammatory response. This response is short-lived (6-8 hours) and is dose- related [Michel, 1997]. Segmental LPS challenge by bronchoscopic instillation of LPS into the airway also produces a systemic and bronchial inflammatory response. A cellular response starts at 2-6 hours, peaks at 24 hours, and resolves at 48-72 hours [O'Grady, 2001]. Roflumilast, an oral PDE4 inhibitor was shown using this challenge model to inhibit airway inflammation [Hohlfeld, 2006], and doses that were effective in the LPS challenge model were subsequently demonstrated to be clinically efficacious in patients with COPD [Rabe, 2005].

Data from this study will be used to support GSK256066 dose selection for future studies in COPD patients.

2. OBJECTIVE(S)

2.1. Primary

• To investigate the effects of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) on lung inflammation following segmental LPS challenge in healthy volunteers.

2.2. Secondary

3. ENDPOINT(S)

3.1. Primary

• Bronchoalveolar lavage (BAL): • Absolute BAL neutrophils at 24 h post LPS exposure • The total and differential cell count in BAL (absolute and percentage cell counts) at 24 h post LPS exposure

3.2. Secondary

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• Lung function (FEV1 and FVC) • Laboratory safety tests (haematology, clinical chemistry, urinalysis) • Adverse Events • Serum concentration of protein inflammatory biomarkers (e.g. SP-D, CC-16). • BAL concentration of protein inflammatory biomarkers (e.g. IL-8, TNFα, IL-6, MPO) • BAL concentrations of GSK256066 and metabolite GSK614917

4. STUDY DESIGN

This is a single centre, randomised, double-blind, parallel-group, 7 day repeat dose study in healthy volunteers.

All subjects will attend the unit for screening within 28 days of their first dosing occasion.

Eligible subjects will be randomised (1:1:1) to receive one of the following treatments, as a single, once daily inhaled dose for 7 days (via an ACCUHALER™ device):

All subjects will attend the unit for a follow up visit within 7-10 days following their final dose.

The overall duration (screening to follow up), for participating subjects, will not exceed 45 days.

5. STUDY POPULATION

5.1. Number of Subjects

An estimated total of 42 healthy male and female subjects will be recruited into the study to allow for completion of 36 evaluable subjects.

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5.2. Eligibility Criteria

5.2.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Healthy as determined by a responsible physician, based on a medical evaluation including history, physical examination, laboratory tests, cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator considers that the finding will not introduce additional risk factors and will not interfere with the study procedures. 2. Male and females who are aged between 18 and 50 years of age. 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 1 year without menses (FSH/LH will be also tested to confirm menopausal status); or b. Child-bearing potential, has a negative pregnancy test (urine) at entry, and agrees to one of the following 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 the first visit, throughout the trial and for 7 days after the completion of the trial; or • Male partner was sterile prior to the female subject’s entry into the study, or • Implants of levonorgestrel inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or • Injectable progestogen administered for at least 1 month prior to the study medication administration and administered for 1 month following study completion; or • Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or • The contraceptive transdermal patch, Ortho Evra (if the subject is less than 89kg); or • Double-barrier method – spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a spermicide and female diaphragm Recent data now shows that certain double-barrier methods have a failure rate below 1% [Trussell, 2003]. Specifically, these are a spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm). This provides validated confirmation of the failure rate of the

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double-barrier method. Thus this method now meets the stated criterion for acceptable contraception in the EMEA guidelines [CPMP/ICH/285/95, 2000]; or • Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; or • An intrauterine device (IUD) or intrauterine system (IUS), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; (not all IUDs meet this criterion) Acceptable IUDs: TCu-380A (Paragard), TCU-380 Slimline (Gyne T Slimline), TCu-220C, MULTILOAD-250 (MLCu-250) and 375, NOVA T and CUNOVAT (Novagard), Levonorgesterol (LNG-20) Intra-uterine System (Mirena/Levonova), and FlexiGard 330/CuFix PP330 (Gynefix). The device must be inserted at least 2 weeks prior to the Screen visit, and remain throughout the study and through the follow-up phase of the study or Any other methods with published data showing that the highest expected failure rate is less than 1% per year. 3. Body weight ≥ 50 kg and Body mass index within the range of 19-31 kg/m2 inclusive. 4. Subjects who are current non-smokers, who have not used any inhaled tobacco products (snuff is permitted) in the 12 month period preceding the screening visit and who have a pack history of ≤ 5 pack years. Pack years = Number of cigarettes per day x Number of years smoked 20 5. No significant abnormality on 12-lead ECG at screening, including the following requirements: • Ventricular rate ≥ 50 beats per minute • PR interval ≤ 200 ms • Q waves < 30 ms (up to 50 ms permitted in lead III only) • QRS interval to be ≥ 60 ms and ≤ 100 ms • QTc interval must be <450 msec (QTcB or QTcF; machine or manual reading) based on a single ECG value, or an average from three ECGs obtained over a brief recording period. 6. Subjects with a screening pre-bronchodilator FEV1 >80 % predicted and FEV1/FVC ratio >0.7. Predicted values are based on the ECCS 1993 normal ranges. 7. Able to provide written informed consent. 8. The subject is able to understand and comply with the protocol requirements, instructions and protocol-stated restrictions. 9. Demonstrated ability to use the ACCUHALER device in a satisfactory and repeatable manner.

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5.2.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. As a result of medical interview, physical examination or screening investigations, the principle investigator or delegate physician deems the subject unsuitable for the study. Subjects must not have a systolic blood pressure above 145 mmHg or a diastolic pressure above 85 mmHg unless the Investigator confirms that it is satisfactory for their age. 2. The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness. 3. Pregnant or nursing females. 4. Women of childbearing potential who are unwilling or unable to use an appropriate method of contraception as outlined Section 7.1 from at least two weeks prior to the first dose of study medication; and to continue until the final pregnancy test has been performed (not less than 72 hours after treatment). 5. The subject has experienced “cold or Flu” symptoms or any respiratory infection/symptoms within 3 weeks of the study start. 6. Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease*, malignancy, hepatic disease, renal disease**, haematological disease, neurological disease, endocrine disease or pulmonary disease (including but not confined to chronic bronchitis, emphysema, bronchiectasis or pulmonary fibrosis). *subjects with abnormal troponin and/or CK MB at screening will be excluded. **subjects will require normal creatinine clearance values at screening [calculated from serum creatinine by a predicting equation using Cockcroft-Gualt formula] and a normal serum creatinine value [local laboratory reference ranges will be used]. If the creatinine clearance value is greater than the upper limit of normal as determined by the local laboratory reference range, the Investigator will determine whether this is a clinically significant finding that would preclude participation. 7. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation. 8. The subject has taken prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is the longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study procedures or compromise subject safety. (Please also refer to Section 7 for alcohol and dietary restrictions following study inclusion). 9. History of alcohol/drug abuse or dependence within 12 months of the study. Abuse of alcohol defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of

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greater than 14 units or an average daily intake of greater than 2 units (females). 1 unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine 10. The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication. 11. Exposure to more than three new chemical entities within 12 months prior to the first dosing day. 12. The subject has donated a unit of blood within the previous 16 weeks or intends to donate within 16 weeks after completing the study. 13. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. 14. The subject has tested positive for HIV antibodies (if tested according to site SOPs). 15. The subject has a positive pre-study urine drug/ alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines. 16. Subjects who have participated in any GlaxoSmithKline (GSK) study involving the administration of COA for ≥ 21 days.

5.2.3. Other Eligibility Criteria Considerations

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 investigational product(s) being used in this study: Clinical Investigator Brochure for GSK256066 [GlaxoSmithKline Document Number:WM2004/00061/03, 2006] Supplement to Clinical Investigator Brochure for GSK256066 [GlaxoSmithKline Document Number: RM2007/00156/00, 2007], Clinical Investigator Brochure for GW857238 (COA) [GlaxoSmithKline Document Number SM2003/00026/04, 2005], Supplement to Clinical Investigator Brochure for GW857238 (COA) ) [GlaxoSmithKline Document Number WM2006/00027/00, 2006].

6. STUDY ASSESSMENTS AND PROCEDURES

6.1. Demographic and Baseline Assessments

Each subject will undergo screening procedures within 28 days before the first treatment period (i.e., administration of the first dose of study medication). Prior to enrolling in the study and having any study procedures completed, subjects must sign the informed consent.

A generic ethics approved screening protocol may be used to identify potential subjects. Data from this generic screen may be used for the purpose of this study provided that it is

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within 60 days of the first dosing administration. Any assessments that are not included in the generic screen and are required for this study will be performed once ethics and regulatory approvals have been received.

During the screening visit, each subject will undergo the assessments to determine eligibility for enrollment as detailed in Section 5.

6.2. Treatment Phase

Subjects will attend the unit on Day 1 for baseline assessments, where they will be dosed in accordance with the randomisation schedule and remain resident until the completion of the 6 hour assessments.

Subjects will be provided with appropriate medication for Day 2 to Day 6 so that they may self administrate medication at home. Where possible this should be taken within +/- 1 hour of the time of dosing on Day 1. Diary cards will be provided for the subjects to record the time and date of all administrations.

On the morning of Day 7 subjects will attend the unit for supervised dosing followed by a bronchoscopy, BAL and segmental LPS challenge. Subjects will then return 24 hours later (Day 8) for repeat bronchoscopy and BAL.

All study procedures to be carried out from Day 1 to Day 8 are detailed in Appendix 1.

6.3. Post Study visit

Follow-up will occur between 7 and 10 days following the final dose of study medication. The study procedures to be carried out during the follow-up visit are detailed in Appendix 1.

6.4. Safety

Subjects participating in this study will not donate blood in excess of 100 mL over a 45 day period.

6.4.1. Adverse Events

Each subject will be monitored by the investigator and designated study personnel for the adverse events occurring throughout the study until follow-up. During the treatment period, when there is an AE enquiry, the Investigator or designee will ask the subject the AE question specified in Section 12.

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6.4.2. Safety Laboratory Tests

Clinical Laboratory tests will be performed at the time points outlined in Appendix 1.

The following samples will be collected for analysis:

• Clinical Chemistry (blood) • Haematology (blood) • Urinalysis (urine) Additional samples may be taken for safety reasons at the discretion of the Investigator.

Clinical laboratory tests will be analysed locally by site.

Note: Troponin tests will be performed at screening and on Day 7 to monitor cardiac safety.

Details of sample collection and processing can be found in the Study Reference Manual.

6.4.3. Vital Signs

Vital signs (BP and HR) will be recorded whilst the subject is in a supine position (having rested for 5 minutes) at the timepoints specified in Appendix 1.

Measurements that deviate substantially from previous readings will be repeated immediately.

6.4.4. Holter Monitoring

Continuous Holter monitoring will be conducted for 6 hours following administration of medication on Day 1 (monitoring may continue for longer than 6 hours if considered clinically necessary by the investigator). In addition, 12-lead ECGs will be performed as described in Section 6.4.5.

Holter monitoring will be used to detect subjects with underlying cardiac arrhythmias.

Analysis of the Holter tapes will be arranged by the site. Rhythms of potential clinical concern will be reported.

6.4.5. 12-Lead ECG

ECGs will be recorded whilst the subject is in a supine position, (having rested for at least 10 minutes) at the timepoints specified in Appendix 1.

Any ECG that shows a significant change or abnormality will be repeated immediately.

All measurements will be recorded in the eCRF.

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Baseline will be defined as the mean of the three pre-dose measurements that occurred prior to dosing on Day 1.

Computerised 12-lead ECG recordings will be obtained. Each lead shall be recorded for at least 3-5 beats at a speed of 25 mm/sec. The following parameters will be recorded:rhythm, ventricular rate, PQ interval, QRS duration, QT and QTcB.

Any results falling outside the normal ranges may be repeated at the discretion of the investigator. If any results falling outside of the normal ranges are deemed not clinically significant by the investigator or appropriately qualified designee, then this should be clearly stated on the hard copies of the ECG and signed and dated by the investigator. If the ECG trace indicates an abnormality that is measured by the equipment but is deemed normal by the investigator then this should be clearly stated on the ECG trace as normal and signed and dated by the investigator or appropriately qualified designee. If the ECG trace indicates an abnormality that is present but deemed as not clinically significant by the investigator or appropriately qualified designee then this should be clearly stated on the ECG trace as “NCS” and signed and dated by the investigator or appropriately qualified designee. If any results falling outside of the normal ranges are deemed clinically significant by the investigator or appropriately qualified designee then these should be recorded in the CRF as an AE/SAE (see Section 12).

ECGs will be stored electronically for manual measurement of intervals, if necessary. If a subject’s QTc interval extends beyond 500 msec, uncorrected QT > 600 msec, or uncorrected QT and/or QTc extends beyond 60 msec compared to baseline on two or more ECG tracings separated by at least 5 minutes then:

• The ECG tracing should be examined and manual measurement by a trained physician should be performed to assess the accuracy of the equipment being used. • If the reading is accurate: • The subject must be withdrawn from the study. • The subject should be monitored closely and followed until the QT and QTcB interval return to within 30msec of their baseline. • Consideration should be given to putting the study on hold until all subjects’ data can be re-evaluated and confirmed. Further details on 12-Lead ECG can be found in the study reference manual.

6.4.6. Lung Function Tests

Spirometry measurements FEV1 and FVC will be recorded at timepoints specified in Appendix 1. Assessments will be performed according to the site’s local operating procedures and the European Respiratory Standards (ERS).

The Investigator (or delegate) will review all readings on an ongoing basis.

All measurements will be recorded in the eCRF.

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Chest examinations (inspection, palpitation, percussion and auscultation) will be performed at various time points as specified in Appendix 1. If there are any findings which the investigator feels warrant further examination, then the subject will be referred for a chest x-ray. Therefore, chest x-rays will only be performed if clinically significant findings are observed during the chest examination. A subject will not be withdrawn from the study unless the x-ray results indicate any abnormalities or the investigator believes that the subject should be withdrawn on safety grounds.

Further details on spirometry assessments can be found in the study reference manual.

6.4.7. Pregnancy

Pregnancy testing and contraceptive methods will be carried out in accordance with the GSK Standard Operating Procedure ‘Reproductive issues in clinical studies’ and the agreement "GSK List of Highly Effective Methods for Avoidance of Pregnancy in Women of Childbearing Potential".

6.4.7.1. Time period for collecting pregnancy information

Females of childbearing potential will be tested for pregnancy by serum or urine methods at the timepoints specified in Appendix 1.

Results on Day 1 are to be obtained prior to dosing. In the case of a positive urine or serum β-hCG test the subject will be withdrawn from the study.

6.4.7.2. Action to be taken if pregnancy occurs

The investigator will collect pregnancy information on any female subject, who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see AE/SAE section of the protocol and the SRM for definitions and a description of follow-up).

A spontaneous abortion is always considered to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the investigational product by the investigator, will be reported to GSK as described in section entitled, "Post-study AEs and SAEs" of the SRM. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

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Pharmacokinetics

The bronchoalveolar lavage (BAL) fluid samples obtained for determination of the primary endpoints will also be used to determine concentrations of GSK256066 and the active metabolite GSK614917, using current approved assay methodology. This sample will be corrected for urea concentration (for further details see Section 6.6). Only the samples taken from subjects who have been administered GSK256066, will be analysed by Worldwide Bioanalysis, DMPK, who will be un-blinded in accordance with current GSK SOPs. Sample analysis will be the responsibility of Worldwide Bioanalysis, DMPK, GSK.

BAL samples for pharmacokinetic analysis will be collected at the timepoints outlined in Appendix 1.

Details of sample collection, processing and shipment can be found in the Study Reference Manual.

6.5. Pharmacodynamics

Bronchoscopy

Bronchoscopy will be performed in accordance with site standard operating procedures (SOPs), at timepoints detailed in Appendix 1. These SOPs will reflect current standards of practice in hospital care and will include (but are not limited to) the following items:

• Bronchoscopy will only be performed by an appropriately qualified member of the medical faculty. • The Bronchoscopist will be assisted by suitably qualified staff. • Subjects will be pre-medicated with bronchodilators, midazolam as appropriate and topical laryngeal Lidocaine. • Oxygen supplementation will be given to all subjects. • Subjects will have a pre-bronchoscopy ECG. Heart rate and oxygen saturation will be monitored continuously throughout the procedure. • Pulmonary function will be monitored before the bronchoscopy and after the bronchoscopy until FEV1 is within 20% of the pre-procedure value. • All subjects will be monitored in a recovery/holding room post bronchoscopy. Subjects will be discharged only after approval is obtained from the supervising physician, and subjects will be given a 24 hour contact number. Admission facilities will be available in the event a subject is not deemed fit for discharge or if overnight observation is deemed necessary by the study physician or site-specific policies. • BAL fluid samples will be collected to determine neutrophil count, and total and differential cell count.

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Following the segmental LPS challenge (and con-lateral control saline challenge) subjects will be monitored for up to 4 hours. However should the investigator have any concern for subject safety, subjects may be requested to remain resident for further observation.

Further details of this procedure, sample collection, processing and shipment can be found in the Study Reference Manual.

Biomarkers

Samples will be collected to determine concentrations of inflammatory biomarkers in BAL (eg. IL-8, TNFα, IL-6, MPO) and blood (eg. SP-D, CC-16) using an appropriately validated assay including ELISA. Samples will be collected at times outlined in Appendix 1.

Biomarkers and GSK256066 (and GSK614917) concentration in BAL will need to be corrected for dilution using urea concentration as a correction factor. Consequently whole blood samples will be taken at the same time as the BAL samples to determine both serum and BAL urea concentrations in order to determine the dilution factor.

Where: Dilution factor = urea(serum)/urea(BAL)

The biomarker strategy for this study is to support the primary outcome measures. The purpose is to provide information on the effect of GSK256066 on markers of inflammation in serum and BAL. The analyses fall into two categories, those that are established, well understood measures, and those that are exploratory or subject to ongoing validation. These latter assays may not be performed if validation is unsatisfactory or new information suggests that they would be unhelpful.

Further details on the collection and processing procedures for biomarker samples can be found in the study reference manual.

6.6. Pharmacogenetics

Information regarding pharmacogenetic research is included in Appendix 3. The IEC/IRB and, where required, the applicable regulatory agency must approve the PGx assessments before these can be conducted at the site. The approval(s) must be in writing and will clearly specify approval of the PGx assessments (i.e., approval of Appendix 3). In some cases, approval of the PGx assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the PGx assessments is being deferred and in most cases, the study, except for PGx assessments, can be initiated. When PGx assessments will not be approved, then the approval for the rest of the study will clearly indicate this and therefore, PGx assessments will not be conducted.

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7. LIFESTYLE AND/OR DIETARY RESTRICTIONS

7.1. Contraception for females:

Appropriate contraceptive methods for female subjects include:

• Abstinence. The lifestyle of the female should be such that there is complete abstinence from intercourse from two weeks prior to the first dose of study medication and to continue until for 7 days after the completion of the trial; One of the following methods is acceptable as the sole method of contraception if there is indisputable data that it is >99% effective otherwise it should be used with a barrier method (condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal foam/gel/film/cream/suppository):

• Male partner was sterile prior to the female subject’s entry into the study, or • Implants of levonorgestrel inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or • Injectable progestogen administered for at least 1 month prior to the study medication administration and administered for 1 month following study completion; or • Oral contraceptive (combined or progestogen only) administered for a least one monthly cycle prior to study medication administration; or • The contraceptive transdermal patch, Ortho Evra (if the subject is less than 89kg); • An intrauterine device (IUD) or intrauterine system (IUS), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year.

7.2. Dietary

• Subjects will be required to fast from midnight before Day 7 and Day 8 prior to bronchoscopy,

7.3. Alcohol

• Subjects should refrain from alcohol 48h prior to the first dose until 48h after the final dose. At all other times during the study (i.e. screening – first dose and last dose - follow-up) no more than 21 units of alcohol (14 units for females) a week or more than 4 units of alcohol (3 units for females) per day should be taken (one unit = 125ml wine or 25ml spirits or 250ml normal strength lager).

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8. INVESTIGATIONAL PRODUCTS

8.1. Description of Investigational Product

GSK256066 containing cellobiose octaacetate and matched placebo will be supplied by Global Supply Operations GSK, Harlow, UK as described in Table 1.

Table 1 Description of GSK256066 Investigational Product

Property Investigational Product GSK256066 Placebo Dry Powder Dry Powder Formulation Lactose Blend containing 1% Lactose Blend cellobiose octaacetate Dosage Form ACCUHALER inhaler ACCUHALER inhaler Unit Dose 12.5, 37.5, 50 (mcg/inhalation) NA Strength1 No of 28 28 Doses/Inhaler Physical ACCUHALER (containing 28 blisters ACCUHALER (containing 60 blisters Description of white to pale yellow coloured, free- white, free-flowing powder) flowing powder) Route of Oral inhalation via ACCUHALER Oral inhalation via ACCUHALER Administration inhaler inhaler 1. Additional strengths of ACCUHALER will be used to administer the required doses as necessary

8.2. Dosage and Administration

Subjects will be dosed in the unit on the mornings of Day 1 and Day 7. On Day 2 to Day 6, subjects will self administrate medication at home. Two ACCUHALER per subject will be provided. Each subject will take one inhalation from each, each morning.

Subjects will be given the following instructions for the use of the ACCUHALER:

1. Exhale fully 2. Place mouthpiece between lips and firmly close lips around mouthpiece ensuring a good seal 3. Inhale as sharply and as fully as possible 4. Remove mouthpiece and hold breath for 10 seconds

8.3. Dose Rationale

GSK256066

This will be the ninth study to be conducted in humans with GSK256066, and the fifth via the inhaled route of administration. Two studies in asthma patients (IPA101985 and

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IPA106620) will have completed at the start of this study (IPC103711). The FTIH study (IPA101935) explored doses up to and including 87.5mcg once daily for 14 days. Sixteen (67%) subjects reported a total of 37 AEs after GSK256066 or placebo given once daily for 14 days, where 8 subjects received 37.5mcg GSK256066, 8 subjects received 87.5mcg GSK256066 and 8 subjects received placebo. All events were mild. There were no SAEs reported. The most common AEs were symptoms related to upper airways tract irritation and headache. Eight reports of upper respiratory tract (URT) symptoms and 5 reports of cough were recorded for 8 subjects. Such upper respiratory tract problems are commonly associated with the use of dry powder inhalers. All the subjects with reported URT symptoms underwent an oropharyngeal examination, no findings of note were observed. Five reports of headache were reported by four subjects.

During the repeat dose phase of the study, no abnormal findings were noted on physical examination including chest auscultation. There were no abnormalities considered of clinical significance on ECGs, vital signs and laboratory investigations.

In a recently completed study of the intranasal formulation in patients with allergic rhinitis, serum troponin was found to be elevated 21 days after having received 200 mcg intranasal GSK256066 for 14 days. The subject was asymptomatic and had a normal ECG and echocardiogram as assessed by a cardiology consultant. The relationship of this adverse event to the administration of GSK256066 has not been determined.

Pharmacokinetics of GSK256066 following single and 14 day repeat inhaled administration have been characterised in healthy volunteers at doses from 0.1-87.5 mcg. Systemic exposure to GSK256066 was only quantifiable at doses at 25 mcg and above. Exposure was only quantifiable after 4 hours post-dose in highest dose group tested (87.5 mcg) in the 14th day of treatment. Exposure after single administration (AUC0-4h) was similar in the 25, 37.5 and 50 mcg dose groups. The steady state of parent compound was attained by day 14 with approximate 2-3 fold accumulation in plasma following once daily repeat dosing at 87.5mcg. A long terminal half-life of the order of several days was observed in the 87.5 mcg dose group at day 14. The median steady state AUC (0-24h) at 87.5mcg was 326 pg*hr/ml. In addition, limited quantifiable plasma levels of the pharmacologically active metabolite GSK614917 were observed, about 8% of parent exposure at 87.5 mcg on day 14.

To provide conservative exposure safety margin estimates, clinical exposures of GSK256066 and metabolite GSK614917 observed following repeated dose of 87.5 mcg were combined for comparison with exposures of GSK256066 observed in preclinical toxicity studies. 7 days repeat dosing is well within the safety margins for cardiac and renal findings in rats, dogs and monkeys, and thus is considered a safe duration for proof of mechanism. Although the pharmacokinetic steady state is achieved by day 14, the exposures observed following 7 days dosing are still expected to fall within a predicted therapeutic range and as such this study will serve as a proof of mechanism for GSK256066, which has been shown pre-clinically to be an extremely potent PDE4 inhibitor.

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Exposure of the upper dose to be administered in this study (87.5µg) are predicted to be 3.5 times below the NOAEL for cardiac toxicity in dogs (1130 pg.h/ml) and 4.2 fold times below the NOAEL for cardiac toxicity in monkeys (1357 pg.h/mL).

The key NOAEL used in the dose rationale is based on the toxicological finding observed at the lowest dose in the most sensitive species. This is the kidney finding observed in the dog following 3 months treatment. The NOAEL in this study is 2mcg/kg/day with a corresponding AUC (0-24) of 344pg.h/ml. To date, no renal safety signals have been observed in humans in the FTIH studies. However as a precaution only subjects with normal renal function will enter this present study and measures of serum creatinine will be taken as part of the laboratory safety samples during the study.

At a dose of 87.5mcg/day, the observed median AUC in healthy volunteers is at parity with the exposure observed at the NOAEL at 3 months. However, there was no target organ toxicity in the 7-day monkey study at any dose (97, 302 and 689 µg/kg), with a resulting exposure margin of 160-fold.

The therapeutic dose range for GSK256066 is expected to be between 5mcg and 150mcg, based on predictions from pre-clinical pharmacology models. At 25mcg/day, a 4-fold exposure margin vs. the NOAEL is anticipated based on a conservative estimate using the 87.5 mcg dose group FTIH data for comparison. Thus, while the doses in this study have been selected based on existing safety cover in healthy volunteers, these are also within the range of an anticipated therapeutic effect. Based on these assumptions, there is adequate safety cover for 7 day repeat dosing in healthy subjects.

A number of features have been incorporated into the study design to ensure the safety of the subjects including renal and cardiac monitoring. Proposed monitoring for lung toxicity includes spirometry and chest examination, with a low threshold for radiological investigation of any unexpected findings.

GW857238X (cellobiose octaacetate; COA)

The excipient GW857238X (cellobiose octaacetate; COA) is included for the purpose of enhancing the physical stability of the dry powder formulation of GSK256066. GW857238X has been administered to healthy subjects and asthmatics in single dose studies (up to 8.64mg) and in a 30 day repeat dose studies in asthmatics (8.64mg BD). No obvious pattern of adverse events related to administration of GW857238X emerged and no pharmacodynamic or pharmacological effects were reported in these studies. GW857238X was not detectable in blood samples (using an assay with a LLQ of 10ng/mL). There was no evidence of episodes of bronchoconstriction induced by GW857238X in these studies. GW857238X was found to be well tolerated and showed an acceptable safety profile when given as single and repeat doses in healthy subjects or asthmatic subjects.

Given the duration of dosing (7 days) in this study, the 6 month toxicology data has been used as a guide to levels of exposure and cover rather than the longer term 12 month data. In the 6 month rat inhalation toxicity study, a No Observed Adverse Effect Level (NOAEL) with respect of lung dose was established to be 0.0840 mg/kg/day. The dose of

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GW857238X to be used in this study IPC103711 is 0.13 mg per inhalation (i.e. 1% of 13 mg per blister pocket). The maximal lung exposure of GW857238X will be 0.00186 mg/kg/day per inhalation, assuming 100% lung deposition in man (70kg), the most conservative approach. As two inhalations are administered to deliver the 25 mcg or 87.5 mcg dose of GSK256066, this amounts to a total maximal lung exposure of GW857238X of 0.00372 mg/kg/day which is approximately 23 fold lower than the NOAEL in rats.

8.4. Blinding

An investigator or other physician managing the subject may decide to unblind that subject’s treatment code, only in the case of a medical emergency or in the event of a serious medical condition, when knowledge of the investigational product is essential for the clinical management or welfare of the subject. The investigator will make every effort to contact the GSK Medical Monitor, on-call physician (if applicable), or appropriate GSK study personnel before unblinding to discuss options. If the blind is broken for any reason and the investigator is unable to contact GSK prior to unblinding, the investigator must notify GSK as soon as possible following the unblinding incident without revealing the subject’s study treatment assignment, unless the information is important to the safety of subjects remaining in the study. In addition, the investigator will record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate data collection tool (as defined in Section 14.7).

A set of code break envelopes will be provided by GSK for the purpose of emergency unblinding.

If a serious adverse event (SAE; as defined in Section 12.2, "Definition of an SAE") is reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may 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, GSK policy, or both.

8.5. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomization schedule produced by Clinical Pharmacology Statistics and Programming (CPSP) department at GSK using the RandAll system.

A randomization schedule will be produced with at least randomization numbers 1-42. Each subject will be assigned a subject number and a randomization number on the occasion of receiving their first dose of study medication. The subject number will be identical to the randomization number. The subject numbers will be assigned in chronological order starting with the lowest number first. Once a subject number has been assigned to a subject it cannot be re-assigned to another subject.

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8.6. Packaging and Labeling

The contents of the label will be in accordance with all applicable regulatory requirements.

8.7. Preparation

The ACCUHALER will require no preparation.

8.8. Handling and Storage

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to the investigator and authorized site staff and under physical conditions that are consistent with investigational product-specific requirements.

8.9. Product Accountability

The investigator, institution, or the head of the medical institution (where applicable) is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or the head of the medical institution (where applicable), or designated site staff (e.g., storage manager, where applicable) must maintain investigational product accountability records throughout the course of the study. The responsible person(s) will document the amount of investigational product received from and returned to GSK (when applicable), the amount supplied and/or administered to and returned by subjects, if applicable.

8.10. Assessment of Compliance

On the mornings of Day 1 and 7, study medication will be administered by two authorised members of the site personnel. Dosing will be witnessed and details of date and time of dosing and staff administering and witnessing dosing will be recorded in the eCRF. On Day 2 to Day 6, subjects will self administrate medication at home. Diary cards will be provided for the subjects to document the date and time medication is taken. Compliance will be verified using the drug accountability records.

8.11. Treatment of Investigational Product Overdose

An overdose for this study will be considered as any dose of study drug more than the planned dose on each dosing occasion. In the event of an overdose, there are no recommended medications or non-drug therapies for treatment. Management should be supportive and the investigator should use his/her clinical judgement in treating any overdose situation.

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8.12. Occupational Safety

Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure notify the monitor.

9. CHALLENGE AGENTS

Lipopolysaccharide (LPS, endotoxin)

Bacterial endotoxin is a component of the cell wall of Gram-negative bacteria present in a variety of occupational and general environmental settings. Chronic exposure to airborne endotoxin, measured in several occupational environments, has been associated with the risk of both pulmonary and systemic disease.

Previous LPS studies have used non-GMP material. The present study will be using cGMP endotoxin manufactured by the National Institute of Health, Bethesda, MD.

The Roflumilast study [Hohlfeld, 2006], similar to numerous studies world-wide, used a formulation by FDA that contained albumin of undisclosed source as carrier [IND master file]. The same preparation has been recently re-vialed by the NIH/NCI in the US as lyophilized endotoxin with no carrier protein under cGMP and the FDA Master File has been updated in November 2006. The proposed study will be the first using this cGMP endotoxin preparation in Germany.

The dose of LPS used in this study is 4 ng/kg, which is 100 times lower than doses used in inhalation models of endotoxin-induced lung inflammation. This dose was chosen based on the data published by O’Grady et al [O'Grady, 2001]. In this study, lavage after 24 h in subjects challenged with 4 ng/kg of endotoxin revealed a localized inflammatory response that was neutrophil-predominant. The most common symptom was cough, which occurred around the time of the bronchoscopy. The systemic response to LPS was characterized as described in Figure 1, taken directly from the paper.

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Figure 1 Table of systemic responses in 28 subjects following endobronchial endotoxin instillation*

The site performing this study also has experience with this model and has used it to test the effects of Roflumilast [Hohlfeld, 2006] and an antibody to MCP-1 [Krug, 2006]. They have shown LPS 4ng/kg to be safe and well-tolerated by healthy volunteers and patients with COPD. In addition, the LPS previously used by the investigators is the same batch used in the O’Grady study and was obtained from the National Institutes of Health (Clinical Center Reference Endotoxin). The LPS in the present study is derived from this original LPS, but is now free of albumin and has been manufactured under GMP conditions.

10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES

10.1. Permitted Medications

All concomitant medications taken during the study will be recorded in the eCRF. The minimum requirement is that drug name and the dates of administration are to be recorded.

The following medication is allowed during the study:

• Paracetamol • Oral contraceptive (female subjects).

10.2. Prohibited Medications

All medications are prohibited from this study with the exception of those detailed in Section 10.1.

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11. SUBJECT COMPLETION AND WITHDRAWAL

11.1. Subject Completion

Subjects will be considered to have completed the study if they have received all of the planned study treatments and have attended the unit for all of the planned study sessions including any required repeat visits after the completion of treatment.

11.2. Subject Withdrawal

11.2.1. Subject Withdrawal from Study

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his/her discretion; discontinue the subject from participation in this study at any time. If a subject is prematurely withdrawn from participation in the study for any reason, the investigator must make every effort to perform the following evaluations:

• Physical examination (if deemed necessary) • 12 lead ECG • Vital signs (BP & pulse rate) • Spirometry Assessment • Collection of blood biomarker sample • Clinical laboratory tests including haematology, biochemistry and urinalysis • Adverse event assessment/Concomitant medication questioning • Pregnancy test These data should be recorded in the eCRF as they comprise an essential evaluation that should be performed before 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 or SAE, the procedures stated in the (AE and SAE) section must be followed.

Subjects are not obliged to state the reason for withdrawal. However, the reasons for withdrawal, or failure to provide a reason, must be documented by the Investigator on the Completion/Withdrawal section of the eCRF. Every effort should be made by the Investigator to follow up subjects who withdraw from the study.

Stopping Criteria

Subject should be withdrawn from treatment if any clinically relevant abnormalities in ECGs are observed after randomisation, including but not limited to:

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• Ventricular rate < 50 beats per minute (measured at three individual timepoints) • PR interval > 200 msec (grade I AV block) • Evidence of second or third degree atrioventricular (AV) block • Pathological Q waves (>40 msec depth greater than 0.4-0.05 mV) • Evidence of frequent supra-ventricular or ventricular ectopics or arrhythmias • Non-specific intraventricular conduction delay, if not present at screening • ST-T wave abnormalities, if clinically significant • Right or left complete bundle branch block • Incomplete right bundle branch block (QRS interval > 100 msec but < 120 msec with right bundle branch block pattern), if not present at screening • QTc(B) interval > 500msec or uncorrected QT > 600 msec (average from 3 ECGs; QTcB or QTcF; machine or manual reading; male or female subject) or a change of >60msec from baseline. Any subject with abnormal liver function test results (ALT ≥3 X ULN and bilirubin ≥1.5 X ULN) must be withdrawn from investigational product and monitored closely (with specialists or hepatology consultation recommended). This event must be reported to GSK within 24 hours of learning of its occurrence. Subjects should be monitored twice weekly until liver function test (ALT, AST, alkaline phosphatase, bilirubin) and prothrombin time resolve, stabilize, or return to within baseline values. Subjects with ALT ≥3 X ULN must be withdrawn from investigational product and monitored weekly until liver function tests (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize, or return to within baseline values.

Subjects will be withdrawn from the study if there is an increase in serum creatinine level ≥ 27 micromoles/L (0.3mg/dL). If a subject’s serum creatinine levels is observed to have a greater than 20% increase compared to baseline levels and confirmed by a repeat testing within 24 hours the investigator will consult with the medical monitor and consider to withdraw the subject.

11.2.2. Subject Withdrawal from Investigational Product

A subject will be considered to have prematurely withdrawn from the study drug if he/she does not complete dosing for the entire planned treatment period for his group, having received the first dose of study drug, for any reason.

Once a subject has discontinued study drug, the subject may not re-enter the study. Dosing of the subjects with study medication may be stopped at any time, at the request of the subject, or at the discretion of the Principal Investigator (i.e. if clinically significant adverse events should occur).

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11.3. Treatment After the End of the Study

Subjects participating in this study will be healthy volunteers. Medication being investigated will provide no further health benefits, therefore continuation of treatment following study completion will not be considered.

11.4. Screen and Baseline Failures

Any subject who is screened for the study and then is withdrawn prior to randomization for any reason will be considered a screen failure. Data from these subjects will not be collected (except for SAE data), but their source data will remain at site, where they can be seen by the study monitor if necessary.

A log of all subjects screened for the study but not entered in the study will be maintained. The reason(s) for excluding these subjects will be recorded

12. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE)

The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the investigator or site staff will be responsible for detecting, documenting and reporting AEs and SAEs, as detailed in both this section of the protocol and in the AE/SAE section of the SRM.

12.1. Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

12.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a. Results in death b. Is life-threatening NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

- 35 - 35 GM2007/00126/02 CONFIDENTIAL GM2008/00234/00GM2007/00126/02 IPC103711IPC103711 c. Requires hospitalization or prolongation of existing hospitalization NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. d. Results in disability/incapacity, or NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption. e. Is a congenital anomaly/birth defect f. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

12.2.1. 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, and vital signs) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE or SAE. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported 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 and do not worsen, will not be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.

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Liver chemistry threshold stopping criteria have been designed to assure subject safety. When subjects meet the following liver chemistry threshold criteria, investigational product must be permanently withdrawn, additional testing performed, and the subject monitored until liver chemistries resolve, stabilize, or return to baseline values. The subject must then be permanently withdrawn from the study:

• ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (>35% direct). • ALT ≥ 3xULN. Subjects with ALT ≥3xULN and bilirubin ≥1.5xULN (>35% direct bilirubin; bilirubin fractionation required) must be immediately and permanently withdrawn from investigational product. Every attempt must be made to have the subject return to clinic (within 24 hours) for repeat liver chemistries and additional testing, and monitored closely (with specialist or hepatology consultation recommended). This event must be reported to GSK within 24 hours of learning of its occurrence. Subjects must be monitored twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values. Upon completion of the safety follow-up, the subject must then be withdrawn from the study.

Subjects with ALT ≥3xULN must be permanently withdrawn from investigational product and monitored weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values. This event must be reported to GSK within 24 hours of learning of its occurrence.

In all the above situations, every attempt must be made to obtain the following:

• Viral hepatitis serology including: • Hepatitis A IgM antibody. • Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). • Hepatitis C RNA. • Cytomegalovirus IgM antibody. • Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing). • Hepatitis E IgM antibody (if subject resides outside the USA or Canada, or has traveled outside USA or Canada in past 3 months). • Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF • Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). • Fractionate bilirubin, if bilirubin≥1.5xULN. • Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash as relevant on the AE report form.

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• Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, putative hepatotoxins, or alcohol on the concomitant medications report form. The following are required for subjects with ALT ≥3xULN and bilirubin ≥1.5xULN but are optional for other abnormal liver chemistries:

• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies. • Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

12.3. Time Period, and Frequency of Detecting AEs and SAEs

From the time a subject consents to participate in the study until he or she has completed the study (including any follow-up period), all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be reported promptly to GSK.

12.4. Prompt Reporting of SAEs to GSK

SAEs will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition of an SAE.

12.4.1. 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" data 24 hrs Updated "SAE" data collection tool collection tool

12.5. AE and SAE Documentation and Follow-up Procedures The investigator will review and adhere to the following procedures, which are outlined in detail in the AE/SAE section of the SRM:

• Method of Detecting AEs and SAEs • Recording of AEs and SAEs • Evaluating of AEs and SAEs • Completion and Transmission of SAE Reports to GSK • Follow-up of AEs and SAEs • Post-study AEs and SAEs • Regulatory Reporting Requirements for SAEs

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13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

13.1. Hypotheses

The primary aim of this study is to investigate the effects of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) on lung inflammation following segmental LPS challenge in healthy volunteers. Therefore the study is based around estimation of differences between GSK256066 doses and placebo.

13.2. Study Design Considerations

13.2.1. Sample Size Assumptions

No formal hypothesis testing will be carried out as this study is based around estimation of differences between GSK256066 doses and placebo. The planned sample size arises primarily from logistic feasibility and not statistical considerations. To take into account potential drop-outs, 14 subjects per group will be recruited, i.e. a total of 42 recruited subjects, in order to reach the goal of 36 evaluable subjects (12 per arm).

There is only sparse external information available from previous LPS challenge studies. One poster (Hohlfeld et al) presents results from a recent LPS challenge however variability estimates could not be appropriately obtained under the assumption of log- normal data. Due to the lack of a variability estimates no formal power calculations have been performed.

13.2.2. Sample Size Sensitivity

Due to the lack of data from previous studies no sample size sensitivity can be carried out for this study.

13.2.3. Sample Size Re-estimation

There is no sample size re-estimation planned for this study.

13.3. Data Analysis Considerations

13.3.1. Analysis Populations

The ‘All Subjects’ population will be defined as all subjects randomised to treatment who received at least one dose of study treatment (including placebo). This population will be used for all listings, tables and figures with the exception of PK concentration listings and tables.

The ‘GSK256066 PK Concentration’ population will be defined as all subjects from the ‘All Subjects’ population for whom a GSK256066 PK sample was taken and analysed. This population will be used for all summaries and figures of GSK256066 PK

- 39 - 39 GM2007/00126/02 CONFIDENTIAL GM2008/00234/00GM2007/00126/02 IPC103711IPC103711 concentration data. The ‘GSK614917 PK Concentration’ population will be defined and used under the same principles. For simplicity, if the same subjects are included in both populations, only one ‘PK Concentration’ population will be defined. If there is PK concentration data for all subjects, then the ‘All Subjects’ population will be used instead.

The ‘PK parameter population’ will be defined as all subjects from the ‘PK Concentration’ population for whom PK parameters are available. This population will be used for all summaries and analysis of pharmacokinetic parameters. If needed, two separate PK parameter populations will be defined for GSK256066 and GSK614917.

All analyses will be based on the actual treatment each subject received. Any departures from the planned treatment according to the randomisation schedule will be documented in the study report.

13.3.2. Analysis Data Sets

Construction of datasets relating to the reporting and analysis of study data will be performed in accordance with all applicable GSK standards and procedures.

Data sets are considered of equal importance.

13.3.3. Treatment Comparisons

13.3.3.1. Primary Comparisons of Interest

The primary treatment comparisons are:

• GSK256066 25µg versus placebo for the absolute change from baseline in BAL neutrophils (cells/mL) at 24 hours post LPS exposure • GSK256066 87.5µg versus placebo for the absolute change from baseline in BAL neutrophils (cells/mL) at 24 hours post LPS exposure.

13.3.3.2. Other Comparisons of Interest

The secondary treatment comparisons are:

• GSK256066 25µg versus placebo • GSK256066 87.5µg versus placebo for the following endpoints:

• The total and differential cell count in BAL • The concentration of BAL inflammatory biomarkers (eg. IL-8, TNFα, IL-6, MPO) • The concentration of serum inflammatory biomarkers (e.g. SP-D, CC-16) No adjustments will be made for multiplicity.

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13.3.4. Interim Analysis

No interim analysis is planned. However, if there is a delay in receiving the urea analysis results, all other data will be processed and a partial database release will be conducted to allow for the reporting of all other data collected in this study. The study will be unblinded at this time. Although the data at time of database release will be as near to final as possible, it is not possible to guarantee that this data won’t change until the database is frozen. Database freeze will occur once all the data including the urea analysis results are in-house.

13.3.5. Key Elements of Analysis Plan

Full details of the statistical analyses will be presented in the RAP (Reporting and Analysis Plan). Any deviation from the planned analysis will be documented in the RAP and the final study report. Data displays will be presented according to Clinical Pharmacology and Core IDSL standards.

13.3.5.1. Pharmacodynamic Analyses

All pharmacodynamic data will be listed and summarised.

The primary analysis will be the comparison of absolute change from baseline in BAL neutrophils at 24 h post LPS exposure between each dose of GSK256066 and placebo on Day 7. Loge-transformed data will be analysed using a fixed effects analysis of variance model, adjusting for effects of loge-transformed baseline (pre-LPS challenge measurement, 2h post-dose on Day 7) and treatment. No sample has been taken pre- treatment (a ‘true’ baseline) for the subjects are limited to two bronchoscopies over a week (see Section 4). The impact of baseline effect in the model will be investigated, further details will be provided in the RAP. An estimate of the treatment comparisons (each dose of GSK256066 against placebo) expressed as a ratio following a back- transformation of the difference of the treatment estimates (LS Means) will be calculated along with the associated 95% confidence interval.

Saline data will not be formally analysed, however it will be summarised along with baseline and endpoint data.

A similar analysis will be performed on total cell count, and absolute and percentage cell count of the BAL inflammatory cell types.

The percentage cell count will be calculated as follows:

Percentage absolute cell count = x 100 cells (%) total cell count

All total and absolute cell count endpoints will be loge transformed prior to analysis if the distributional properties of the data suggest this is necessary. Percent cell count data will not be transformed unless the distributional properties of the data suggest a transformation is necessary.

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For all the statistical models fitted, model and distributional assumptions underlying each analysis will be assessed by visual inspection of residual plots. Homogeneity of variance will be assessed by plotting the residuals against the predicted values from the model, whilst normality will be assessed using normal probability plots. If assumptions are grossly violated, alternative analyses will be performed.

BAL Biomarkers

BAL concentrations will be first corrected for dilution. For this purpose, a urea analysis will be performed on serum and BAL fluid. Corrected concentrations will be calculated as follows:

Corrected concentration = ConcentrationBAL × dilution factor,

where dilution factor = UREAserum / UREABAL

Only corrected concentrations will be used for the analysis.

Raw and corrected concentration BAL biomarker data, and dilution factor will be listed by treatment and planned time relative to dosing (i.e. Day 7, 2 hours or 26 hours post- dose), however only corrected concentration BAL biomarker data will be summarised. Corrected concentration will be loge-transformed and analysed using a fixed effects model adjusting for loge(pre-LPS challenge) and treatment. From the above analysis, adjusted geometric means for each treatment group on Day 7 26 hours will be presented, along with corresponding 95% confidence intervals. Estimates of treatment ratios for both the doses of GSK256066 compared to placebo will be calculated by exponentiating the difference between the adjusted means. Corresponding 95% confidence intervals of these ratios will also be presented.

Blood Biomarkers

Serum concentrations of inflammatory biomarkers will be listed and summarised by treatment and planned time relative to dosing. Serum concentrations on Day 7 pre-dose and 26 hours pre-bronchoscopy (expressed as a ratio to baseline, Day 1 pre-dose) will be calculated for each subject and will be loge-transformed and analysed using a repeated measures mixed effects model. Loge(Day 1 pre-dose), time point (Day 7 pre-dose or 26hours), treatment and interaction terms will be fitted as mixed effects and subject as a random effect. The interaction terms will be detailed in the RAP. From the above analysis, adjusted geometric means for each treatment group on Day 7 pre-dose and 26hours post-dose will be presented, along with corresponding 95% confidence intervals. Estimate of treatment ratios for both the doses of GSK256066 compared to placebo will be calculated by exponentiating the difference between the adjusted means. Corresponding 95% confidence intervals of these ratios will be presented.

13.3.5.2. Safety Analyses

All safety endpoints will be listed and summarised using the All Subjects population. No formal statistical analysis will be carried out on the safety endpoints.

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Extent of Exposure

The dates and times of the treatment dosing will be listed to indicate exposure to study drug.

Adverse Events

Adverse events will be coded using the MedDRA coding dictionary, to give a group code and a system organ class (SOC), which will then be used when summarising the data. The verbatim text will be used in listings.

The incidence of all adverse events (regardless of causality) will be summarised for each treatment group and sorted by SOC and then by total incidence (i.e. across all treatment groups). System organ classes will not be presented when the overall incidence for any adverse event within the particular system is 0. If the total incidence for any two or more adverse events is equal, the events will be presented in alphabetical order. In addition, adverse events considered to be possibly drug-related by the investigator will be summarised separately.

Listings of all adverse events and adverse events considered to be possibly drug-related will be produced. Only subjects with at least one AE will appear in the listings. The listings will be sorted by treatment group, subject number and onset date of the adverse event.

The association between the adverse event SOC, group terms and the verbatim text will be presented.

Deaths and adverse events regarded by the investigator as fulfilling the definition of serious will be listed and summarised. Subjects with treatment-limiting adverse events will be also listed and summarised by treatment group.

Clinical Laboratory Evaluations

Data from haematology, clinical chemistry and urinalysis laboratory tests will be listed. All haematology and clinical chemistry laboratory values will be flagged high or low relative to their reported normal ranges.

Separate listings describing all subjects with haematology and clinical chemistry laboratory values outside threshold ranges will be produced. A listing of the laboratory threshold ranges will also be produced.

Other Safety Measures

All vital signs, holter monitoring and ECG data will be listed and summarised by treatment group and planned relative time.

Lung function data (FEV1 and FVC) will also be listed and summarised by treatment group and planned relative time.

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13.3.5.3. Pharmacokinetic Analyses

Raw Bronchoalveolar Lavage (BAL) Fluid Concentrations

Individual BAL concentrations of GSK256066 and metabolite GSK614917 will be listed and summarised by nominal time and treatment.

13.3.5.4. Pharmacokinetics/Pharmacodynamics Analyses

If the summary statistics indicates a correlation between dose and the primary endpoints, exploratory data-driven analysis may be conducted to investigate the relationship between dose, BAL concentration of GSK256066 and active metabolite GSK614917, and the primary endpoints. The analysis may involve PK/PD modelling, as appropriate.

14. STUDY CONDUCT CONSIDERATIONS

14.1. Regulatory and Ethical Considerations, Including the Informed Consent Process

GSK will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will also be conducted in accordance with "good clinical practice" (GCP), all applicable subject privacy requirements, and, the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following:

• IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents • Subject informed consent • Investigator reporting requirements GSK will provide full details of the above either verbally, in writing or both.

Written informed consent will be obtained for each subject before he or she can participate in the study.

14.2. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the eCRF will serve as the source document.

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GSK will monitor the study consistent with the demands of the study and site activity 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 other study agreements, GCP, and all applicable regulatory requirements. The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

14.3. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

14.4. Study and Site Closure

Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and GSK procedures.

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with the investigator or the head of the medical institution (where applicable), including the reasons for taking such action, at that time. When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect.

GSK will promptly inform all other investigators or the head of the medical institution (where applicable), and/or institutions conducting the study if the study is suspended or prematurely discontinued for safety reasons. GSK will also promptly inform the regulatory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action. If required by applicable regulations, the investigator or the head of the medical institution (where applicable) must inform the IEC/IRB promptly and provide the reason for the suspension or premature discontinuation.

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14.5. Records Retention

Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site.

14.6. Provision of Study Results and Information to Investigators

When required by applicable regulations, the investigator signatory for the clinical study report will be determined at the time the report is written. When the clinical study report is completed, GSK will provide the investigator with a full summary of the study results. The investigator is encouraged to share the summary results with the subjects, as appropriate. In addition, the investigator will be given reasonable access to review the relevant statistical tables, figures, and reports and will be able to review the results for the entire study at a GSK site or other mutually agreeable location.

GSK will provide the investigator with the randomization codes for their site after the statistical analysis for the entire study has been completed.

14.7. Data Management

The data collection tool for this study will be electronic GSK-defined case report forms (eCRFs). In all cases, subject initials will not be collected nor transmitted to GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures.

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15. REFERENCES

Barnette MS. Phosphodiesterase 4 (PDE4) inhibitors in asthma and chronic obstructive pulmonary disease (COPD). Prog Drug Res. 1999;53:193-229.

European Agency for the Evaluation of Medicinal Products (EMEA) guidelines [CPMP/ICH/285/95, 2000]

GlaxoSmithKline Document Number: WM2004/00061/03 Clinical Investigator Brochure for GSK256066. Report Date 10-Nov-2006.

GlaxoSmithKline Document Number: RM2007/00156/00 Supplement to Clinical Investigator Brochure for GSK256066. Report Date 02-Mar-2007.

GlaxoSmithKline Document Number SM2003/00026/04 Investigator's Brochure for GW857238 (COA). Report Date 02-Dec-2005.

GlaxoSmithKline Document Number WM2006/00027/00 Supplement to Clinical Investigator Brochure for GW857238 (COA). Report Date 10-Apr-2006.

Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, Schaumann F, Mueller M, Bethke TD, Manegold A, Bredenbroeker D, Krug N, Hermann R. Roflumilast inhibits recruitment of inflammatory cells into the lung after segmental LPS challenge in healthy subjects. Proc Amer Thoracic Soc. 2006. A849

Krug N, Larbig M, Bonner J, Mueller M, Erpenbeck VJ, Schaumann F, Lloyd P, Hohlfeld JM, Pascoe S. Anti-MCP-1 monoclonal antibody (ANB912) attenuates LPS- induced monocyte recruitment into the lung in patients with COPD. Proc Amer Thoracic Soc. 2006. A849.

Michel O, Nagy AM, Schroeven M, Duchateau J, Neve J, Fondu P and Sergysels R. Dose-response relationship to inhaled endotoxin in normal subjects. Am J Respir Crit Care Med , 1997 156:1157-1164.

O'Grady NP, Preas HL, Pugin J, Fiuza C, Tropea M, Reda D, Banks SM, Suffredini AF. Local inflammatory responses following bronchial endotoxin instillation in humans. Am J Respir Crit Care Med. 2001. 163:1591-98.

Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast- -an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005. 366:563-71.

Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998 Feb;157(2):351-70

Trussell, J; Hatcher, RA; Stewart, F. Contraceptive Technology, 18th edition, 2003.

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Appendices GM2007/00126/02

Appendix 1: General Time and Events Table

Assessment Screening Day Early Follow-up With- drawal1

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Time relative to baseline (Days) 1 2 3 4 5 6 7 8 18-22 Informed consent x Medical & surgical history x Physical examination 2 x x x Height and weight measurement x Clinical Laboratory testing x3,16 x14 x14,16 x 7 x CONFIDENTIAL Urinalysis x x14 x14 x Tests for DoA, alcohol, cotinine x x14 X14 48 Pregnancy test x x14 x Unit visits x x x x x x Dosing x x x x x x x Vital signs (blood pressure, pulse, temp) in x4 x5 x6 x7 x x supine position Holter monitoring X15 Resting 12-lead ECG x4 x5 X13 x7 x x Spirometry x4,8 x8 x8 x8 x Bronchoscopy x x LPS instillation x GM2008/00234/00 BAL fluid collection x 11 x11 Blood sample for Pharmacogenetics x9 Continued… IPC103711

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CONFIDENTIAL GM2007/00126/02 IPC103711

Appendix 1: General Time and Events Table (continued) GM2007/00126/02

Assessment Screening Day Early Follow-up With- drawal1 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Blood Biomarkers X10 x10 x10 x Blood sample for measurement of urea 12 12

x x AE/Con Med questioning x x x x x x x x x x 1. Subjects who stop taking study medication prior to Day 7 will attend an early withdrawal visit within 24h 2. To include a chest exam 3. Includes serology (hepatitis and HIV) 4. In triplicate at screening only 5. Pre-dose and 30min, 1h, 2h post-dose 6. Pre-dose, 3h, 4h post dose CONFIDENTIAL 7. 24 hours after dosing on Day 7 8. FVC will be performed at screening only. FEV1 pre-dose on Day 1 and 7, and after bronchoscopy (on Day 7 & Day 8) if required. 49 9. Blood sample for PGx may be collected at any time post-dose (although preferably at Visit 2) if the informed consent has been signed 10. Blood for biomarkers collected pre-dose Day 1 and 7, and pre-bronchoscopy on Day 8 11. BAL samples will be collected for baseline at 2 hours post dose and following LPS instillation and saline control challenge at 26 hours post-dose on Day 7. BAL concentrations of GSK25066 and GSK614917 will also be determined at these time points 12. Where possible, blood sampling should be taken simultaneously to BAL sample collection 13. Pre-dose and 3h 14. Pre-dose 15. Continuous Holter monitoring for 6hrs post dose 16. To include Troponin testing NB: where multiple assessments are scheduled at the same timepoints, assessments should be conducted in the following order: vital signs, 12 Lead-ECG, Spirometry or, Biomarker blood sample, Bronchoscopy, BAL fluid collection, GM2008/00234/00 IPC103711

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GM2007/00126/02 CONFIDENTIAL GM2008/00234/00GM2007/00126/02 IPC103711IPC103711

Appendix 2: Study Schematic Figure

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Appendix 3: PGx Pharmacogenetic Research

Pharmacogenetics – Background

Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx analysis include:

Drug Disease Gene Outcome

Abacavir HIV HLA Caucasian males with HLA B57 variant were at [Hetherington, (human increased risk for experiencing hypersensitivity to 2002; Mallal, leukocyte abacavir 2002] antigen)

Tranilast Restenosis UGT1A1 Drug induced hyperbilirubinemia explained by high prevention proportion of affected patients having 7/7 TA following repeat genotype, consistent with clinically benign coronary bypass Gilbert’s Syndrome [Roses, 2002]

ABT-761 Asthma [Drazen, ALOX5 ALOX5 Sp1 promoter genotype (x,x) associated 1999] with reduced response to 5-lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies.

Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to GSK256066.

Pharmacogenetic Research Objectives

The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to GSK256066. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with GSK256066 that may be attributable to genetic variations of subjects, the following objectives may be investigated:

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• Relationship between genetic variants and the pharmacokinetics of investigational product • Relationship between genetic variants and safety and/or tolerability of investigational product • Relationship between genetic variants and efficacy of investigational product Study Population

Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research.

Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled.

Study Assessments and Procedures

In addition to any blood samples take for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labeled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study.

If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

The need to conduct PGx analysis may be identified after a study (or a set of studies) of GSK256066 has been completed and the study data reviewed. For this reason, samples may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. In special cases, the samples may not be studied. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond to GSK256066. GSK or those working with GSK (for example, other researchers) will only work with samples collected from the study for the use stated in this protocol and in the informed consent form. Samples will be stored securely. Subjects can request their sample to be destroyed at any time.

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Subject Withdrawal from Study

If a subject who has consented to participate in PGx research withdraws from the clinical study for any reason other than lost to follow-up, the subject will be given the following options concerning the PGx sample, if already collected:

• PGx research continues per the subject’s consent; or, • Any remaining sample is destroyed If a subject withdraws consent from the PGx research or requests sample destruction, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records. In either case, GSK will only keep study information collected/generated up to that point.

Screen and Baseline Failures

If a blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records.

Pharmacogenetics Analyses

The need to conduct PGx analysis may be identified after a study (or set of studies) of GSK256066 has been completed and the study data reviewed. For this reason, samples may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. In special cases, the samples may not be studied. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond GSK256066.

Generally GSK will utilize two approaches to explore genetic variation in drug response.

1. Specific sections of DNA may be selected from areas of the genome (e.g., candidate genes) known to encode the drug target, drug metabolizing enzymes, areas associated with mechanisms underlying adverse events, and those linked to study disease and, thus, linked to drug response. 2. By evaluating large numbers of polymorphic markers (e.g., single nucleotide polymorphisms or SNPs) throughout the genome, sets of markers may be identified that correspond to differential drug response. Hardy-Weinberg Equilibrium Testing

The genotypic frequencies of each polymorphism will be evaluated for conformity to those expected under normal conditions by employing Hardy-Weinberg Equilibrium testing.

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Comparison of Demographic and Baseline Characteristics by Genotype

Differences in baseline clinical characteristics and potential contributing covariates may be summarized and compared among genotype (or haplotype) subgroups.

Evaluation of Genotypic Effects

Analyses may be carried out to evaluate the degree of association between subject genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and safety). Where such genotypic tests are inappropriate (for example, where the number of marker genotypes is too large and/or the frequency of individual genotypes too small), allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker allele is the same in responders and non-responders.

Evaluation of Treatment by Genotype and Gene-Gene Interaction

In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the selected parameters, the possibility of a treatment group by genotype (haplotype or allele) interaction will also be explored. If appropriate, the joint effects of multiple markers (gene-gene interactions) may also be evaluated.

Linkage Disequilibrium

For pairs of polymorphisms, the degree to which alleles from the two sites are correlated (linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic sites within a gene are shown to be statistically associated with a response to investigational product, the degree of linkage disequilibrium will aid interpretation in that it will indicate the extent to which the two sites are exerting independent effects.

Multiple Comparisons and Multiplicity

To the extent that multiple markers are evaluated (especially in the case of a genome scan for association), an adjustment to observed p-values may be made to limit erroneous conclusions due to multiple tests.

Power and Sample Size Considerations

The ability to detect differential drug response among genotypes at a polymorphic site depends on the total number of subjects genotyped and the frequency distribution of the different genotypes. Consequently, genotyping analyses are plausible for those polymorphic sites where the number of subjects comprising the genotypic groups is sufficiently large; however, these frequencies will not be known until sufficient samples have been collected and genotyping is complete.

Estimates of sample sizes required to demonstrate genotype effects vary considerably, depending on the assumptions made about allele frequency, genetic effect size, and mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson [Palmer, 2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300 cases and 600 controls would be needed to conduct a genetic association

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analysis. In contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls would be needed to demonstrate an association.

Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002; Mallal, 2002] and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic markers have been found to significantly associate with hypersensitivity reaction (abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample sizes typically encountered in Phase I and Phase II studies may be sufficient to identify clinically relevant genetic associations.

Informed Consent

Subjects who do not wish to participate in the PGx research may still participate in the clinical study. PGx informed consent must be obtained prior to any blood being taken for PGx research.

Provision of Study Results and Confidentiality of Subject’s PGx Data

GSK may summarize the cumulative PGx research results in the clinical study report.

In general, GSK does not inform the investigator, subject, or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of the PGx research results because the information generated from PGx studies is preliminary in nature, and the significance and scientific validity of the results are undetermined at such an early stage of research, under any circumstances unless required by law.

References

Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics. 2000; 10:503-10.

Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 1999; 22:168-70.

Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32.

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McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol. 2000; 18:505-8.

Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res. 2001; 2:102-12.

Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov. 2002; 1:541-9.

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Appendix 4: Country Specific Requirements

No country-specific requirements exist.

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Appendix 5: Protocol Changes

This amendment is applicable to all sites.

Rationale for Amendment 1:

In response to guidance from the regulatory authority (BfArm) to further enhance subject cardiac safety; the stopping criteria for 12-Lead ECG has been made more stringent and holter monitoring and troponin analysis have been added to the planned study assessments. As a result of this, subjects will now be required to reside in the unit for a total of 6 hours on Day 1.

Points affected by this amendment are:

Section 3.2: Secondary (Endpoints)

Previous Text

• Safety and tolerability: • Vital Signs: systolic and diastolic blood pressure (BP), heart rate (HR) • 12-lead ECG including QTc(B), QT, QRS, PR, and ventricular rate (VR). • Lung function (FEV1 and FVC) • Laboratory safety tests (haematology, clinical chemistry, urinalysis) • Adverse Events • Serum concentration of protein inflammatory biomarkers (e.g. SP-D, CC-16). • BAL concentration of protein inflammatory biomarkers (e.g. IL-8, TNFα, IL-6, MPO) • BAL concentrations of GSK256066 and metabolite GSK614917 Amended Text

• Safety and tolerability: • Vital Signs: systolic and diastolic blood pressure (BP), heart rate (HR) • Holter monitoring • 12-lead ECG including QTc(B), QT, QRS, PR, and ventricular rate (VR). • Lung function (FEV1 and FVC) • Laboratory safety tests (haematology, clinical chemistry, urinalysis) • Adverse Events • Serum concentration of protein inflammatory biomarkers (e.g. SP-D, CC-16).

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• BAL concentration of protein inflammatory biomarkers (e.g. IL-8, TNFα, IL-6, MPO) • BAL concentrations of GSK256066 and metabolite GSK614917

Section 6.2: Treatment Phase

Previous Text

Amended Text

Section 6.4.2: Safety Laboratory Tests

Previous Text

Clinical Laboratory tests will be performed at the time points outlined in Appendix 1.

The following samples will be collected for analysis:

• Clinical Chemistry (blood) • Haematology (blood) • Urinalysis (urine) Additional samples may be taken for safety reasons at the discretion of the Investigator.

Clinical laboratory tests will be analysed locally by site.

Details of sample collection and processing can be found in the Study Reference Manual.

Amended Text

Clinical Laboratory tests will be performed at the time points outlined in Appendix 1.

The following samples will be collected for analysis:

• Clinical Chemistry (blood) • Haematology (blood) • Urinalysis (urine) Additional samples may be taken for safety reasons at the discretion of the Investigator.

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Clinical laboratory tests will be analysed locally by site.

Note: Troponin tests will be performed at screening and on Day 7 to monitor cardiac safety.

Details of sample collection and processing can be found in the Study Reference Manual.

Additional section added within Section 6:

Section 6.4.4: Holter monitoring

Holter monitoring will be used to detect subjects with underlying cardiac arrhythmias.

Analysis of the Holter tapes will be arranged by the site. Rhythms of potential clinical concern will be reported.

Section 6.4.5: 12-Lead ECG

Previous Text

• The ECG tracing should be examined and manual measurement by a trained physician should be performed to assess the accuracy of the equipment being used. • If the reading is accurate: • The subject should be monitored closely and followed until the QT and QTcB interval return to within 30msec of their baseline. • The subject should be considered for withdrawal from treatment. • Consideration should be given to the subject’s safety prior to receiving further study medication. • Consideration should be given to putting the study on hold until all subjects’ data can be re-evaluated and confirmed. Amended Text

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• The ECG tracing should be examined and manual measurement by a trained physician should be performed to assess the accuracy of the equipment being used. • If the reading is accurate: • The subject must be withdrawn from the study. • The subject should be monitored closely and followed until the QT and QTcB interval return to within 30msec of their baseline. • Consideration should be given to the subject’s safety prior to receiving further study medication. • Consideration should be given to putting the study on hold until all subjects’ data can be re-evaluated and confirmed.

Section 11.2.1: Stopping Criteria

Previous Text

Subjects should be withdrawn from treatment if any clinically relevant abnormalities in ECGs are observed after randomisation, including but not limited to:

• Ventricular rate < 37 beats per minute • PR interval > 240 msec Amended Text

Subject should be withdrawn from treatment if any clinically relevant abnormalities in ECGs are observed after randomisation, including but not limited to:

• Ventricular rate < 50 beats per minute (measured at three individual timepoints) • PR interval > 200 msec (grade I AV block)

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Additional text added GM2007/00126/02

Appendix 1: General Time and Events Table

Assessment Screening Day Early Follow-up With- drawal1

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Time relative to baseline (Days) 1 2 3 4 5 6 7 8 18-22 Informed consent x Medical & surgical history x Physical examination 2 x x x Height and weight measurement x Clinical Laboratory testing x3,16 x14 x14,16 x 7 x CONFIDENTIAL Urinalysis x x14 x14 x Tests for DoA, alcohol, cotinine 14 14 62 x x X Pregnancy test x x14 x Unit visits x x x x x x Dosing x x x x x x x Vital signs (blood pressure, pulse, temp) in x4 x5 x6 x7 x x supine position Holter monitoring X15 Resting 12-lead ECG x4 x5 X13 x7 x x Spirometry x4,8 x8 x8 x8 x Bronchoscopy x x LPS instillation x GM2008/00234/00 BAL fluid collection x 11 x11 Blood sample for Pharmacogenetics 9

x IPC103711 Blood Biomarkers X10 x10 x10 x Continued…

CONFIDENTIAL GM2007/00126/02 IPC103711 GM2007/00126/02 Appendix 1: General Time and Events Table (continued)

Assessment Screening Day Early Follow-up With- drawal1 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Blood sample for measurement of urea x12 x12 AE/Con Med questioning x x x x x x x x x x 1. Subjects who stop taking study medication prior to Day 7 will attend an early withdrawal visit within 24h 2. To include a chest exam 3. Includes serology (hepatitis and HIV) 4. In triplicate at screening only 5. Pre-dose and 30min, 1h, 2h post-dose

6. Pre-dose, 3h, 4h post dose CONFIDENTIAL 7. 24 hours after dosing on Day 7 8. FVC will be performed at screening only. FEV1 pre-dose on Day 1 and 7, and after bronchoscopy (on Day 7 & Day 8) if required. 9. Blood sample for PGx may be collected at any time post-dose (although preferably at Visit 2) if the informed consent has been signed 63 10. Blood for biomarkers collected pre-dose Day 1 and 7, and pre-bronchoscopy on Day 8 11. BAL samples will be collected for baseline at 2 hours post dose and following LPS instillation and saline control challenge at 26 hours post-dose on Day 7. BAL concentrations of GSK25066 and GSK614917 will also be determined at these time points 12. Where possible, blood sampling should be taken simultaneously to BAL sample collection 13. Pre-dose and 3h 14. Pre-dose 15. Continuous cardiac monitoring for 6hrs post dose 16. To include Troponin testing NB: where multiple assessments are scheduled at the same timepoints, assessments should be conducted in the following order: vital signs, 12 Lead-ECG, Spirometry or , Biomarker blood sample, Bronchoscopy, BAL fluid collection,

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May 2, 2008 9:17AM

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Time and Events Schedule For Study: IPC103711_SHZ Assessment CRF Screen DAY 1 DAY 7 DAY 8 Follow-up Logs/Repeats Liver Event PGx EARLY WITHDRAWAL Conflict (Screen) (DAY 1) (DAY 7) (DAY 8) (F/U) (Logs/Rpts) (LE) (PGx) (EARLY WITHDRAWAL) (Conflict) [ S ] [ S ] [ S ] [ S ] [ S ] [ U ] [ S ] [ S ] [ U/D ] [ U/R/D ] 1 DATE OF VISIT DoV 1 1 1 1 1 1 1 2 DEMOGRAPHY Demog 2 3 VITAL SIGNS VS 3 4 12-LEAD ECG ECG 4 5 ELIGIBILITY QUESTION ELIG 5 6 SUBJECT IDENTIFICATION Subj ID 6 7 LABORATORY - HAEMATOLOGY Lab H 7 4 8 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C 8 9 LOCAL LABORATORY - CLINICAL CHEMISTRY EXTRA Lab C EXTRA 9 6 10 URINALYSIS - LOCAL Lab U 10 7 11 URINALYSIS - LOCAL: MICROSCOPY DETAILS Lab Mic 11-DF 8-DF 12 PULMONARY FUNCTION TESTS PFT 12 13 INVESTIGATIONAL PRODUCT- GSK256066 Dose 2 2 14 INVESTIGATIONAL PRODUCT- GSK256066 DAYS 2-6 DOSE 3 15 VITAL SIGNS VS 4 16 12-LEAD ECG ECG 5 17 RANDOMISATION NUMBER Rand 6 18 PULMONARY FUNCTION TESTS PFT-PREDOSE 7 5 19 PHARMACODYNAMICS - [Analyte and PD sample type] BIOMARKER 8 9 20 SUMMARY HOLTER Holter 9 21 SUMMARY HOLTER ABNORMALITIES Holter Abn 10-DF 22 LOCAL LABORATORY - HAEMATOLOGY Lab H PREDOSE 11 11 23 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C PREDOSE 12 24 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C Extra - PREDOSE 13 14 25 URINALYSIS - LOCAL Lab U PREDOSE 14 17 26 URINALYSIS - LOCAL: MICROSCOPY DETAILS Lab Mic 15-DF 18-DF 27 EARLY WITHDRAWAL Early_Withdrawal 16 28 VITAL SIGNS VS 3 29 12-LEAD ECG ECG 4 30 LPS INSTILLATION LPS INSTILLATION 6 31 BRONCHOSCOPY BRONCHOSCOPY 7 2 32 PULMONARY FUNCTION TESTS PFT 8 4 33 Blood and BAL samples for Urea and PK Blood/BAL 10 34 LOCAL LABORATORY - HAEMATOLOGY Lab H 24H 12 35 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C PREDOSE 13 36 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C 24H 15 37 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C EXTRA - 24H 16 38 PHARMACODYNAMICS - [Analyte and PD sample type] BIOMARKER 3 39 VITAL SIGNS VS 2 40 12-LEAD ECG ECG 3 41 STATUS OF TREATMENT BLIND Blind 4 42 STUDY CONCLUSION Conclusion 5 43 PREGNANCY INFORMATION Preg F 6-DF 44 LOGS AND REPEATS Logs/Rpts 1 45 CONCOMITANT MEDICATIONS Con Meds 2-RF-DF 46 NON-SERIOUS ADVERSE EVENT AE 3-RF-DF 47 SERIOUS ADVERSE EVENTS SAE 4-RF-DF 48 LOCAL LABORATORY Lab Rpt 5-RF-DF Annotated Trial Design Page 3 of 166

49 URINALYSIS - LOCAL Lab U Rpt 6-RF-DF 50 12-LEAD ECG ECG Rpt 7-RF-DF 51 ECG ABNORMALITIES ECG Abn 8-RF-DF 52 VITAL SIGNS VS Rpt 9-RF-DF 53 REPEAT PHARMACODYNAMICS - [Analyte and PD sample type] PD Rpt 10-RF-DF 54 REPEAT PULMONARY FUNCTION TESTS PFT Rpt 11-RF-DF 55 REPEAT PHARMACOKINETICS BLOOD - [drug name] PK Rpt 12-RF-DF 56 Liver Event DOV Liver DoV 1 57 LIVER EVENTS LIVER EVENTS 2-DF 58 INVESTIGATIONAL PRODUCT (LIVER) LIVER IP 3-DF 59 PHARMACOKINETICS LIVER PK 4-DF 60 MEDICAL CONDITIONS LIVER MEDHX 5-DF 61 ALCOHOL INTAKE LIVER ALCOHOL 6-DF 62 LIVER IMAGING IMAGING 7-RF-DF 63 LIVER BIOPSY BIOPSY 8-RF-DF 64 PGx-PHARMACOGENETIC RESEARCH CONSENT PGx Consent 2 65 PHARMACOGENETIC (PGx) RESEARCH WITHDRAWAL OF CONSENT PGx Withdraw 3-DF 66 Reg Docs REG 67 VITAL SIGNS VS 2 68 12-LEAD ECG ECG 3 69 LOCAL LABORATORY - CLINICAL CHEMISTRY Lab C 5 70 PULMONARY FUNCTION TESTS PFT 9 71 PHARMACODYNAMICS - BIOMARKER 10

Key: [S] = Scheduled Visit [O] = Optional Visit [D] = Dynamic Visit [U] = Unscheduled Visit [R] = Repeating Visit C = Common Form DF = Dynamic Form RF = Repeating Form

Annotated Trial Design Page 4 of 166

IPC103711_SHZ : INFORM SCREENING (SCREEN) INFORM SCREENING

1.* Subject initials [hidden] A3 (MAPPINGS1:t_SCREEN.txtScrSINIT) (MAPPINGS2:t_SCREEN.txtScrSINIT)

2. Date of birth Req / Req / Req (1900-2007) (MAPPINGS1:t_SCREEN.BIRTHDT) (MAPPINGS2:t_SCREEN.BIRTHDT)

* Item is not required

Form Design Note:

Trial designers must use this form as specified here. Allowed changes are mentioned in the particular item level notes.

Item Design Notes:

Item No. Design Note

1. This item is hidden to all users and will be autopopulated by the system as "---"

2. Will be automatically mapped to demography form from screening form

CDD: MAPPINGS1 Table: t_SCREEN Key Type: PATIENTVISIT Column Name Column Data Type Design Note txtScrSINIT STRING(3) - A3 BIRTHDT DATE - DDMONYYYY

CDD: MAPPINGS2 Table: t_SCREEN Key Type: PATIENTVISIT Column Name Column Data Type Design Note txtScrSINIT STRING(3) - A3 BIRTHDT DATE - DDMONYYYY

Annotated Trial Design Page 5 of 166

IPC103711_SHZ : INFORM ENROLMENT (ENROL) SUBJECT NUMBER

1. Subject number A6 (MAPPINGS1:t_ENROL.mtxtSubjectNumber) (MAPPINGS2:t_ENROL.mtxtSubjectNumber)

CDD: MAPPINGS1 Table: t_ENROL Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtSubjectNumber STRING(6) - A6

CDD: MAPPINGS2 Table: t_ENROL Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtSubjectNumber STRING(6) - A6

Annotated Trial Design Page 6 of 166

IPC103711_SHZ : DATE OF VISIT (DoV) Adverse Events/Concomitant Medications » Record details of any new serious adverse event or any changes to ongoing serious adverse events in the SAE form in the Logs/Rpts visit. » From visit 1 onwards, record details of any new non-serious adverse event or any changes to ongoing non-serious adverse events in the appropriate AE form in the Logs/Rpts visit » Record any changes to the subject's concomitant medication or any new medication taken since the last visit in the Con Meds form in the Logs/Rpts visit. DATE OF VISIT/ASSESSMENT

1. Date of visit/assessment Req / Req / Req (2007-2009) (MAPPINGS1:t_VISIT.DOV) (MAPPINGS2:t_VISIT.DOV)

CDD: MAPPINGS1 Table: t_VISIT Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY

CDD: MAPPINGS2 Table: t_VISIT Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY

Annotated Trial Design Page 7 of 166

IPC103711_SHZ : DEMOGRAPHY (Demog) DEMOGRAPHY

1. Date of birth Req / Req / Req (1956-2000) (MAPPINGS1:t_DEMO.BIRTHDT) (MAPPINGS2:t_DEMO.BIRTHDT)

2. Sex (MAPPINGS1:t_DEMO.SEX) (MAPPINGS2:t_DEMO.SEX) [M] Male [F] (MAPPINGS1:t_DEMO.CHDPOTCD) (MAPPINGS2:t_DEMO.CHDPOTCD) Female : Record child-bearing potential [1] Pre-menarcheal [2] Post-menopausal [3] Sterile (of child-bearing age) [4] Potentially able to bear children

3. Ethnicity (MAPPINGS1:t_DEMO.ETHNICCD) (MAPPINGS2:t_DEMO.ETHNICCD) [1] Hispanic or Latino [2] Not Hispanic or Latino

4. Geographic ancestry Check all that apply (MAPPINGS1:t_DEMO.RACECCD11) (MAPPINGS2:t_DEMO.RACECCD11) [11] African American/African Heritage (MAPPINGS1:t_DEMO.RACECCD12) (MAPPINGS2:t_DEMO.RACECCD12) [12] American Indian or Alaskan Native (MAPPINGS1:t_DEMO.RACECCD13) (MAPPINGS2:t_DEMO.RACECCD13) [13] Asian - Central/South Asian Heritage (MAPPINGS1:t_DEMO.RACECCD14) (MAPPINGS2:t_DEMO.RACECCD14) [14] Asian - East Asian Heritage (MAPPINGS1:t_DEMO.RACECCD15) (MAPPINGS2:t_DEMO.RACECCD15) [15] Asian - Japanese Heritage (MAPPINGS1:t_DEMO.RACECCD16) (MAPPINGS2:t_DEMO.RACECCD16) [16] Asian - South East Asian Heritage (MAPPINGS1:t_DEMO.RACECCD17) (MAPPINGS2:t_DEMO.RACECCD17) [17] Native Hawaiian or Other Pacific Islander (MAPPINGS1:t_DEMO.RACECCD18) (MAPPINGS2:t_DEMO.RACECCD18) [18] White - Arabic/North African Heritage (MAPPINGS1:t_DEMO.RACECCD19) (MAPPINGS2:t_DEMO.RACECCD19) [19] White - White/Caucasian/European Heritage

Item Design Notes:

Item No. Design Note

1. Will be automatically mapped to demography form from screening form

CDD: MAPPINGS1 Table: t_DEMO Key Type: PATIENTVISIT Column Name Column Data Type Design Note BIRTHDT DATE - DDMONYYYY SEX STRING(1) CHDPOTCD STRING(1) ETHNICCD STRING(1) RACECCD11 STRING(255) RACECCD12 STRING(255) RACECCD13 STRING(255) RACECCD14 STRING(255) Annotated Trial Design Page 8 of 166

RACECCD15 STRING(255) RACECCD16 STRING(255) RACECCD17 STRING(255) RACECCD18 STRING(255) RACECCD19 STRING(255)

CDD: MAPPINGS2 Table: t_DEMO Key Type: PATIENTVISIT Column Name Column Data Type Design Note BIRTHDT DATE - DDMONYYYY SEX STRING(1) CHDPOTCD STRING(1) ETHNICCD STRING(1) RACECCD11 STRING(255) RACECCD12 STRING(255) RACECCD13 STRING(255) RACECCD14 STRING(255) RACECCD15 STRING(255) RACECCD16 STRING(255) RACECCD17 STRING(255) RACECCD18 STRING(255) RACECCD19 STRING(255)

Annotated Trial Design Page 9 of 166

IPC103711_SHZ : VITAL SIGNS (VS) MEASUREMENT 1 (OF 3)

1. Actual date/time Req / Req / Req (2007-2009) (MAPPINGS1:t_VITALS_A_SCR.VSACTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_A_SCR.VSACTDTTM) Req : Req 24-hour clock

2. Height xxx ( n >= 0 ) cm (MAPPINGS1:t_VITALS_A_SCR.HEIGHT) (MAPPINGS2:t_VITALS_A_SCR.HEIGHT)

3. Weight xxx.x ( n >= 0.0 ) kg (MAPPINGS1:t_VITALS_A_SCR.WEIGHT) (MAPPINGS2:t_VITALS_A_SCR.WEIGHT)

Body mass index (MAPPINGS1:t_VITALS_A_SCR.VSBMI) (MAPPINGS2:t_VITALS_A_SCR.VSBMI)

4. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_A_SCR.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_A_SCR.DIABP) (MAPPINGS2:t_VITALS_A_SCR.SYSBP) (MAPPINGS2:t_VITALS_A_SCR.DIABP) (systolic/diastolic)

5. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_A_SCR.HEART) (MAPPINGS2:t_VITALS_A_SCR.HEART)

6. Temperature xx.x °C (MAPPINGS1:t_VITALS_A_SCR.TEMP) (MAPPINGS2:t_VITALS_A_SCR.TEMP)

MEASUREMENT 2 (OF 3)

7. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_A_SCR.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_A_SCR.CDDVSACTTM)

8. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_A_SCR.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_A_SCR.DIABP) (MAPPINGS2:t_VITALS_A_SCR.SYSBP) (MAPPINGS2:t_VITALS_A_SCR.DIABP) (systolic/diastolic)

9. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_A_SCR.HEART) (MAPPINGS2:t_VITALS_A_SCR.HEART)

10. Temperature xx.x °C (MAPPINGS1:t_VITALS_A_SCR.TEMP) (MAPPINGS2:t_VITALS_A_SCR.TEMP)

MEASUREMENT 3 (OF 3)

11. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_A_SCR.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_A_SCR.CDDVSACTTM)

12. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_A_SCR.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_A_SCR.DIABP) (MAPPINGS2:t_VITALS_A_SCR.SYSBP) (MAPPINGS2:t_VITALS_A_SCR.DIABP) (systolic/diastolic)

13. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_A_SCR.HEART) (MAPPINGS2:t_VITALS_A_SCR.HEART)

14. Temperature xx.x °C (MAPPINGS1:t_VITALS_A_SCR.TEMP) (MAPPINGS2:t_VITALS_A_SCR.TEMP)

Form Design Note:

Screening vital signs

Item Design Notes:

Item No. Design Note

itmVSBMI Item to be calculated as: Weight in kilograms divided by the square of height in meters

6. Item is optional

10. Item is optional

14. Item is optional

CDD: MAPPINGS1 Table: t_VITALS_A_SCR Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM Annotated Trial Design Page 10 of 166

HEIGHT NUMERIC - N3 WEIGHT FLOAT - F5.1 VSBMI STRING(255) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1 CDDVSACTTM DATE - HHMM

CDD: MAPPINGS2 Table: t_VITALS_A_SCR Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM HEIGHT NUMERIC - N3 WEIGHT FLOAT - F5.1 VSBMI STRING(255) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1 CDDVSACTTM DATE - HHMM

Annotated Trial Design Page 11 of 166

IPC103711_SHZ : 12-LEAD ECG (ECG) MEASUREMENT 1 (OF 3)

1. Date and Time of ECG Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_A_SCR.EGDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_A_SCR.EGDTTM) Req : Req 24-hour clock

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_A_SCR.EGHR) (MAPPINGS2:t_ECG_A_SCR.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.PR__) (MAPPINGS2:t_ECG_A_SCR.PR__)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QRS__) (MAPPINGS2:t_ECG_A_SCR.QRS__)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QT__) (MAPPINGS2:t_ECG_A_SCR.QT__)

6. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QTC__) (MAPPINGS2:t_ECG_A_SCR.QTC__)

7. Method of QTc Calculation (MAPPINGS1:t_ECG_A_SCR.EGMTCLCD) (MAPPINGS2:t_ECG_A_SCR.EGMTCLCD) [1] Machine [2] Manual

8. Result of the ECG (MAPPINGS1:t_ECG_A_SCR.EGINTPCD) (MAPPINGS2:t_ECG_A_SCR.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) MEASUREMENT 2 (OF 3)

9. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_A_SCR.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_A_SCR.EGACTTM)

10. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_A_SCR.EGHR) (MAPPINGS2:t_ECG_A_SCR.EGHR)

11. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.PR__) (MAPPINGS2:t_ECG_A_SCR.PR__)

12. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QRS__) (MAPPINGS2:t_ECG_A_SCR.QRS__)

13. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QT__) (MAPPINGS2:t_ECG_A_SCR.QT__)

14. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QTC__) (MAPPINGS2:t_ECG_A_SCR.QTC__)

15. Method of QTc Calculation (MAPPINGS1:t_ECG_A_SCR.EGMTCLCD) (MAPPINGS2:t_ECG_A_SCR.EGMTCLCD) [1] Machine [2] Manual

16. Result of the ECG (MAPPINGS1:t_ECG_A_SCR.EGINTPCD) (MAPPINGS2:t_ECG_A_SCR.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) MEASUREMENT 3 (OF 3)

17. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_A_SCR.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_A_SCR.EGACTTM)

18. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_A_SCR.EGHR) (MAPPINGS2:t_ECG_A_SCR.EGHR)

19. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.PR__) (MAPPINGS2:t_ECG_A_SCR.PR__)

20. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QRS__) (MAPPINGS2:t_ECG_A_SCR.QRS__)

21. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QT__) (MAPPINGS2:t_ECG_A_SCR.QT__) Annotated Trial Design Page 12 of 166

22. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QTC__) (MAPPINGS2:t_ECG_A_SCR.QTC__)

23. Method of QTc Calculation (MAPPINGS1:t_ECG_A_SCR.EGMTCLCD) (MAPPINGS2:t_ECG_A_SCR.EGMTCLCD) [1] Machine [2] Manual

24. Result of the ECG (MAPPINGS1:t_ECG_A_SCR.EGINTPCD) (MAPPINGS2:t_ECG_A_SCR.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available)

Form Design Note:

Screening ECG

CDD: MAPPINGS1 Table: t_ECG_A_SCR Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1) EGACTTM DATE - HHMM

CDD: MAPPINGS2 Table: t_ECG_A_SCR Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1) EGACTTM DATE - HHMM

Annotated Trial Design Page 13 of 166

IPC103711_SHZ : ELIGIBILITY QUESTION (ELIG) ELIGIBILITY QUESTION 1. Did the subject meet all the entry criteria? (MAPPINGS1:t_ELIG.IEELIG) (MAPPINGS2:t_ELIG.IEELIG) [Y] Yes [N] No, please select all boxes corresponding to violations of any inclusion/exclusion criteria

Inclusion Criteria

(MAPPINGS1:t_ELIG.IECRTNUMI01) (MAPPINGS2:t_ELIG.IECRTNUMI01) [I01] Inclusion Criteria 1 (MAPPINGS1:t_ELIG.IECRTNUMI02) (MAPPINGS2:t_ELIG.IECRTNUMI02) [I02] Inclusion Criteria 2 (MAPPINGS1:t_ELIG.IECRTNUMI03) (MAPPINGS2:t_ELIG.IECRTNUMI03) [I03] Inclusion Criteria 3 (MAPPINGS1:t_ELIG.IECRTNUMI04) (MAPPINGS2:t_ELIG.IECRTNUMI04) [I04] Inclusion Criteria 4 (MAPPINGS1:t_ELIG.IECRTNUMI05) (MAPPINGS2:t_ELIG.IECRTNUMI05) [I05] Inclusion Criteria 5 (MAPPINGS1:t_ELIG.IECRTNUMI06) (MAPPINGS2:t_ELIG.IECRTNUMI06) [I06] Inclusion Criteria 6 (MAPPINGS1:t_ELIG.IECRTNUMI07) (MAPPINGS2:t_ELIG.IECRTNUMI07) [I07] Inclusion Criteria 7 (MAPPINGS1:t_ELIG.IECRTNUMI08) (MAPPINGS2:t_ELIG.IECRTNUMI08) [I08] Inclusion Criteria 8 (MAPPINGS1:t_ELIG.IECRTNUMI09) (MAPPINGS2:t_ELIG.IECRTNUMI09) [I09] Inclusion Criteria 9

Exclusion Criteria

(MAPPINGS1:t_ELIG.IECRTNUME01) (MAPPINGS2:t_ELIG.IECRTNUME01) [E01] Exclusion Criteria 1 (MAPPINGS1:t_ELIG.IECRTNUME02) (MAPPINGS2:t_ELIG.IECRTNUME02) [E02] Exclusion Criteria 2 (MAPPINGS1:t_ELIG.IECRTNUME03) (MAPPINGS2:t_ELIG.IECRTNUME03) [E03] Exclusion Criteria 3 (MAPPINGS1:t_ELIG.IECRTNUME04) (MAPPINGS2:t_ELIG.IECRTNUME04) [E04] Exclusion Criteria 4 (MAPPINGS1:t_ELIG.IECRTNUME05) (MAPPINGS2:t_ELIG.IECRTNUME05) [E05] Exclusion Criteria 5 (MAPPINGS1:t_ELIG.IECRTNUME06) (MAPPINGS2:t_ELIG.IECRTNUME06) [E06] Exclusion Criteria 6 (MAPPINGS1:t_ELIG.IECRTNUME07) (MAPPINGS2:t_ELIG.IECRTNUME07) [E07] Exclusion Criteria 7 (MAPPINGS1:t_ELIG.IECRTNUME08) (MAPPINGS2:t_ELIG.IECRTNUME08) [E08] Exclusion Criteria 8 (MAPPINGS1:t_ELIG.IECRTNUME09) (MAPPINGS2:t_ELIG.IECRTNUME09) [E09] Exclusion Criteria 9 (MAPPINGS1:t_ELIG.IECRTNUME10) (MAPPINGS2:t_ELIG.IECRTNUME10) [E10] Exclusion Criteria 10 (MAPPINGS1:t_ELIG.IECRTNUME11) (MAPPINGS2:t_ELIG.IECRTNUME11) [E11] Exclusion Criteria 11 (MAPPINGS1:t_ELIG.IECRTNUME12) Annotated Trial Design Page 14 of 166

(MAPPINGS2:t_ELIG.IECRTNUME12) [E12] Exclusion Criteria 12 (MAPPINGS1:t_ELIG.IECRTNUME13) (MAPPINGS2:t_ELIG.IECRTNUME13) [E13] Exclusion Criteria 13 (MAPPINGS1:t_ELIG.IECRTNUME14) (MAPPINGS2:t_ELIG.IECRTNUME14) [E14] Exclusion Criteria 14 (MAPPINGS1:t_ELIG.IECRTNUME15) (MAPPINGS2:t_ELIG.IECRTNUME15) [E15] Exclusion Criteria 15 (MAPPINGS1:t_ELIG.IECRTNUME16) (MAPPINGS2:t_ELIG.IECRTNUME16) [E16] Exclusion Criteria 16

Form Design Note:

IDSL Version 02.00A - 22 NOV 06

CDD: MAPPINGS1 Table: t_ELIG Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG STRING(1) IECRTNUMI01 STRING(255) IECRTNUMI02 STRING(255) IECRTNUMI03 STRING(255) IECRTNUMI04 STRING(255) IECRTNUMI05 STRING(255) IECRTNUMI06 STRING(255) IECRTNUMI07 STRING(255) IECRTNUMI08 STRING(255) IECRTNUMI09 STRING(255) IECRTNUME01 STRING(255) IECRTNUME02 STRING(255) IECRTNUME03 STRING(255) IECRTNUME04 STRING(255) IECRTNUME05 STRING(255) IECRTNUME06 STRING(255) IECRTNUME07 STRING(255) IECRTNUME08 STRING(255) IECRTNUME09 STRING(255) IECRTNUME10 STRING(255) IECRTNUME11 STRING(255) IECRTNUME12 STRING(255) IECRTNUME13 STRING(255) IECRTNUME14 STRING(255) IECRTNUME15 STRING(255) IECRTNUME16 STRING(255)

CDD: MAPPINGS2 Table: t_ELIG Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG STRING(1) IECRTNUMI01 STRING(255) IECRTNUMI02 STRING(255) IECRTNUMI03 STRING(255) IECRTNUMI04 STRING(255) Annotated Trial Design Page 15 of 166

IECRTNUMI05 STRING(255) IECRTNUMI06 STRING(255) IECRTNUMI07 STRING(255) IECRTNUMI08 STRING(255) IECRTNUMI09 STRING(255) IECRTNUME01 STRING(255) IECRTNUME02 STRING(255) IECRTNUME03 STRING(255) IECRTNUME04 STRING(255) IECRTNUME05 STRING(255) IECRTNUME06 STRING(255) IECRTNUME07 STRING(255) IECRTNUME08 STRING(255) IECRTNUME09 STRING(255) IECRTNUME10 STRING(255) IECRTNUME11 STRING(255) IECRTNUME12 STRING(255) IECRTNUME13 STRING(255) IECRTNUME14 STRING(255) IECRTNUME15 STRING(255) IECRTNUME16 STRING(255)

Annotated Trial Design Page 16 of 166

IPC103711_SHZ : SUBJECT IDENTIFICATION (Subj ID) SUBJECT NUMBER

1. Subject number A6 (MAPPINGS1:t_SUBID.mtxtSubjectNumber) (MAPPINGS2:t_SUBID.mtxtSubjectNumber)

CDD: MAPPINGS1 Table: t_SUBID Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtSubjectNumber STRING(6) - A6

CDD: MAPPINGS2 Table: t_SUBID Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtSubjectNumber STRING(6) - A6

Annotated Trial Design Page 17 of 166

IPC103711_SHZ : LABORATORY - HAEMATOLOGY (Lab H) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. HAEMATOLOGY

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_HAEMA_A.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_HAEMA_A.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_HAEMA_A.LBFAST) (MAPPINGS2:t_LAB_HAEMA_A.LBFAST) [Y] Yes [N] No

3. WBC (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 4. RBC (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 5. Haemoglobin (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 6. Haematocrit (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 7. Neutrophils (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 8. Lymphocytes (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 9. Monocytes (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] Annotated Trial Design Page 18 of 166

10. Eosinophils (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 11. Basophils (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 12. Platelets (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 13. MCV (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 14. MCH (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 15. MCHC (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99] 16. Reticulocytes (MAPPINGS1:t_LAB_HAEMA_A.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_A.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Haem form Clone A

Section Design Notes:

Title Design Note

HAEMATOLOGY Use separate items for Name and address for the first occurance of this form, and use the combined item for subsequent visits. Annotated Trial Design Page 19 of 166

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_HAEMA_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_HAEMA_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 20 of 166

IPC103711_SHZ : LOCAL LABORATORY - CLINICAL CHEMISTRY (Lab C) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. CLINICAL CHEMISTRY

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_CHEM_A.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_CHEM_A.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM_A.LBFAST) (MAPPINGS2:t_LAB_CHEM_A.LBFAST) [Y] Yes [N] No

3. ALT (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 4. AST (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 5. Total Bilirubin (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 6. Glucose (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 7. GGT (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 8. Total Protein (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 9. Albumin (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] Annotated Trial Design Page 21 of 166

10. Potassium (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 11. Sodium (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 12. Chloride (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 13. Urea (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 14. Creatinine (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 15. Uric Acid (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 16. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 17. Globulin (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 18. Phosphate (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) Annotated Trial Design Page 22 of 166

[- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 19. Bicarbonate (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99] 20. Troponin T (MAPPINGS1:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone A

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_CHEM_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_CHEM_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 23 of 166

IPC103711_SHZ : LOCAL LABORATORY - CLINICAL CHEMISTRY EXTRA (Lab C EXTRA) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. CLINICAL CHEMISTRY EXTRA 1. Creatinine Kinase (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 2. Creatinine Kinase-MB (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 3. Calcium (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 4. LDH (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 5. CRP (MAPPINGS2:t_LAB_CHEM_A.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone F

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY EXTRA Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Annotated Trial Design Page 24 of 166

CDD: MAPPINGS2 Table: t_LAB_CHEM_D Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 25 of 166

IPC103711_SHZ : URINALYSIS - LOCAL (Lab U) Complete the Adverse Events (AE) form if clinically significant abnormalities meet the protocol definition for an AE. URINALYSIS - LOCAL

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_URIN_A.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_URIN_A.LBDTTM) Req : Req 24-hour clock

2. Result of dipstick (MAPPINGS1:t_LAB_URIN_A.RSLTCHARU) (MAPPINGS2:t_LAB_URIN_A.RSLTCHARU) [NR] No result [NEG] Negative [POS] (MAPPINGS1:t_LAB_URIN_A.rdcMICROSCOPY) (MAPPINGS2:t_LAB_URIN_A.rdcMICROSCOPY) Positive Was sedimentary microscopy performed? [N] No [Y] Yes, provide details on the MICROSCOPY form

URINALYSIS - LOCAL: DIPSTICK DETAILS 3. Protein (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 4. Glucose (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 5. Ketones (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 6. Bilirubin (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 7. Blood (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 8. Urobilinogen (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 9. Leucocytes (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) Annotated Trial Design Page 26 of 166

(MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 10. Specific Gravity (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 11. Nitrites (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99] 12. pH (MAPPINGS1:t_LAB_URIN_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_A.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Urinalysis Clone A

Section Design Notes:

Title Design Note

URINALYSIS - LOCAL Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

URINALYSIS - LOCAL: DIPSTICK DETAILS Remove or add tests per protocol

Item Design Notes:

Item No. Design Note

2. This item is optional.

CDD: MAPPINGS1 Table: t_LAB_URIN_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM RSLTCHARU STRING(3) rdcMICROSCOPY STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_URIN_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note Annotated Trial Design Page 27 of 166

LBDTTM DATE - DDMONYYYY HHMM RSLTCHARU STRING(3) rdcMICROSCOPY STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 28 of 166

IPC103711_SHZ : URINALYSIS - LOCAL: MICROSCOPY DETAILS (Lab Mic) URINALYSIS - LOCAL: MICROSCOPY DETAILS

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.LBDTTM) Hr:Min (00:00-23:59) [read-only] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.LBDTTM) Req : Req 24-hour clock

2. White blood cells (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) [- No result 99] 3. Red blood cells (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) [- No result 99] 4. Hyaline casts (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) [- No result 99] 5. Granular casts (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) [- No result 99] 6. Cellular casts (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_A.RSLTCHAR) [- No result 99]

Form Design Note:

Bench lab urine microscopy Clone A. This form is created dynamically when question 6 on the Urinalysis form is answered Yes

Section Design Notes:

Title Design Note

URINALYSIS - LOCAL: MICROSCOPY DETAILS Remove or add tests per protocol

CDD: MAPPINGS1 Table: t_LAB_URIN_MICROSCOPY_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 29 of 166

CDD: MAPPINGS2 Table: t_LAB_URIN_MICROSCOPY_A Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 30 of 166

IPC103711_SHZ : PULMONARY FUNCTION TESTS (PFT)

1. Date/time of test Req / Req / Req (2007-2009) (MAPPINGS1:t_PFT_X1_A.PFTDTTM) (MAPPINGS2:t_PFT_X1_A.PFTDTTM) Req : Req 24-hour clock

2. FEV1 (3 readings) Reading (MAPPINGS1:t_PFT_X1_A.FEV1A) Reading (MAPPINGS1:t_PFT_X1_A.FEV1B) Reading (MAPPINGS1:t_PFT_X1_A.FEV1C) 1 (MAPPINGS2:t_PFT_X1_A.FEV1A) 2 (MAPPINGS2:t_PFT_X1_A.FEV1B) 3 (MAPPINGS2:t_PFT_X1_A.FEV1C) xxxx. L xxxx. L xxxx. L

3. FVC (3 readings) Reading (MAPPINGS1:t_PFT_X1_A.FVCA) Reading (MAPPINGS1:t_PFT_X1_A.FVCB) Reading (MAPPINGS1:t_PFT_X1_A.FVCC) 1 (MAPPINGS2:t_PFT_X1_A.FVCA) 2 (MAPPINGS2:t_PFT_X1_A.FVCB) 3 (MAPPINGS2:t_PFT_X1_A.FVCC) xxxx. L xxxx. L xxxx. L

Form Design Note:

Bench PFT (x1) clone A

CDD: MAPPINGS1 Table: t_PFT_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note PFTDTTM DATE - DDMONYYYY HHMM FEV1A FLOAT - F5.0 FEV1B FLOAT - F5.0 FEV1C FLOAT - F5.0 FVCA FLOAT - F5.0 FVCB FLOAT - F5.0 FVCC FLOAT - F5.0

CDD: MAPPINGS2 Table: t_PFT_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note PFTDTTM DATE - DDMONYYYY HHMM FEV1A FLOAT - F5.0 FEV1B FLOAT - F5.0 FEV1C FLOAT - F5.0 FVCA FLOAT - F5.0 FVCB FLOAT - F5.0 FVCC FLOAT - F5.0

Annotated Trial Design Page 31 of 166

IPC103711_SHZ : INVESTIGATIONAL PRODUCT- GSK256066 (Dose) INVESTIGATIONAL PRODUCT

1. Date/time of dose Req / Req / Req (2007-2009) (MAPPINGS1:t_EXPOSURE_SINGLE_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_SINGLE_A.EXSTDTTM) Req : Req 24-hour clock

TREATMENT CONFIRMATION 2. Did the subject receive the correct treatment (e.g., treatment which the subject was (MAPPINGS1:t_EXPOSURE_SINGLE_A.EXTRTCFM) assigned to) during this dosing interval? (MAPPINGS2:t_EXPOSURE_SINGLE_A.EXTRTCFM) [Y] Yes [N] No, record reason(s) (MAPPINGS1:t_EXPOSURE_SINGLE_A.EXTRTRS) (MAPPINGS2:t_EXPOSURE_SINGLE_A.EXTRTRS) A200

Form Design Note:

Bench IP form single dose Clone A

CDD: MAPPINGS1 Table: t_EXPOSURE_SINGLE_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXSTDTTM DATE - DDMONYYYY HHMM EXTRTCFM STRING(1) EXTRTRS STRING(200) - A200

CDD: MAPPINGS2 Table: t_EXPOSURE_SINGLE_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXSTDTTM DATE - DDMONYYYY HHMM EXTRTCFM STRING(1) EXTRTRS STRING(200) - A200

Annotated Trial Design Page 32 of 166

IPC103711_SHZ : INVESTIGATIONAL PRODUCT- GSK256066 (DAYS 2-6 DOSE) DAY 2

1. Start date/time of dose Req / Req / Req (2007-2009) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXSTDTTM) Req : Req 24-hour clock

TREATMENT CONFIRMATION 2. Did the subject receive the correct treatment (e.g., treatment which the subject was (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTCFM) assigned to) during this dosing interval? (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTCFM) [Y] Yes [N] No, record reason(s) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTRS) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTRS) A200

DAY 3

3. Start date/time of dose Req / Req / Req (2007-2009) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXSTDTTM) Req : Req 24-hour clock

TREATMENT CONFIRMATION 4. Did the subject receive the correct treatment (e.g., treatment which the subject was (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTCFM) assigned to) during this dosing interval? (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTCFM) [Y] Yes [N] No, record reason(s) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTRS) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTRS) A200

DAY 4

5. Start date/time of dose Req / Req / Req (2007-2009) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXSTDTTM) Req : Req 24-hour clock

TREATMENT CONFIRMATION 6. Did the subject receive the correct treatment (e.g., treatment which the subject was (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTCFM) assigned to) during this dosing interval? (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTCFM) [Y] Yes [N] No, record reason(s) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTRS) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTRS) A200

DAY 5

7. Start date/time of dose Req / Req / Req (2007-2009) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXSTDTTM) Req : Req 24-hour clock

TREATMENT CONFIRMATION 8. Did the subject receive the correct treatment (e.g., treatment which the subject was (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTCFM) assigned to) during this dosing interval? (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTCFM) [Y] Yes [N] No, record reason(s) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTRS) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTRS) A200

DAY 6

9. Start date/time of dose Req / Req / Req (2007-2009) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXSTDTTM) Req : Req 24-hour clock

TREATMENT CONFIRMATION 10. Did the subject receive the correct treatment (e.g., treatment which the subject was (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTCFM) assigned to) during this dosing interval? (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTCFM) [Y] Yes [N] No, record reason(s) (MAPPINGS1:t_EXPOSURE_MULTI_A.EXTRTRS) (MAPPINGS2:t_EXPOSURE_MULTI_A.EXTRTRS) A200 Annotated Trial Design Page 33 of 166

Form Design Note:

Bench IP form multi dose Clone A

CDD: MAPPINGS1 Table: t_EXPOSURE_MULTI_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note EXSTDTTM DATE - DDMONYYYY HHMM EXTRTCFM STRING(1) EXTRTRS STRING(200) - A200

CDD: MAPPINGS2 Table: t_EXPOSURE_MULTI_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note EXSTDTTM DATE - DDMONYYYY HHMM EXTRTCFM STRING(1) EXTRTRS STRING(200) - A200

Annotated Trial Design Page 34 of 166

IPC103711_SHZ : VITAL SIGNS (VS) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2007) (MAPPINGS1:t_VITALS_X20_A.CDDDOSEDTTM) (MAPPINGS2:t_VITALS_X20_A.CDDDOSEDTTM) Req : Req 24-hour clock

PREDOSE

2. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_A.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_A.CDDVSACTTM)

3. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_A.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_A.DIABP) (MAPPINGS2:t_VITALS_X20_A.SYSBP) (MAPPINGS2:t_VITALS_X20_A.DIABP) (systolic/diastolic)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_A.HEART) (MAPPINGS2:t_VITALS_X20_A.HEART)

5. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_A.TEMP) (MAPPINGS2:t_VITALS_X20_A.TEMP)

30 MIN POST DOSE

6. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_A.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_A.CDDVSACTTM)

7. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_A.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_A.DIABP) (MAPPINGS2:t_VITALS_X20_A.SYSBP) (MAPPINGS2:t_VITALS_X20_A.DIABP) (systolic/diastolic)

8. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_A.HEART) (MAPPINGS2:t_VITALS_X20_A.HEART)

9. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_A.TEMP) (MAPPINGS2:t_VITALS_X20_A.TEMP)

1 HR POST DOSE

10. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_A.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_A.CDDVSACTTM)

11. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_A.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_A.DIABP) (MAPPINGS2:t_VITALS_X20_A.SYSBP) (MAPPINGS2:t_VITALS_X20_A.DIABP) (systolic/diastolic)

12. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_A.HEART) (MAPPINGS2:t_VITALS_X20_A.HEART)

13. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_A.TEMP) (MAPPINGS2:t_VITALS_X20_A.TEMP)

2 HR POST DOSE

14. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_A.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_A.CDDVSACTTM)

15. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_A.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_A.DIABP) (MAPPINGS2:t_VITALS_X20_A.SYSBP) (MAPPINGS2:t_VITALS_X20_A.DIABP) (systolic/diastolic)

16. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_A.HEART) (MAPPINGS2:t_VITALS_X20_A.HEART)

17. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_A.TEMP) (MAPPINGS2:t_VITALS_X20_A.TEMP)

* Item is not required

Form Design Note:

Bench vitals (x20) clone A

Item Design Notes:

Item No. Design Note

5. Item is optional Annotated Trial Design Page 35 of 166

9. Item is optional

13. Item is optional

17. Item is optional

CDD: MAPPINGS1 Table: t_VITALS_X20_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDVSACTTM DATE - HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1

CDD: MAPPINGS2 Table: t_VITALS_X20_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDVSACTTM DATE - HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1

Annotated Trial Design Page 36 of 166

IPC103711_SHZ : 12-LEAD ECG (ECG) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2007) (MAPPINGS1:t_ECG_X20_A.CDDDOSEDTTM) (MAPPINGS2:t_ECG_X20_A.CDDDOSEDTTM) Req : Req 24-hour clock

PREDOSE

2. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_X20_A.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X20_A.EGACTTM)

3. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X20_A.EGHR) (MAPPINGS2:t_ECG_X20_A.EGHR)

4. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.PR__) (MAPPINGS2:t_ECG_X20_A.PR__)

5. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QRS__) (MAPPINGS2:t_ECG_X20_A.QRS__)

6. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QT__) (MAPPINGS2:t_ECG_X20_A.QT__)

7. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QTC__) (MAPPINGS2:t_ECG_X20_A.QTC__)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X20_A.EGMTCLCD) (MAPPINGS2:t_ECG_X20_A.EGMTCLCD) [1] Machine [2] Manual

9. Result of the ECG (MAPPINGS1:t_ECG_X20_A.EGINTPCD) (MAPPINGS2:t_ECG_X20_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) 30 MIN POST DOSE

10. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_X20_A.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X20_A.EGACTTM)

11. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X20_A.EGHR) (MAPPINGS2:t_ECG_X20_A.EGHR)

12. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.PR__) (MAPPINGS2:t_ECG_X20_A.PR__)

13. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QRS__) (MAPPINGS2:t_ECG_X20_A.QRS__)

14. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QT__) (MAPPINGS2:t_ECG_X20_A.QT__)

15. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QTC__) (MAPPINGS2:t_ECG_X20_A.QTC__)

16. Method of QTc Calculation (MAPPINGS1:t_ECG_X20_A.EGMTCLCD) (MAPPINGS2:t_ECG_X20_A.EGMTCLCD) [1] Machine [2] Manual

17. Result of the ECG (MAPPINGS1:t_ECG_X20_A.EGINTPCD) (MAPPINGS2:t_ECG_X20_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) 1 HR POST DOSE

18. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_X20_A.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X20_A.EGACTTM)

19. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X20_A.EGHR) (MAPPINGS2:t_ECG_X20_A.EGHR)

20. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.PR__) (MAPPINGS2:t_ECG_X20_A.PR__) Annotated Trial Design Page 37 of 166

21. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QRS__) (MAPPINGS2:t_ECG_X20_A.QRS__)

22. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QT__) (MAPPINGS2:t_ECG_X20_A.QT__)

23. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QTC__) (MAPPINGS2:t_ECG_X20_A.QTC__)

24. Method of QTc Calculation (MAPPINGS1:t_ECG_X20_A.EGMTCLCD) (MAPPINGS2:t_ECG_X20_A.EGMTCLCD) [1] Machine [2] Manual

25. Result of the ECG (MAPPINGS1:t_ECG_X20_A.EGINTPCD) (MAPPINGS2:t_ECG_X20_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) 2 HR POST DOSE

26. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_X20_A.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X20_A.EGACTTM)

27. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X20_A.EGHR) (MAPPINGS2:t_ECG_X20_A.EGHR)

28. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.PR__) (MAPPINGS2:t_ECG_X20_A.PR__)

29. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QRS__) (MAPPINGS2:t_ECG_X20_A.QRS__)

30. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QT__) (MAPPINGS2:t_ECG_X20_A.QT__)

31. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X20_A.QTC__) (MAPPINGS2:t_ECG_X20_A.QTC__)

32. Method of QTc Calculation (MAPPINGS1:t_ECG_X20_A.EGMTCLCD) (MAPPINGS2:t_ECG_X20_A.EGMTCLCD) [1] Machine [2] Manual

33. Result of the ECG (MAPPINGS1:t_ECG_X20_A.EGINTPCD) (MAPPINGS2:t_ECG_X20_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available)

* Item is not required

Form Design Note:

Bench ECG (x20) clone A

CDD: MAPPINGS1 Table: t_ECG_X20_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM EGACTTM DATE - HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1) Annotated Trial Design Page 38 of 166

CDD: MAPPINGS2 Table: t_ECG_X20_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM EGACTTM DATE - HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1)

Annotated Trial Design Page 39 of 166

IPC103711_SHZ : RANDOMISATION NUMBER (Rand) RANDOMISATION 1. Was the subject able to be randomised? (MAPPINGS1:t_RAND.rdcRandYN) (MAPPINGS2:t_RAND.rdcRandYN) [Y] Yes, provide: Randomisation number (MAPPINGS1:t_RAND.RANDNUM) xxxxxx (MAPPINGS2:t_RAND.RANDNUM) Date of randomisation Req / Req / Req (2007-2009) (MAPPINGS1:t_RAND.RANDDT) (MAPPINGS2:t_RAND.RANDDT) [N] No

CDD: MAPPINGS1 Table: t_RAND Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcRandYN STRING(1) RANDNUM NUMERIC - N6 RANDDT DATE - DDMONYYYY

CDD: MAPPINGS2 Table: t_RAND Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcRandYN STRING(1) RANDNUM NUMERIC - N6 RANDDT DATE - DDMONYYYY

Annotated Trial Design Page 40 of 166

IPC103711_SHZ : PULMONARY FUNCTION TESTS (PFT-PREDOSE) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2007) (MAPPINGS1:t_PFT_X1_B.CDDDOSEDTTM) (MAPPINGS2:t_PFT_X1_B.CDDDOSEDTTM) Req : Req 24-hour clock

PREDOSE

2. Date/time of test Req / Req / Req (2007-2009) (MAPPINGS1:t_PFT_X1_B.PFTDTTM) (MAPPINGS2:t_PFT_X1_B.PFTDTTM) Req : Req 24-hour clock

3. FEV1 xxxx. L (MAPPINGS1:t_PFT_X1_B.FEV1) (MAPPINGS2:t_PFT_X1_B.FEV1)

* Item is not required

Form Design Note:

Bench PFT (x1) clone B

CDD: MAPPINGS1 Table: t_PFT_X1_B Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM PFTDTTM DATE - DDMONYYYY HHMM FEV1 FLOAT - F5.0

CDD: MAPPINGS2 Table: t_PFT_X1_B Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM PFTDTTM DATE - DDMONYYYY HHMM FEV1 FLOAT - F5.0

Annotated Trial Design Page 41 of 166

IPC103711_SHZ : PHARMACODYNAMICS - [Analyte and PD sample type] (BIOMARKER) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2007) (MAPPINGS1:t_PD_X1_A.CDDDOSEDTTM) (MAPPINGS2:t_PD_X1_A.CDDDOSEDTTM) Req : Req 24-hour clock

PREDOSE

2. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X1_A.PDACTDTTM) (MAPPINGS2:t_PD_X1_A.PDACTDTTM) Req : Req 24-hour clock

* Item is not required

Form Design Note:

Bench PD (x1) clone A

CDD: MAPPINGS1 Table: t_PD_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM PDACTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_PD_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM PDACTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 42 of 166

IPC103711_SHZ : SUMMARY HOLTER (Holter) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2009) (MAPPINGS1:t_HMSUM.CDDDOSEDTTM) (MAPPINGS2:t_HMSUM.CDDDOSEDTTM) Req : Req 24-hour clock

0-6 hours (3 Lead ECG)

2. Start Date and Time of Holter Req / Req / Req (2007-2009) (MAPPINGS1:t_HMSUM.HMSTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_HMSUM.HMSTDTTM) Req : Req 24-hour clock

3. Stop Date and Time of Holter Req / Req / Req (2007-2009) (MAPPINGS1:t_HMSUM.HMENDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_HMSUM.HMENDTTM) Req : Req 24-hour clock

4. Interpretation of Holter (MAPPINGS1:t_HMSUM.HMORRSCD1) (MAPPINGS2:t_HMSUM.HMORRSCD1) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant [4] No result [8] Unable to evaluate

* Item is not required

Form Design Note:

Version 01.00A 19 Feb 07

Item Design Notes:

Item No. Design Note

4. No result and unable to evaluate are optional items

CDD: MAPPINGS1 Table: t_HMSUM Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM HMSTDTTM DATE - DDMONYYYY HHMM HMENDTTM DATE - DDMONYYYY HHMM HMORRSCD1 STRING(1)

CDD: MAPPINGS2 Table: t_HMSUM Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM HMSTDTTM DATE - DDMONYYYY HHMM HMENDTTM DATE - DDMONYYYY HHMM HMORRSCD1 STRING(1)

Annotated Trial Design Page 43 of 166

IPC103711_SHZ : SUMMARY HOLTER ABNORMALITIES (Holter Abn) SUMMARY HOLTER ABNORMALITIES

1. Start Date and Time of Holter Req / Req / Req (2007-2009) (MAPPINGS1:t_HMSUM_AB.HMSTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_HMSUM_AB.HMSTDTTM) Req : Req 24-hour clock

2. Stop Date and Time of Holter Req / Req / Req (2007-2009) (MAPPINGS1:t_HMSUM_AB.HMENDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_HMSUM_AB.HMENDTTM) Req : Req 24-hour clock

RECORD CLINICALLY SIGNIFICANT ABNORMALITIES BELOW 3. Check all that apply (MAPPINGS1:t_HMSUM_AB.HMORRSCD7) (MAPPINGS2:t_HMSUM_AB.HMORRSCD7) [A01] Sinus bradycardia (50-59 beats/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD8) (MAPPINGS2:t_HMSUM_AB.HMORRSCD8) [A02] Sinus bradycardia (40-49 beats/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD9) (MAPPINGS2:t_HMSUM_AB.HMORRSCD9) [A03] Sinus bradycardia (30-39 beats/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD10) (MAPPINGS2:t_HMSUM_AB.HMORRSCD10) [A04] Sinus bradycardia (<30 beats/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD11) (MAPPINGS2:t_HMSUM_AB.HMORRSCD11) [A05] Sinus pause (MAPPINGS1:t_HMSUM_AB.HMORRSCD12) (MAPPINGS2:t_HMSUM_AB.HMORRSCD12) [A06] Sinus tachycardia (>100 beats/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD13) (MAPPINGS2:t_HMSUM_AB.HMORRSCD13) [A07] Ectopic supraventricular beats (MAPPINGS1:t_HMSUM_AB.HMORRSCD14) (MAPPINGS2:t_HMSUM_AB.HMORRSCD14) [A08] Ectopic supraventricular rhythm (MAPPINGS1:t_HMSUM_AB.HMORRSCD15) (MAPPINGS2:t_HMSUM_AB.HMORRSCD15) [A09] Wandering atrial pacemaker (MAPPINGS1:t_HMSUM_AB.HMORRSCD16) (MAPPINGS2:t_HMSUM_AB.HMORRSCD16) [A10] Multifocal atrial tachycardia (wandering atrial pacemarker w/ rate >100beat/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD17) (MAPPINGS2:t_HMSUM_AB.HMORRSCD17) [A11] Non-sustained supraventricular tachycardia (>100 beats/min, 3-30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD18) (MAPPINGS2:t_HMSUM_AB.HMORRSCD18) [A12] Sustained supraventricular tachycardia (>100 beats/min, >30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD19) (MAPPINGS2:t_HMSUM_AB.HMORRSCD19) [A!3] Atrial flutter (MAPPINGS1:t_HMSUM_AB.HMORRSCD20) (MAPPINGS2:t_HMSUM_AB.HMORRSCD20) [A14] Atrial fibrillation (MAPPINGS1:t_HMSUM_AB.HMORRSCD21) (MAPPINGS2:t_HMSUM_AB.HMORRSCD21) [A15] Junctional rhythm (<=100 beats/min, defined by narrow QRS complex) (MAPPINGS1:t_HMSUM_AB.HMORRSCD22) (MAPPINGS2:t_HMSUM_AB.HMORRSCD22) [A16] Junctional tachycardia (>100 beats/min) (MAPPINGS1:t_HMSUM_AB.HMORRSCD23) (MAPPINGS2:t_HMSUM_AB.HMORRSCD23) [A17] Ventricular premature depolarisation (MAPPINGS1:t_HMSUM_AB.HMORRSCD24) (MAPPINGS2:t_HMSUM_AB.HMORRSCD24) [A18] Ventricular couplets (MAPPINGS1:t_HMSUM_AB.HMORRSCD25) (MAPPINGS2:t_HMSUM_AB.HMORRSCD25) [A19] Bigeminy (MAPPINGS1:t_HMSUM_AB.HMORRSCD26) (MAPPINGS2:t_HMSUM_AB.HMORRSCD26) [A20] Trigeminy (MAPPINGS1:t_HMSUM_AB.HMORRSCD27) (MAPPINGS2:t_HMSUM_AB.HMORRSCD27) [A21] Electrical alternans Annotated Trial Design Page 44 of 166

(MAPPINGS1:t_HMSUM_AB.HMORRSCD28) (MAPPINGS2:t_HMSUM_AB.HMORRSCD28) [A22] R on T phenomenon (MAPPINGS1:t_HMSUM_AB.HMORRSCD29) (MAPPINGS2:t_HMSUM_AB.HMORRSCD29) [A23] Ventricular fibrillation (MAPPINGS1:t_HMSUM_AB.HMORRSCD30) (MAPPINGS2:t_HMSUM_AB.HMORRSCD30) [A24] Idioventricular rhythm (<=100 beats/min, defined by wide QRS complex) (MAPPINGS1:t_HMSUM_AB.HMORRSCD31) (MAPPINGS2:t_HMSUM_AB.HMORRSCD31) [A25] Non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD32) (MAPPINGS2:t_HMSUM_AB.HMORRSCD32) [A26] Sustained ventricular tachycardia (>100 beats/min, >30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD33) (MAPPINGS2:t_HMSUM_AB.HMORRSCD33) [A27] Wide QRS tachycardia (diagnosis unknown) (MAPPINGS1:t_HMSUM_AB.HMORRSCD34) (MAPPINGS2:t_HMSUM_AB.HMORRSCD34) [A28] Monomorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD35) (MAPPINGS2:t_HMSUM_AB.HMORRSCD35) [A29] Monomorphic sustained ventricular tachycardia (>100 beats/min, >30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD36) (MAPPINGS2:t_HMSUM_AB.HMORRSCD36) [A30] Polymorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD37) (MAPPINGS2:t_HMSUM_AB.HMORRSCD37) [A31] Polymorphic sustained ventricular tachycardia (>100 beats/min, >30 beats) (MAPPINGS1:t_HMSUM_AB.HMORRSCD38) (MAPPINGS2:t_HMSUM_AB.HMORRSCD38) [A32] Torsade de Pointes (TdP) (MAPPINGS1:t_HMSUM_AB.HMORRSCD39) (MAPPINGS2:t_HMSUM_AB.HMORRSCD39) [A33] Pacemaker (MAPPINGS1:t_HMSUM_AB.HMORRSCD40) (MAPPINGS2:t_HMSUM_AB.HMORRSCD40) [A34] First degree AV block (PR interval >200msec) (MAPPINGS1:t_HMSUM_AB.HMORRSCD41) (MAPPINGS2:t_HMSUM_AB.HMORRSCD41) [A35] Short PR Interval (MAPPINGS1:t_HMSUM_AB.HMORRSCD42) (MAPPINGS2:t_HMSUM_AB.HMORRSCD42) [A36] Second degree AV block (Mobitz type 1) (MAPPINGS1:t_HMSUM_AB.HMORRSCD43) (MAPPINGS2:t_HMSUM_AB.HMORRSCD43) [A37] Second degree AV block (Mobitz type 2) (MAPPINGS1:t_HMSUM_AB.HMORRSCD44) (MAPPINGS2:t_HMSUM_AB.HMORRSCD44) [A38] 2:1 AV block (MAPPINGS1:t_HMSUM_AB.HMORRSCD45) (MAPPINGS2:t_HMSUM_AB.HMORRSCD45) [A39] Third degree AV block (MAPPINGS1:t_HMSUM_AB.HMORRSCD46) (MAPPINGS2:t_HMSUM_AB.HMORRSCD46) [A40] Left axis deviation (QRS axis more negative than -30 degrees) (MAPPINGS1:t_HMSUM_AB.HMORRSCD47) (MAPPINGS2:t_HMSUM_AB.HMORRSCD47) [A41] Right axis deviation (QRS axis more positive than +110 degrees) (MAPPINGS1:t_HMSUM_AB.HMORRSCD48) (MAPPINGS2:t_HMSUM_AB.HMORRSCD48) [A42] Incomplete right bundle branch block (MAPPINGS1:t_HMSUM_AB.HMORRSCD49) (MAPPINGS2:t_HMSUM_AB.HMORRSCD49) [A43] Incomplete left bundle branch block (MAPPINGS1:t_HMSUM_AB.HMORRSCD50) (MAPPINGS2:t_HMSUM_AB.HMORRSCD50) [A44] Right bundle branch block (MAPPINGS1:t_HMSUM_AB.HMORRSCD51) (MAPPINGS2:t_HMSUM_AB.HMORRSCD51) [A45] Left anterior hemiblock (MAPPINGS1:t_HMSUM_AB.HMORRSCD52) (MAPPINGS2:t_HMSUM_AB.HMORRSCD52) [A46] Left posterior hemiblock Annotated Trial Design Page 45 of 166

(MAPPINGS1:t_HMSUM_AB.HMORRSCD53) (MAPPINGS2:t_HMSUM_AB.HMORRSCD53) [A47] Left bundle branch block (MAPPINGS1:t_HMSUM_AB.HMORRSCD54) (MAPPINGS2:t_HMSUM_AB.HMORRSCD54) [A48] Bifascicular block (MAPPINGS1:t_HMSUM_AB.HMORRSCD55) (MAPPINGS2:t_HMSUM_AB.HMORRSCD55) [A49] Non-specific intraventricular conduction delay (QRS >=120 msec) (MAPPINGS1:t_HMSUM_AB.HMORRSCD56) (MAPPINGS2:t_HMSUM_AB.HMORRSCD56) [A50] Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine) (MAPPINGS1:t_HMSUM_AB.HMORRSCD57) (MAPPINGS2:t_HMSUM_AB.HMORRSCD57) [A51] QTc prolongation >=500 msec (MAPPINGS1:t_HMSUM_AB.HMORRSCD58) (MAPPINGS2:t_HMSUM_AB.HMORRSCD58) [A52] AV dissociation (MAPPINGS1:t_HMSUM_AB.HMORRSCD59) (MAPPINGS2:t_HMSUM_AB.HMORRSCD59) [A53] Myocardial infarction, old (MAPPINGS1:t_HMSUM_AB.HMORRSCD60) (MAPPINGS2:t_HMSUM_AB.HMORRSCD60) [A54] Myocardial infarction, non Q-wave (MAPPINGS1:t_HMSUM_AB.HMORRSCD61) (MAPPINGS2:t_HMSUM_AB.HMORRSCD61) [A55] Non-specific ST-T changes (MAPPINGS1:t_HMSUM_AB.HMORRSCD62) (MAPPINGS2:t_HMSUM_AB.HMORRSCD62) [A56] J point elevation (MAPPINGS1:t_HMSUM_AB.HMORRSCD63) (MAPPINGS2:t_HMSUM_AB.HMORRSCD63) [A57] ST elevation (MAPPINGS1:t_HMSUM_AB.HMORRSCD64) (MAPPINGS2:t_HMSUM_AB.HMORRSCD64) [A58] ST depression (MAPPINGS1:t_HMSUM_AB.HMORRSCD65) (MAPPINGS2:t_HMSUM_AB.HMORRSCD65) [A59] ST segment abnormality (MAPPINGS1:t_HMSUM_AB.HMORRSCD66) (MAPPINGS2:t_HMSUM_AB.HMORRSCD66) [A60] U waves (MAPPINGS1:t_HMSUM_AB.HMORRSCD67) (MAPPINGS2:t_HMSUM_AB.HMORRSCD67) [A61] T wave inversion (MAPPINGS1:t_HMSUM_AB.HMORRSCD68) (MAPPINGS2:t_HMSUM_AB.HMORRSCD68) [A62] T wave peaked (MAPPINGS1:t_HMSUM_AB.HMORRSCD69) (MAPPINGS2:t_HMSUM_AB.HMORRSCD69) [A63] T waves biphasic (MAPPINGS1:t_HMSUM_AB.HMORRSCD70) (MAPPINGS2:t_HMSUM_AB.HMORRSCD70) [A64] T waves flat (MAPPINGS1:t_HMSUM_AB.HMORRSCD71) (MAPPINGS2:t_HMSUM_AB.HMORRSCD71) [A65] Notched T-waves (MAPPINGS1:t_HMSUM_AB.HMORRSCD72) (MAPPINGS2:t_HMSUM_AB.HMORRSCD72) [A66] Low QRS voltage (MAPPINGS1:t_HMSUM_AB.HMORRSCD73) (MAPPINGS2:t_HMSUM_AB.HMORRSCD73) [A67] T wave abnormality (MAPPINGS1:t_HMSUM_AB.HMORRSCD74) (MAPPINGS2:t_HMSUM_AB.HMORRSCD74) (MAPPINGS1:t_HMSUM_AB.HMORRSSP) [A94] Other abnormal rhythm A200 (MAPPINGS2:t_HMSUM_AB.HMORRSSP) (MAPPINGS1:t_HMSUM_AB.HMORRSCD75) (MAPPINGS2:t_HMSUM_AB.HMORRSCD75) (MAPPINGS1:t_HMSUM_AB.HMORRSSP1) [A95] Other morphology A200 (MAPPINGS2:t_HMSUM_AB.HMORRSSP1) (MAPPINGS1:t_HMSUM_AB.HMORRSCD76) (MAPPINGS2:t_HMSUM_AB.HMORRSCD76) (MAPPINGS1:t_HMSUM_AB.HMORRSSP2) [A96] Other conduction A200 (MAPPINGS2:t_HMSUM_AB.HMORRSSP2) Annotated Trial Design Page 46 of 166

(MAPPINGS1:t_HMSUM_AB.HMORRSCD77) (MAPPINGS2:t_HMSUM_AB.HMORRSCD77) (MAPPINGS1:t_HMSUM_AB.HMORRSSP3) [A97] Other myocardial infarction A200 (MAPPINGS2:t_HMSUM_AB.HMORRSSP3) (MAPPINGS1:t_HMSUM_AB.HMORRSCD78) (MAPPINGS2:t_HMSUM_AB.HMORRSCD78) (MAPPINGS1:t_HMSUM_AB.HMORRSSP4) [A98] Other depolarisation/repolarisation A200 (MAPPINGS2:t_HMSUM_AB.HMORRSSP4) (MAPPINGS1:t_HMSUM_AB.HMORRSCD79) (MAPPINGS2:t_HMSUM_AB.HMORRSCD79) (MAPPINGS1:t_HMSUM_AB.HMORRSSP5) [A99] Other abnormality/Cardiologist comments A200 (MAPPINGS2:t_HMSUM_AB.HMORRSSP5)

Form Design Note:

Version 01.00A 30 Apr 07

CDD: MAPPINGS1 Table: t_HMSUM_AB Key Type: PATIENTVISIT Column Name Column Data Type Design Note HMSTDTTM DATE - DDMONYYYY HHMM HMENDTTM DATE - DDMONYYYY HHMM HMORRSCD7 STRING(255) HMORRSCD8 STRING(255) HMORRSCD9 STRING(255) HMORRSCD10 STRING(255) HMORRSCD11 STRING(255) HMORRSCD12 STRING(255) HMORRSCD13 STRING(255) HMORRSCD14 STRING(255) HMORRSCD15 STRING(255) HMORRSCD16 STRING(255) HMORRSCD17 STRING(255) HMORRSCD18 STRING(255) HMORRSCD19 STRING(255) HMORRSCD20 STRING(255) HMORRSCD21 STRING(255) HMORRSCD22 STRING(255) HMORRSCD23 STRING(255) HMORRSCD24 STRING(255) HMORRSCD25 STRING(255) HMORRSCD26 STRING(255) HMORRSCD27 STRING(255) HMORRSCD28 STRING(255) HMORRSCD29 STRING(255) HMORRSCD30 STRING(255) HMORRSCD31 STRING(255) HMORRSCD32 STRING(255) HMORRSCD33 STRING(255) HMORRSCD34 STRING(255) HMORRSCD35 STRING(255) HMORRSCD36 STRING(255) HMORRSCD37 STRING(255) HMORRSCD38 STRING(255) HMORRSCD39 STRING(255) Annotated Trial Design Page 47 of 166

HMORRSCD40 STRING(255) HMORRSCD41 STRING(255) HMORRSCD42 STRING(255) HMORRSCD43 STRING(255) HMORRSCD44 STRING(255) HMORRSCD45 STRING(255) HMORRSCD46 STRING(255) HMORRSCD47 STRING(255) HMORRSCD48 STRING(255) HMORRSCD49 STRING(255) HMORRSCD50 STRING(255) HMORRSCD51 STRING(255) HMORRSCD52 STRING(255) HMORRSCD53 STRING(255) HMORRSCD54 STRING(255) HMORRSCD55 STRING(255) HMORRSCD56 STRING(255) HMORRSCD57 STRING(255) HMORRSCD58 STRING(255) HMORRSCD59 STRING(255) HMORRSCD60 STRING(255) HMORRSCD61 STRING(255) HMORRSCD62 STRING(255) HMORRSCD63 STRING(255) HMORRSCD64 STRING(255) HMORRSCD65 STRING(255) HMORRSCD66 STRING(255) HMORRSCD67 STRING(255) HMORRSCD68 STRING(255) HMORRSCD69 STRING(255) HMORRSCD70 STRING(255) HMORRSCD71 STRING(255) HMORRSCD72 STRING(255) HMORRSCD73 STRING(255) HMORRSCD74 STRING(255) HMORRSSP STRING(200) - A200 HMORRSCD75 STRING(255) HMORRSSP1 STRING(200) - A200 HMORRSCD76 STRING(255) HMORRSSP2 STRING(200) - A200 HMORRSCD77 STRING(255) HMORRSSP3 STRING(200) - A200 HMORRSCD78 STRING(255) HMORRSSP4 STRING(200) - A200 HMORRSCD79 STRING(255) HMORRSSP5 STRING(200) - A200

CDD: MAPPINGS2 Table: t_HMSUM_AB Key Type: PATIENTVISIT Column Name Column Data Type Design Note HMSTDTTM DATE - DDMONYYYY HHMM HMENDTTM DATE - DDMONYYYY HHMM Annotated Trial Design Page 48 of 166

HMORRSCD7 STRING(255) HMORRSCD8 STRING(255) HMORRSCD9 STRING(255) HMORRSCD10 STRING(255) HMORRSCD11 STRING(255) HMORRSCD12 STRING(255) HMORRSCD13 STRING(255) HMORRSCD14 STRING(255) HMORRSCD15 STRING(255) HMORRSCD16 STRING(255) HMORRSCD17 STRING(255) HMORRSCD18 STRING(255) HMORRSCD19 STRING(255) HMORRSCD20 STRING(255) HMORRSCD21 STRING(255) HMORRSCD22 STRING(255) HMORRSCD23 STRING(255) HMORRSCD24 STRING(255) HMORRSCD25 STRING(255) HMORRSCD26 STRING(255) HMORRSCD27 STRING(255) HMORRSCD28 STRING(255) HMORRSCD29 STRING(255) HMORRSCD30 STRING(255) HMORRSCD31 STRING(255) HMORRSCD32 STRING(255) HMORRSCD33 STRING(255) HMORRSCD34 STRING(255) HMORRSCD35 STRING(255) HMORRSCD36 STRING(255) HMORRSCD37 STRING(255) HMORRSCD38 STRING(255) HMORRSCD39 STRING(255) HMORRSCD40 STRING(255) HMORRSCD41 STRING(255) HMORRSCD42 STRING(255) HMORRSCD43 STRING(255) HMORRSCD44 STRING(255) HMORRSCD45 STRING(255) HMORRSCD46 STRING(255) HMORRSCD47 STRING(255) HMORRSCD48 STRING(255) HMORRSCD49 STRING(255) HMORRSCD50 STRING(255) HMORRSCD51 STRING(255) HMORRSCD52 STRING(255) HMORRSCD53 STRING(255) HMORRSCD54 STRING(255) HMORRSCD55 STRING(255) HMORRSCD56 STRING(255) HMORRSCD57 STRING(255) Annotated Trial Design Page 49 of 166

HMORRSCD58 STRING(255) HMORRSCD59 STRING(255) HMORRSCD60 STRING(255) HMORRSCD61 STRING(255) HMORRSCD62 STRING(255) HMORRSCD63 STRING(255) HMORRSCD64 STRING(255) HMORRSCD65 STRING(255) HMORRSCD66 STRING(255) HMORRSCD67 STRING(255) HMORRSCD68 STRING(255) HMORRSCD69 STRING(255) HMORRSCD70 STRING(255) HMORRSCD71 STRING(255) HMORRSCD72 STRING(255) HMORRSCD73 STRING(255) HMORRSCD74 STRING(255) HMORRSSP STRING(200) - A200 HMORRSCD75 STRING(255) HMORRSSP1 STRING(200) - A200 HMORRSCD76 STRING(255) HMORRSSP2 STRING(200) - A200 HMORRSCD77 STRING(255) HMORRSSP3 STRING(200) - A200 HMORRSCD78 STRING(255) HMORRSSP4 STRING(200) - A200 HMORRSCD79 STRING(255) HMORRSSP5 STRING(200) - A200

Annotated Trial Design Page 50 of 166

IPC103711_SHZ : LOCAL LABORATORY - HAEMATOLOGY (Lab H PREDOSE) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. HAEMATOLOGY- PREDOSE

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_HAEMA_B.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_HAEMA_B.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_HAEMA_B.LBFAST) (MAPPINGS2:t_LAB_HAEMA_B.LBFAST) [Y] Yes [N] No

3. WBC (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 4. RBC (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 5. Haemoglobin (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 6. Haematocrit (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 7. Neutrophils (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 8. Lymphocytes (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 9. Monocytes (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] Annotated Trial Design Page 51 of 166

10. Eosinophils (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 11. Basophils (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 12. Platelets (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 13. MCV (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 14. MCH (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 15. MCHC (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99] 16. Reticulocytes (MAPPINGS1:t_LAB_HAEMA_B.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_B.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Haem form Clone B

Section Design Notes:

Title Design Note

HAEMATOLOGY- PREDOSE Use separate items for Name and address for the first occurance of this form, and use the combined item for subsequent visits. Annotated Trial Design Page 52 of 166

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_HAEMA_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_HAEMA_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 53 of 166

IPC103711_SHZ : LOCAL LABORATORY - CLINICAL CHEMISTRY (Lab C PREDOSE) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. CLINICAL CHEMISTRY - PREDOSE

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_CHEM_B.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_CHEM_B.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM_B.LBFAST) (MAPPINGS2:t_LAB_CHEM_B.LBFAST) [Y] Yes [N] No

3. ALT (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 4. AST (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 5. Total Bilirubin (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 6. Glucose (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 7. GGT (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 8. Total Protein (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 9. Albumin (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] Annotated Trial Design Page 54 of 166

10. Potassium (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 11. Sodium (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 12. Chloride (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 13. Urea (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 14. Creatinine (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 15. Uric Acid (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 16. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 17. Globulin (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 18. Phosphate (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) Annotated Trial Design Page 55 of 166

[- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99] 19. Bicarbonate (MAPPINGS1:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone B

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY - PREDOSE Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_CHEM_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_CHEM_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 56 of 166

IPC103711_SHZ : LOCAL LABORATORY - CLINICAL CHEMISTRY (Lab C Extra - PREDOSE) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. CLINICAL CHEMISTRY - PREDOSE 1. Creatinine Kinase (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 2. Creatinine Kinase-MB (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 3. Calcium (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 4. LDH (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 5. CRP (MAPPINGS2:t_LAB_CHEM_B.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone G

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY - PREDOSE Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Annotated Trial Design Page 57 of 166

CDD: MAPPINGS2 Table: t_LAB_CHEM_E Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 58 of 166

IPC103711_SHZ : URINALYSIS - LOCAL (Lab U PREDOSE) Complete the Adverse Events (AE) form if clinically significant abnormalities meet the protocol definition for an AE. URINALYSIS - LOCAL: PREDOSE

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_URIN_B.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_URIN_B.LBDTTM) Req : Req 24-hour clock

2. Result of dipstick (MAPPINGS1:t_LAB_URIN_B.RSLTCHARU) (MAPPINGS2:t_LAB_URIN_B.RSLTCHARU) [NR] No result [NEG] Negative [POS] (MAPPINGS1:t_LAB_URIN_B.rdcMICROSCOPY) (MAPPINGS2:t_LAB_URIN_B.rdcMICROSCOPY) Positive Was sedimentary microscopy performed? [N] No [Y] Yes, provide details on the MICROSCOPY form

URINALYSIS - LOCAL: DIPSTICK DETAILS 3. Protein (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 4. Glucose (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 5. Ketones (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 6. Bilirubin (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 7. Blood (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 8. Urobilinogen (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 9. Leucocytes (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) Annotated Trial Design Page 59 of 166

(MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 10. Specific Gravity (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 11. Nitrites (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99] 12. pH (MAPPINGS1:t_LAB_URIN_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_B.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Urinalysis Clone B

Section Design Notes:

Title Design Note

URINALYSIS - LOCAL: PREDOSE Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

URINALYSIS - LOCAL: DIPSTICK DETAILS Remove or add tests per protocol

Item Design Notes:

Item No. Design Note

2. This item is optional.

CDD: MAPPINGS1 Table: t_LAB_URIN_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM RSLTCHARU STRING(3) rdcMICROSCOPY STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_URIN_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note Annotated Trial Design Page 60 of 166

LBDTTM DATE - DDMONYYYY HHMM RSLTCHARU STRING(3) rdcMICROSCOPY STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 61 of 166

IPC103711_SHZ : URINALYSIS - LOCAL: MICROSCOPY DETAILS (Lab Mic) URINALYSIS - LOCAL: MICROSCOPY DETAILS: PREDOSE

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.LBDTTM) Hr:Min (00:00-23:59) [read-only] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.LBDTTM) Req : Req 24-hour clock

2. White blood cells (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) [- No result 99] 3. Red blood cells (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) [- No result 99] 4. Hyaline casts (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) [- No result 99] 5. Granular casts (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) [- No result 99] 6. Cellular casts (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_MICROSCOPY_B.RSLTCHAR) [- No result 99]

Form Design Note:

Bench lab urine microscopy Clone B. This form is created dynamically when question 6 on the Urinalysis form is answered Yes

Section Design Notes:

Title Design Note

URINALYSIS - LOCAL: MICROSCOPY DETAILS: PREDOSE Remove or add tests per protocol

CDD: MAPPINGS1 Table: t_LAB_URIN_MICROSCOPY_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 62 of 166

CDD: MAPPINGS2 Table: t_LAB_URIN_MICROSCOPY_B Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 63 of 166

IPC103711_SHZ : EARLY WITHDRAWAL (Early_Withdrawal) EARLY WITHDRAWAL 1. Did the patient withdraw early from the study? (MAPPINGS1:t_EARLY_WITHDRAWAL.WITHDRAW) (MAPPINGS2:t_EARLY_WITHDRAWAL.WITHDRAW) [Y] YES [N] NO

Form Design Note:

Early withdrawal form

CDD: MAPPINGS1 Table: t_EARLY_WITHDRAWAL Key Type: PATIENTVISIT Column Name Column Data Type Design Note WITHDRAW STRING(1)

CDD: MAPPINGS2 Table: t_EARLY_WITHDRAWAL Key Type: PATIENTVISIT Column Name Column Data Type Design Note WITHDRAW STRING(1)

Annotated Trial Design Page 64 of 166

IPC103711_SHZ : VITAL SIGNS (VS) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2006-2007) (MAPPINGS1:t_VITALS_X20_B.CDDDOSEDTTM) (MAPPINGS2:t_VITALS_X20_B.CDDDOSEDTTM) Req : Req 24-hour clock

PREDOSE

2. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_B.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_B.CDDVSACTTM)

3. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_B.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_B.DIABP) (MAPPINGS2:t_VITALS_X20_B.SYSBP) (MAPPINGS2:t_VITALS_X20_B.DIABP) (systolic/diastolic)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_B.HEART) (MAPPINGS2:t_VITALS_X20_B.HEART)

5. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_B.TEMP) (MAPPINGS2:t_VITALS_X20_B.TEMP)

3 HR POST DOSE

6. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_B.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_B.CDDVSACTTM)

7. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_B.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_B.DIABP) (MAPPINGS2:t_VITALS_X20_B.SYSBP) (MAPPINGS2:t_VITALS_X20_B.DIABP) (systolic/diastolic)

8. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_B.HEART) (MAPPINGS2:t_VITALS_X20_B.HEART)

9. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_B.TEMP) (MAPPINGS2:t_VITALS_X20_B.TEMP)

4 HR POST DOSE

10. Actual time Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_B.CDDVSACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_B.CDDVSACTTM)

11. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_B.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_B.DIABP) (MAPPINGS2:t_VITALS_X20_B.SYSBP) (MAPPINGS2:t_VITALS_X20_B.DIABP) (systolic/diastolic)

12. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_B.HEART) (MAPPINGS2:t_VITALS_X20_B.HEART)

13. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_B.TEMP) (MAPPINGS2:t_VITALS_X20_B.TEMP)

24 HR POST DOSE

14. Actual date/time Req / Req / Req (2007-2008) (MAPPINGS1:t_VITALS_X20_B.VSACTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X20_B.VSACTDTTM) Req : Req 24-hour clock

15. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_B.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_B.DIABP) (MAPPINGS2:t_VITALS_X20_B.SYSBP) (MAPPINGS2:t_VITALS_X20_B.DIABP) (systolic/diastolic)

16. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_B.HEART) (MAPPINGS2:t_VITALS_X20_B.HEART)

17. Temperature xx.x °C (MAPPINGS1:t_VITALS_X20_B.TEMP) (MAPPINGS2:t_VITALS_X20_B.TEMP)

* Item is not required

Form Design Note:

Bench vitals (x20) clone B

Item Design Notes:

Item No. Design Note Annotated Trial Design Page 65 of 166

5. Item is optional

9. Item is optional

13. Item is optional

17. Item is optional

CDD: MAPPINGS1 Table: t_VITALS_X20_B Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDVSACTTM DATE - HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1 VSACTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_VITALS_X20_B Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDVSACTTM DATE - HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1 VSACTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 66 of 166

IPC103711_SHZ : 12-LEAD ECG (ECG) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_X3_A.CDDDOSEDTTM) (MAPPINGS2:t_ECG_X3_A.CDDDOSEDTTM) Req : Req 24-hour clock

PREDOSE

2. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_X3_A.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X3_A.EGACTTM)

3. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_A.EGHR) (MAPPINGS2:t_ECG_X3_A.EGHR)

4. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.PR__) (MAPPINGS2:t_ECG_X3_A.PR__)

5. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QRS__) (MAPPINGS2:t_ECG_X3_A.QRS__)

6. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QT__) (MAPPINGS2:t_ECG_X3_A.QT__)

7. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QTC__) (MAPPINGS2:t_ECG_X3_A.QTC__)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_A.EGMTCLCD) (MAPPINGS2:t_ECG_X3_A.EGMTCLCD) [1] Machine [2] Manual

9. Result of the ECG (MAPPINGS1:t_ECG_X3_A.EGINTPCD) (MAPPINGS2:t_ECG_X3_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) 4 HR POST DOSE

10. Time of ECG Req : Req 24-hour clock (MAPPINGS1:t_ECG_X3_A.EGACTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X3_A.EGACTTM)

11. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_A.EGHR) (MAPPINGS2:t_ECG_X3_A.EGHR)

12. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.PR__) (MAPPINGS2:t_ECG_X3_A.PR__)

13. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QRS__) (MAPPINGS2:t_ECG_X3_A.QRS__)

14. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QT__) (MAPPINGS2:t_ECG_X3_A.QT__)

15. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QTC__) (MAPPINGS2:t_ECG_X3_A.QTC__)

16. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_A.EGMTCLCD) (MAPPINGS2:t_ECG_X3_A.EGMTCLCD) [1] Machine [2] Manual

17. Result of the ECG (MAPPINGS1:t_ECG_X3_A.EGINTPCD) (MAPPINGS2:t_ECG_X3_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available) 24 HR POST DOSE

18. Date and Time of ECG Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_X3_A.EGDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X3_A.EGDTTM) Req : Req 24-hour clock

19. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_A.EGHR) (MAPPINGS2:t_ECG_X3_A.EGHR)

20. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.PR__) (MAPPINGS2:t_ECG_X3_A.PR__) Annotated Trial Design Page 67 of 166

21. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QRS__) (MAPPINGS2:t_ECG_X3_A.QRS__)

22. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QT__) (MAPPINGS2:t_ECG_X3_A.QT__)

23. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QTC__) (MAPPINGS2:t_ECG_X3_A.QTC__)

24. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_A.EGMTCLCD) (MAPPINGS2:t_ECG_X3_A.EGMTCLCD) [1] Machine [2] Manual

25. Result of the ECG (MAPPINGS1:t_ECG_X3_A.EGINTPCD) (MAPPINGS2:t_ECG_X3_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available)

* Item is not required

Form Design Note:

Bench ECG (x3) clone A

CDD: MAPPINGS1 Table: t_ECG_X3_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM EGACTTM DATE - HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1) EGDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_ECG_X3_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM EGACTTM DATE - HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1) EGDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 68 of 166

IPC103711_SHZ : LPS INSTILLATION (LPS INSTILLATION)

1. LPS Instillation date/time Req / Req / Req (2007-2008) (MAPPINGS1:t_TPTREF_X1_B.TPTREFDTTM) (MAPPINGS2:t_TPTREF_X1_B.TPTREFDTTM) Req : Req 24-hour clock

Form Design Note:

Screening

CDD: MAPPINGS1 Table: t_TPTREF_X1_B Key Type: PATIENTVISIT Column Name Column Data Type Design Note TPTREFDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_TPTREF_X1_B Key Type: PATIENTVISIT Column Name Column Data Type Design Note TPTREFDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 69 of 166

IPC103711_SHZ : BRONCHOSCOPY (BRONCHOSCOPY)

1. Bronchoscopy date and time Req / Req / Req (2007-2009) (MAPPINGS1:t_TPTREF_X1_A.TPTREFDTTM) (MAPPINGS2:t_TPTREF_X1_A.TPTREFDTTM) Req : Req 24-hour clock

Form Design Note:

Screening

CDD: MAPPINGS1 Table: t_TPTREF_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note TPTREFDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_TPTREF_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note TPTREFDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 70 of 166

IPC103711_SHZ : PULMONARY FUNCTION TESTS (PFT) BRONCHOSCOPY DATE AND TIME

* 1. Bronchoscopy date/time [read-only] Req / Req / Req (2007-2007) (MAPPINGS1:t_PFT_X1_C.CDDBRONDTTM) (MAPPINGS2:t_PFT_X1_C.CDDBRONDTTM) Req : Req 24-hour clock

POST BRONCHOSCOPY

2. Date/time of test Req / Req / Req (2007-2009) (MAPPINGS1:t_PFT_X1_C.PFTDTTM) (MAPPINGS2:t_PFT_X1_C.PFTDTTM) Req : Req 24-hour clock

3. FEV1 xxxx. L (MAPPINGS1:t_PFT_X1_C.FEV1) (MAPPINGS2:t_PFT_X1_C.FEV1)

* Item is not required

Form Design Note:

Bench PFT (x1) clone C

CDD: MAPPINGS1 Table: t_PFT_X1_C Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDBRONDTTM DATE - DDMONYYYY HHMM PFTDTTM DATE - DDMONYYYY HHMM FEV1 FLOAT - F5.0

CDD: MAPPINGS2 Table: t_PFT_X1_C Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDBRONDTTM DATE - DDMONYYYY HHMM PFTDTTM DATE - DDMONYYYY HHMM FEV1 FLOAT - F5.0

Annotated Trial Design Page 71 of 166

IPC103711_SHZ : Blood and BAL samples for Urea and PK (Blood/BAL) DOSING DATE AND TIME

* 1. Dosing date/time [read-only] Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X20_A.CDDDOSEDTTM) (MAPPINGS2:t_PD_X20_A.CDDDOSEDTTM) Req : Req 24-hour clock

2 HR POST DOSE BLOOD (UREA)

2. Time of sample Req : Req 24-hour clock (MAPPINGS1:t_PD_X20_A.CDDPDACTTM) (MAPPINGS2:t_PD_X20_A.CDDPDACTTM)

2 HR POST DOSE BAL (PK + UREA)

3. Time of sample Req : Req 24-hour clock (MAPPINGS1:t_PD_X20_A.CDDPDACTTM) (MAPPINGS2:t_PD_X20_A.CDDPDACTTM)

26 HR POST DOSE BLOOD - (UREA)

4. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X20_A.PDACTDTTM) (MAPPINGS2:t_PD_X20_A.PDACTDTTM) Req : Req 24-hour clock

26 HR POST DOSE SALINE - BAL (PK + UREA)

5. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X20_A.PDACTDTTM) (MAPPINGS2:t_PD_X20_A.PDACTDTTM) Req : Req 24-hour clock

26 HR POST DOSE LPS - BAL (PK + UREA)

6. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X20_A.PDACTDTTM) (MAPPINGS2:t_PD_X20_A.PDACTDTTM) Req : Req 24-hour clock

* Item is not required

Form Design Note:

Bench PD (X20) clone A

CDD: MAPPINGS1 Table: t_PD_X20_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDPDACTTM DATE - HHMM PDACTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_PD_X20_A Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDPDACTTM DATE - HHMM PDACTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 72 of 166

IPC103711_SHZ : LOCAL LABORATORY - HAEMATOLOGY (Lab H 24H) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. HAEMATOLOGY - 24 HR POST DOSE

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_HAEMA_C.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_HAEMA_C.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_HAEMA_C.LBFAST) (MAPPINGS2:t_LAB_HAEMA_C.LBFAST) [Y] Yes [N] No

3. WBC (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 4. RBC (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 5. Haemoglobin (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 6. Haematocrit (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 7. Neutrophils (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 8. Lymphocytes (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 9. Monocytes (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] Annotated Trial Design Page 73 of 166

10. Eosinophils (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 11. Basophils (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 12. Platelets (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 13. MCV (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 14. MCH (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 15. MCHC (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99] 16. Reticulocytes (MAPPINGS1:t_LAB_HAEMA_C.rdcLBORRES) (MAPPINGS2:t_LAB_HAEMA_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_HAEMA_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_HAEMA_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_HAEMA_C.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Haem form Clone C

Section Design Notes:

Title Design Note

HAEMATOLOGY - 24 HR POST DOSE Use separate items for Name and address for the first occurance of this form, and use the combined item for subsequent visits. Annotated Trial Design Page 74 of 166

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_HAEMA_C Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_HAEMA_C Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 75 of 166

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_CHEM_E.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_CHEM_E.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM_E.LBFAST) (MAPPINGS2:t_LAB_CHEM_E.LBFAST) [Y] Yes [N] No

3. ALT (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 4. AST (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 5. Total Bilirubin (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 6. Glucose (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 7. GGT (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 8. Total Protein (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 9. Albumin (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] Annotated Trial Design Page 76 of 166

10. Potassium (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 11. Sodium (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 12. Chloride (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 13. Urea (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 14. Creatinine (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 15. Uric Acid (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 16. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 17. Globulin (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 18. Phosphate (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) Annotated Trial Design Page 77 of 166

[- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 19. Bicarbonate (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99] 20. Troponin T (MAPPINGS1:t_LAB_CHEM_E.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_E.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_E.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_E.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_E.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_E.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone A

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY - PREDOSE Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_CHEM_E Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_CHEM_E Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 78 of 166

IPC103711_SHZ : LOCAL LABORATORY - CLINICAL CHEMISTRY (Lab C 24H) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. CLINICAL CHEMISTRY - 24 HR POST DOSE

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_CHEM_C.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_CHEM_C.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM_C.LBFAST) (MAPPINGS2:t_LAB_CHEM_C.LBFAST) [Y] Yes [N] No

3. ALT (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 4. AST (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 5. Total Bilirubin (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 6. Glucose (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 7. GGT (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 8. Total Protein (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 9. Albumin (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] Annotated Trial Design Page 79 of 166

10. Potassium (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 11. Sodium (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 12. Chloride (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 13. Urea (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 14. Creatinine (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 15. Uric Acid (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 16. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 17. Globulin (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 18. Phosphate (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) Annotated Trial Design Page 80 of 166

[- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99] 19. Bicarbonate (MAPPINGS1:t_LAB_CHEM_C.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_C.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_C.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone C

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY - 24 HR POST DOSE Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_CHEM_C Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_CHEM_C Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 81 of 166

IPC103711_SHZ : LOCAL LABORATORY - CLINICAL CHEMISTRY (Lab C EXTRA - 24H) If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. CLINICAL CHEMISTRY EXTRA - 24 HR POST DOSE 1. Creatinine Kinase (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) 97] [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) 98] [- No result 99] 2. Creatinine Kinase-MB (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) 97] [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) 98] [- No result 99] 3. Calcium (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) 97] [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) 98] [- No result 99] 4. LDH (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) 97] [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) 98] [- No result 99] 5. CRP (MAPPINGS2:t_LAB_CHEM_C.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS2:t_LAB_CHEM_C.RSLTNUM) 97] [- Character result: A20 (MAPPINGS2:t_LAB_CHEM_C.RSLTCHAR) 98] [- No result 99]

Form Design Note:

Bench Lab Chem Clone H

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY EXTRA - 24 HR POST DOSE Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Annotated Trial Design Page 82 of 166

IPC103711_SHZ : PHARMACODYNAMICS - [Analyte and PD sample type] (BIOMARKER) BRONCHOSCOPY DATE AND TIME

* 1. Bronchoscopy date/time [read-only] Req / Req / Req (2007-2007) (MAPPINGS1:t_PD_X1_B.CDDBRONDTTM) (MAPPINGS2:t_PD_X1_B.CDDBRONDTTM) Req : Req 24-hour clock

PRE-BRONCHOSCOPY

2. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X1_B.PDACTDTTM) (MAPPINGS2:t_PD_X1_B.PDACTDTTM) Req : Req 24-hour clock

* Item is not required

Form Design Note:

Bench PD (x1) clone B

CDD: MAPPINGS1 Table: t_PD_X1_B Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDBRONDTTM DATE - DDMONYYYY HHMM PDACTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_PD_X1_B Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDBRONDTTM DATE - DDMONYYYY HHMM PDACTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 83 of 166

IPC103711_SHZ : VITAL SIGNS (VS) VITAL SIGNS

1. Actual date/time Req / Req / Req (2007-2009) (MAPPINGS1:t_VITALS_Z_FU.VSACTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_Z_FU.VSACTDTTM) Req : Req 24-hour clock

2. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_Z_FU.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_Z_FU.DIABP) (MAPPINGS2:t_VITALS_Z_FU.SYSBP) (MAPPINGS2:t_VITALS_Z_FU.DIABP) (systolic/diastolic)

3. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_Z_FU.HEART) (MAPPINGS2:t_VITALS_Z_FU.HEART)

4. Temperature xx.x °C (MAPPINGS1:t_VITALS_Z_FU.TEMP) (MAPPINGS2:t_VITALS_Z_FU.TEMP)

Form Design Note:

Follow-up vital signs

Item Design Notes:

Item No. Design Note

4. Item is optional

CDD: MAPPINGS1 Table: t_VITALS_Z_FU Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1

CDD: MAPPINGS2 Table: t_VITALS_Z_FU Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1

Annotated Trial Design Page 84 of 166

IPC103711_SHZ : 12-LEAD ECG (ECG) 12-LEAD ECG

1. Date and Time of ECG Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_Z_FU.EGDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_Z_FU.EGDTTM) Req : Req 24-hour clock

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_Z_FU.EGHR) (MAPPINGS2:t_ECG_Z_FU.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_Z_FU.PR__) (MAPPINGS2:t_ECG_Z_FU.PR__)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_Z_FU.QRS__) (MAPPINGS2:t_ECG_Z_FU.QRS__)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_Z_FU.QT__) (MAPPINGS2:t_ECG_Z_FU.QT__)

6. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_Z_FU.QTC__) (MAPPINGS2:t_ECG_Z_FU.QTC__)

7. Method of QTc Calculation (MAPPINGS1:t_ECG_Z_FU.EGMTCLCD) (MAPPINGS2:t_ECG_Z_FU.EGMTCLCD) [1] Machine [2] Manual

8. Result of the ECG (MAPPINGS1:t_ECG_Z_FU.EGINTPCD) (MAPPINGS2:t_ECG_Z_FU.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available)

Form Design Note:

Follow-up ECG

CDD: MAPPINGS1 Table: t_ECG_Z_FU Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1)

CDD: MAPPINGS2 Table: t_ECG_Z_FU Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1)

Annotated Trial Design Page 85 of 166

IPC103711_SHZ : STATUS OF TREATMENT BLIND (Blind) STATUS OF TREATMENT BLIND 1. Was the treatment blind broken during the study?If yes, complete the Adverse Event form and/or Investigational Product forms (MAPPINGS1:t_BLIND.BLBRK) as appropriate (MAPPINGS2:t_BLIND.BLBRK) Hr:Min (00:00-23:59) [N] No [Y] Yes, complete the following : Date/time blind broken Req / Req / Req (2007-2009) (MAPPINGS1:t_BLIND.BLDTTM) (MAPPINGS2:t_BLIND.BLDTTM) NReq : NReq 24-hour clock (MAPPINGS1:t_BLIND.BLREASCD) (MAPPINGS2:t_BLIND.BLREASCD) Reason blind broken [1] Medical emergency requiring identification of investigational product for further treatment [Z] Other, specify (MAPPINGS1:t_BLIND.BLRSOTH) (MAPPINGS2:t_BLIND.BLRSOTH) A200

Item Design Notes:

Item No. Design Note

1. Time blind broken is optional

CDD: MAPPINGS1 Table: t_BLIND Key Type: PATIENTVISIT Column Name Column Data Type Design Note BLBRK STRING(1) BLDTTM DATE - DDMONYYYY HHMM BLREASCD STRING(1) BLRSOTH STRING(200) - A200

CDD: MAPPINGS2 Table: t_BLIND Key Type: PATIENTVISIT Column Name Column Data Type Design Note BLBRK STRING(1) BLDTTM DATE - DDMONYYYY HHMM BLREASCD STRING(1) BLRSOTH STRING(200) - A200

Annotated Trial Design Page 86 of 166

IPC103711_SHZ : STUDY CONCLUSION (Conclusion)

1. Date of subject completion or date and time of subject withdrawal Req / Req / Req (2007-2009) (MAPPINGS1:t_DISPOSIT.DSDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_DISPOSIT.DSDTTM) NReq : NReq 24-hour clock

2. Was the subject withdrawn from the study? (MAPPINGS1:t_DISPOSIT.DSWD) (MAPPINGS2:t_DISPOSIT.DSWD) [N] No [Y] (MAPPINGS1:t_DISPOSIT.DSREASCD) (MAPPINGS2:t_DISPOSIT.DSREASCD) Yes, specify primary reason for withdrawal [1] Adverse event [2] Lost to follow-up [3] Protocol violation [4] Subject decided to withdraw from the study [6] Sponsor terminated study [Z] Other, specify A200 (MAPPINGS1:t_DISPOSIT.DSRSOTH) (MAPPINGS2:t_DISPOSIT.DSRSOTH)

3.* Case book ready for signature [hidden] (MAPPINGS1:t_DISPOSIT.chkReadyForSig) (MAPPINGS2:t_DISPOSIT.chkReadyForSig) [Y] Yes Data owner should check the box when data cleaning is complete

Office Use 1 [hidden] (MAPPINGS1:t_DISPOSIT.COMPLETERADIO) (MAPPINGS2:t_DISPOSIT.COMPLETERADIO) [N] No [Y] Yes

Office Use 2 [hidden] (MAPPINGS1:t_DISPOSIT.REASONRADIO) (MAPPINGS2:t_DISPOSIT.REASONRADIO) [?] 1 [?] 2 [?] 3 [?] 4 [?] 5 [?] 6 [?] 7 [?] 8 [?] 9

* Item is not required

CDD: MAPPINGS1 Table: t_DISPOSIT Key Type: PATIENTVISIT Column Name Column Data Type Design Note DSDTTM DATE - DDMONYYYY HHMM DSWD STRING(1) DSREASCD STRING(1) DSRSOTH STRING(200) - A200 chkReadyForSig STRING(255) COMPLETERADIO STRING(1) REASONRADIO STRING(42)

CDD: MAPPINGS2 Table: t_DISPOSIT Key Type: PATIENTVISIT Column Name Column Data Type Design Note DSDTTM DATE - DDMONYYYY HHMM DSWD STRING(1) DSREASCD STRING(1) DSRSOTH STRING(200) - A200 chkReadyForSig STRING(255) COMPLETERADIO STRING(1) REASONRADIO STRING(42)

Annotated Trial Design Page 87 of 166

IPC103711_SHZ : PREGNANCY INFORMATION (Preg F) PREGNANCY INFORMATION 1. Did the subject become pregnant during the study? (MAPPINGS1:t_STATUS_PREG_F.PGYN) If Yes, complete the paper Pregnancy Notification form (MAPPINGS2:t_STATUS_PREG_F.PGYN) [N] No [Y] Yes

Form Design Note:

This is an optional form but is conditional upon females in the trial; This form will be dynamically generated to appear at the End visit if Female is selected on the Demographics form

CDD: MAPPINGS1 Table: t_STATUS_PREG_F Key Type: PATIENTVISIT Column Name Column Data Type Design Note PGYN STRING(1)

CDD: MAPPINGS2 Table: t_STATUS_PREG_F Key Type: PATIENTVISIT Column Name Column Data Type Design Note PGYN STRING(1)

Annotated Trial Design Page 88 of 166

IPC103711_SHZ : LOGS AND REPEATS (Logs/Rpts) Date below is the start of the study for this subject DATE OF VISIT/ASSESSMENT

1. Date of visit/assessment Req / Req / Req (2007-2009) (MAPPINGS1:t_STATUS_LOGS.DOV) (MAPPINGS2:t_STATUS_LOGS.DOV)

ADVERSE EVENT/CONCOMITANT MEDICATION/REPEAT ASSESSMENT CHECK QUESTIONS 2. Were any concomitant medications taken by the subject during the study? (MAPPINGS1:t_STATUS_LOGS.CMANY) (MAPPINGS2:t_STATUS_LOGS.CMANY) [Y] Yes [N] No

3. Did the subject experience any non-serious adverse events during the study? (MAPPINGS1:t_STATUS_LOGS.AEANY) (MAPPINGS2:t_STATUS_LOGS.AEANY) [Y] Yes [N] No

4. Did the subject experience any serious adverse events during the study? (MAPPINGS1:t_STATUS_LOGS.SAEANY) (MAPPINGS2:t_STATUS_LOGS.SAEANY) [Y] Yes [N] No

5. Were any repeat haematology or clinical chemistry samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

6. Were any repeat urinalysis samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

7. Were any repeat ECGs performed? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

8. Were any abnormal, clinically significant ECG measurements recorded for this subject during the study? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

9. Were any repeat vital signs recorded? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

10. Were any repeat PD samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

11. Were any repeat Pulmonary Function Tests performed? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

12. Were any repeat PK blood samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No

CDD: MAPPINGS1 Table: t_STATUS_LOGS Key Type: PATIENTTOITEM Column Name Column Data Type Design Note DOV DATE - DDMONYYYY CMANY STRING(1) AEANY STRING(1) SAEANY STRING(1) rdcRptTrigger STRING(1)

CDD: MAPPINGS2 Table: t_STATUS_LOGS Key Type: PATIENTTOITEM Column Name Column Data Type Design Note DOV DATE - DDMONYYYY CMANY STRING(1) AEANY STRING(1) SAEANY STRING(1) rdcRptTrigger STRING(1)

Annotated Trial Design Page 89 of 166

IPC103711_SHZ : CONCOMITANT MEDICATIONS (Con Meds) - Repeating Form # Sequence Number Drug Name Unit Dose Units Frequency Route Reason for Medication Start Date and Time Taken Prior to Study? Ongoing?

(Trade Name preferred) 1

CONCOMITANT MEDICATIONS Sequence Number (MAPPINGS1:t_CONMEDS.CMSEQ) (MAPPINGS2:t_CONMEDS.CMSEQ)

1. Drug Name (MAPPINGS1:t_CONMEDS.CMTERM) A100 (MAPPINGS2:t_CONMEDS.CMTERM) (Trade Name preferred) * Modified reported term [hidden] (CM_CODE:0.LogsRpts.CONMEDS.sctCM.0.itmCMDRGCOL.CMDRGCOL) 2. A100 (CM_FAILED:0.LogsRpts.CONMEDS.sctCM.0.itmCM_FAILED.calCM_FAILED) (CM_SYNONYM:0.LogsRpts.CONMEDS.sctCM.0.itmCMDRGSYN.CMDRGSYN) (MAPPINGS1:t_CONMEDS.CMMODIFY) (MAPPINGS2:t_CONMEDS.CMMODIFY)

GSK Drug synonym [hidden] (MAPPINGS1:t_CONMEDS.CMDRGSYN) (MAPPINGS2:t_CONMEDS.CMDRGSYN)

GSK Drug Collection code [hidden] (MAPPINGS1:t_CONMEDS.CMDRGCOL) (MAPPINGS2:t_CONMEDS.CMDRGCOL)

Failed coding [hidden] (MAPPINGS1:t_CONMEDS.calCM_FAILED) (MAPPINGS2:t_CONMEDS.calCM_FAILED)

3. Unit Dose A10 (MAPPINGS1:t_CONMEDS.CMUDOS) (MAPPINGS2:t_CONMEDS.CMUDOS)

4. Units Pulldown List 1 (MAPPINGS1:t_CONMEDS.CMUNIT) (MAPPINGS2:t_CONMEDS.CMUNIT)

5. Frequency Pulldown List 2 (MAPPINGS1:t_CONMEDS.CMFREQ) (MAPPINGS2:t_CONMEDS.CMFREQ)

6. Route Pulldown List 3 (MAPPINGS1:t_CONMEDS.CMROUTCD) (MAPPINGS2:t_CONMEDS.CMROUTCD)

7. Reason for Medication (MAPPINGS1:t_CONMEDS.CMREAS) A70 (MAPPINGS2:t_CONMEDS.CMREAS)

8. Start Date and Time Req/Unk / Req/Unk / Req/Unk (1970-2009) (MAPPINGS1:t_CONMEDS.CMSTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_CONMEDS.CMSTDTTM) NReq : NReq 24-hour clock

9. Taken Prior to Study? (MAPPINGS1:t_CONMEDS.CMPRIOR) (MAPPINGS2:t_CONMEDS.CMPRIOR) [Y] Yes [N] No

10. Ongoing? (MAPPINGS1:t_CONMEDS.CMONGO) Hr:Min (00:00-23:59) (MAPPINGS2:t_CONMEDS.CMONGO) [Y] Yes [N] No, specify End Date and Time Req/Unk / Req/Unk / Req/Unk (2007-2009) (MAPPINGS1:t_CONMEDS.CMENDTTM) (MAPPINGS2:t_CONMEDS.CMENDTTM) NReq : NReq 24-hour clock

* Item is not required

Item Design Notes:

Item No. Design Note

3. This item is conditional

Pulldown List 1: RefName Display Text Value Design Note mestrUnitACTU Actuation ACTU mestrUnitAMP Ampoule AMP Annotated Trial Design Page 90 of 166

mestrUnitAPP Application APP mestrUnitAUC Area under curve AUC mestrUnitBOT Bottle BOT mestrUnitCAP Capsule CAP mestrUnitCC Cubic centimeter CC mestrUnitCUP Cup CUP mestrUnitGAKGM Gamma per kilogram per minute GA/KG/MIN mestrUnitGM Gram G mestrUnitGTT Drops GTT mestrUnitHIUML 100 International units/ml 100IU/ML mestrUnitINH Inhalation INH mestrUnitIU International units IU mestrUnitIUKG International units per kilogram IU/KG mestrUnitIUKGH International units per kilogram per hour IU/KG/HR mestrUnitIUML International units per millilitre IU/ML mestrUnitL Litre L mestrUnitLOZ Lozenge LOZ mestrUnitLPM Litre per minute L/MIN mestrUnitMAC Minimum alveolar concentration MAC mestrUnitMBQ Mega becquerels (MBq) MBQ mestrUnitMCG Microgram (MCG) MCG mestrUnitMCGH Micrograms per hour MCG/HR mestrUnitMCGKG Microgram/kilogram MCG/KG mestrUnitMCGKGMIN Microgram/kilogram per minute MCG/KG/MIN mestrUnitMCGMIN Micrograms per minute MCG/MIN mestrUnitMCGML Micrograms per millitre MCG/ML mestrUnitMCL Microlitre MCL mestrUnitMEQ Milliequivalent MEQ mestrUnitMEQ24HR Milliequivalent per 24 hours MEQ/24HR mestrUnitMG Milligram MG mestrUnitMGD Milligram per day MG/DAY mestrUnitMGHR Milligram per hour MG/HR mestrUnitMGKG Milligram/kilogram MG/KG mestrUnitMGKGHR Milligram/kilogram per hour MG/KG/HR mestrUnitMGKGMIN Milligram/kilogram per minute MG/KG/MIN mestrUnitMGM2 Milligram/metre squared MG/M2 mestrUnitMGML Milligram/millilitre MG/ML mestrUnitMGPER Milligrams percent MG% mestrUnitMIU Million international units MIU mestrUnitML Millilitre ML mestrUnitMLHR Millilitre per hour ML/HR mestrUnitMLMIN Millilitre per minute ML/MIN mestrUnitMMOL Millimole MMOL mestrUnitMU Megaunits (million units) MU mestrUnitNEB Nebule NEB mestrUnitOZ Ounce OZ mestrUnitPATCH Patch PATCH mestrUnitPer Percent % mestrUnitPUFF Puff PUFF mestrUnitSACH Sachet SACH mestrUnitSP Spray SPR Annotated Trial Design Page 91 of 166

mestrUnitSUPP Suppository SUPP mestrUnitTAB Tablet TAB mestrUnitTBSP Tablespoon TBLSP mestrUnitTSP Teaspoon TSP mestrUnitUG Microgram (UG) UG mestrUnitUHR Units per hour U/HR mestrUnitUKGM Units per kilogram per minute U/KG/MIN mestrUnitUMN Units per minute U/MIN mestrUnitUNIT Units U mestrUnitUNK Unknown UNK mestrUnitVIAL Vial VIAL

Pulldown List 2: RefName Display Text Value Design Note mestrFreq2XWK 2 times per week 2XWK mestrFreq3XWK 3 times per week 3XWK mestrFreq4XWK 4 times per week 4XWK mestrFreq5XD 5 times per day 5XD mestrFreq5XWK 5 times per week 5XWK mestrFreqAC AC AC mestrFreqBID BID BID mestrFreqCINF Continuous infusion CINF mestrFreqHS HS HS mestrFreqOD Once daily OD mestrFreqONE Once only ONE mestrFreqPC PC PC mestrFreqPRN PRN PRN mestrFreqQ12H Q12H Q12H mestrFreqQ2H Q2H Q2H mestrFreqQ2WK Every 2 weeks Q2WK mestrFreqQ3D Q3D Q3D mestrFreqQ3M Every 3 months Q3M mestrFreqQ3WK Every 3 weeks Q3WK mestrFreqQ4D Q4D Q4D mestrFreqQ4H Q4H Q4H mestrFreqQ6H Q6H Q6H mestrFreqQ8H Q8H Q8H mestrFreqQAM QAM QAM mestrFreqQH QH QH mestrFreqQID QID QID mestrFreqQM Once a month QM mestrFreqQOD Every other day QOD mestrFreqQPM QPM QPM mestrFreqQWK Once a week QWK mestrFreqTID TID TID mestrFreqUNK Unknown UNK

Pulldown List 3: RefName Display Text Value Design Note mestrRouteEP Epidural EP mestrRouteGTT Gastrostomy tube GTT Annotated Trial Design Page 92 of 166

mestrRouteIA Intra-arterial IA mestrRouteIART Intra-articular IART mestrRouteIB Intra-bursa IB mestrRouteID Intradermal ID mestrRouteIH Inhalation IH mestrRouteIL Intralesional ILES mestrRouteIM Intramuscular IM mestrRouteIN Intranasal IN mestrRouteINJ Injection INJ mestrRouteIO Intraocular IO mestrRouteIOS Intraosteal IOS mestrRouteIP Intraperitoneal IP mestrRouteIT Intrathecal IT mestrRouteIU Intrauterine IU mestrRouteIV Intravenous IV mestrRouteNG Nasogastric NG mestrRouteNS Nasal NS mestrRouteOD Right eye OD mestrRouteOP Ophthalmic OP mestrRouteOS Left eye OS mestrRouteOT Otic OT mestrRouteOTH Other OTH mestrRouteOU Both eyes OU mestrRoutePO Oral PO mestrRoutePR Rectal PR mestrRouteSC Subcutaneous SC mestrRouteSL Sublingual SL mestrRouteTD Transdermal TD mestrRouteTP Topical TP mestrRouteUNK Unknown UNK mestrRouteVG Vaginal VG

CDD: MAPPINGS1 Table: t_CONMEDS Key Type: PATIENTVISIT Column Name Column Data Type Design Note CMSEQ STRING(255) CMTERM STRING(100) - A100 CMMODIFY STRING(100) - A100 CMDRGSYN STRING(255) CMDRGCOL STRING(255) calCM_FAILED STRING(255) CMUDOS STRING(10) - A10 CMUNIT STRING(255) - ACTU, AMP, APP, AUC, BOT, CAP, CC, CUP, GA/KG/MIN, G, GTT, 100IU/ML, INH, IU, IU/KG, IU/KG/HR, IU/ML, L, LOZ, L/MIN, MAC, MBQ, MCG, MCG/HR, MCG/KG, MCG/KG/MIN, MCG/MIN, MCG/ML, MCL, MEQ, MEQ/24HR, MG, MG/DAY, MG/HR, MG/KG, MG/KG/HR, MG/KG/MIN, MG/M2, MG/ML, MG%, MIU, ML, ML/HR, ML/MIN, MMOL, MU, NEB, OZ, PATCH, %, PUFF, SACH, SPR, SUPP, TAB, TBLSP, TSP, UG, U/HR, U/KG/MIN, U/MIN, U, UNK, VIAL CMFREQ STRING(255) - 2XWK, 3XWK, 4XWK, 5XD, 5XWK, AC, BID, CINF, HS, OD, ONE, PC, PRN, Q12H, Q2H, Q2WK, Q3D, Q3M, Q3WK, Q4D, Q4H, Q6H, Q8H, QAM, QH, QID, QM, QOD, QPM, QWK, TID, UNK CMROUTCD STRING(255) - EP, GTT, IA, IART, IB, ID, IH, ILES, IM, IN, INJ, IO, IOS, IP, IT, IU, IV, NG, NS, OD, OP, OS, OT, OTH, OU, PO, PR, SC, SL, TD, TP, UNK, VG CMREAS STRING(70) - A70 CMSTDTTM DATE - DDMONYYYY HHMM CMPRIOR STRING(1) CMONGO STRING(1) CMENDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 93 of 166

CDD: MAPPINGS2 Table: t_CONMEDS Key Type: PATIENTVISIT Column Name Column Data Type Design Note CMSEQ STRING(255) CMTERM STRING(100) - A100 CMMODIFY STRING(100) - A100 CMDRGSYN STRING(255) CMDRGCOL STRING(255) calCM_FAILED STRING(255) CMUDOS STRING(10) - A10 CMUNIT STRING(255) - ACTU, AMP, APP, AUC, BOT, CAP, CC, CUP, GA/KG/MIN, G, GTT, 100IU/ML, INH, IU, IU/KG, IU/KG/HR, IU/ML, L, LOZ, L/MIN, MAC, MBQ, MCG, MCG/HR, MCG/KG, MCG/KG/MIN, MCG/MIN, MCG/ML, MCL, MEQ, MEQ/24HR, MG, MG/DAY, MG/HR, MG/KG, MG/KG/HR, MG/KG/MIN, MG/M2, MG/ML, MG%, MIU, ML, ML/HR, ML/MIN, MMOL, MU, NEB, OZ, PATCH, %, PUFF, SACH, SPR, SUPP, TAB, TBLSP, TSP, UG, U/HR, U/KG/MIN, U/MIN, U, UNK, VIAL CMFREQ STRING(255) - 2XWK, 3XWK, 4XWK, 5XD, 5XWK, AC, BID, CINF, HS, OD, ONE, PC, PRN, Q12H, Q2H, Q2WK, Q3D, Q3M, Q3WK, Q4D, Q4H, Q6H, Q8H, QAM, QH, QID, QM, QOD, QPM, QWK, TID, UNK CMROUTCD STRING(255) - EP, GTT, IA, IART, IB, ID, IH, ILES, IM, IN, INJ, IO, IOS, IP, IT, IU, IV, NG, NS, OD, OP, OS, OT, OTH, OU, PO, PR, SC, SL, TD, TP, UNK, VG CMREAS STRING(70) - A70 CMSTDTTM DATE - DDMONYYYY HHMM CMPRIOR STRING(1) CMONGO STRING(1) CMENDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 94 of 166

IPC103711_SHZ : NON-SERIOUS ADVERSE EVENT (AE) - Repeating Form # Event Start Date and Time Outcome Frequency Maximum Intensity Action Taken Subject Withdrawn? Relationship 1

NON-SERIOUS ADVERSE EVENT

1.* Sequence Number [hidden] A5 (MAPPINGS1:t_AE.AESEQ) (MAPPINGS2:t_AE.AESEQ)

2. Event (MAPPINGS1:t_AE.AETERM) A100 Diagnosis Only (if known) Otherwise Sign/Symptom (MAPPINGS2:t_AE.AETERM)

* Modified term [hidden] (AE_CODE:0.LogsRpts.AE.sctAE.0.itmAELLTCD.AELLTCD) 3. A100 (AE_FAILED:0.LogsRpts.AE.sctAE.0.itmAE_FAILED.calAE_FAILED) (AE_SYNONYM:0.LogsRpts.AE.sctAE.0.itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE.AEMODIFY) (MAPPINGS2:t_AE.AEMODIFY)

MedDRA synonym [hidden] (MAPPINGS1:t_AE.AEMEDSYN) (MAPPINGS2:t_AE.AEMEDSYN)

MedDRA lower level term code [hidden] (MAPPINGS1:t_AE.AELLTCD) (MAPPINGS2:t_AE.AELLTCD)

Failed coding [hidden] (MAPPINGS1:t_AE.calAE_FAILED) (MAPPINGS2:t_AE.calAE_FAILED)

4. Start Date and Time Req / Req / Req (2007-2009) (MAPPINGS1:t_AE.AESTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_AE.AESTDTTM) NReq : NReq 24-hour clock

5. Outcome / End Date and Time (MAPPINGS1:t_AE.AEOUTCD) Hr:Min (00:00-23:59) (MAPPINGS2:t_AE.AEOUTCD) [1] Recovered/Resolved, provide End Date and Time Req / Req / Req (2007-2009) (MAPPINGS1:t_AE.AEENDTTM1) (MAPPINGS2:t_AE.AEENDTTM1) NReq : NReq 24-hour clock [2] Recovering/Resolving [3] Not recovered/Not resolved [4] Recovered/Resolved with sequelae, provide End Date and Time Req / Req / Req (2007-2009) (MAPPINGS1:t_AE.AEENDTTM2) (MAPPINGS2:t_AE.AEENDTTM2) NReq : NReq 24-hour clock

6. Frequency (MAPPINGS1:t_AE.AEFREQCD) (MAPPINGS2:t_AE.AEFREQCD) [1] Single Episode [2] Intermittent

7.* Maximum Intensity (MAPPINGS1:t_AE.AESEVCD) (MAPPINGS2:t_AE.AESEVCD) [1] Mild [2] Moderate [3] Severe [X] Not applicable

8.* Maximum Grade [hidden] (MAPPINGS1:t_AE.AETOXCD) (MAPPINGS2:t_AE.AETOXCD) [1] Grade 1 [2] Grade 2 [3] Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable

9.* Maximum Grade or Intensity [hidden] (MAPPINGS1:t_AE.AETXHVCD) (MAPPINGS2:t_AE.AETXHVCD) [1] Mild or Grade 1 [2] Moderate or Grade 2 [3] Severe or Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable

10. Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE.AEACTRCD) Annotated Trial Design Page 95 of 166

(MAPPINGS2:t_AE.AEACTRCD) [1] Investigational product(s) withdrawn [2] Dose reduced [3] Dose increased [4] Dose not changed [5] Dose interrupted [X] Not applicable

11. Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE.AEWD) (MAPPINGS2:t_AE.AEWD) [Y] Yes [N] No

12. Is there a reasonable possibility that the AE may have been caused by the investigational product? (MAPPINGS1:t_AE.AEREL) (MAPPINGS2:t_AE.AEREL) [Y] Yes [N] No

13.* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 ) (MAPPINGS1:t_AE.AEDURHR) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE.AEDURMIN) (MAPPINGS2:t_AE.AEDURHR) (MAPPINGS2:t_AE.AEDURMIN) Hr(s) Min(s)

14.* Time to Onset Since Last Dose [hidden] xx (MAPPINGS1:t_AE.AEONLDSH) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE.AEONLDSM) (MAPPINGS2:t_AE.AEONLDSH) (MAPPINGS2:t_AE.AEONLDSM) Hr(s) Min(s)

* Item is not required

Form Design Note:

IDSL Version 03.01A - 16 NOV 2005

Item Design Notes:

Item No. Design Note

4. Start Time is optional

5. End Time is optional

6. This item is optional

7. Optional item: This item may be hidden if either the "Maximum Grade" or "Maximum Grade or Intensity" item has been used. Grade 5 is optional.

8. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade or Intensity" item has been used Grade 5 is optional.

9. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade" item has been used Grade 5 is optional.

13. If AE start and end time are used this item must be hidden.

14. This item is optional

CDD: MAPPINGS1 Table: t_AE Key Type: PATIENTVISIT Column Name Column Data Type Design Note AESEQ STRING(5) - A5 AETERM STRING(100) - A100 AEMODIFY STRING(100) - A100 AEMEDSYN STRING(255) AELLTCD STRING(255) calAE_FAILED STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM Annotated Trial Design Page 96 of 166

AEENDTTM2 DATE - DDMONYYYY HHMM AEFREQCD STRING(1) AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2

CDD: MAPPINGS2 Table: t_AE Key Type: PATIENTVISIT Column Name Column Data Type Design Note AESEQ STRING(5) - A5 AETERM STRING(100) - A100 AEMODIFY STRING(100) - A100 AEMEDSYN STRING(255) AELLTCD STRING(255) calAE_FAILED STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM AEFREQCD STRING(1) AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2

Annotated Trial Design Page 97 of 166

IPC103711_SHZ : SERIOUS ADVERSE EVENTS (SAE) - Repeating Form # Initial Follow-Up Did SAE occur after SERIOUS Serious? RELEVANT RELEVANT MEDICAL Relevant RELEVANT Relevant If Investigational product(s) Report Report initiation of study ADVERSE CONCOMITANT/TREATMENT CONDITIONS/RISK Medical DIAGNOSTIC diagnostic stopped, did the reported event(s) medication? EVENT MEDICATIONS FACTORS History / Risk RESULTS results recur after further investigational Factors product(s) were administered? 1

If you wish to record a new SAE please determine if the new SAE is clinically or temporally related to an SAE previously entered on this form. If yes, record the details below using the 'Add Entry' button in this form. If not clinically or temporally related, create a new SAE form for this subject by clicking on the 'New' button at the top of the page. Do not record pre and post randomization events on the same form. TYPE OF REPORT

1.* Initial Report (MAPPINGS1:t_AE_SER.chkSAE) [read-only] (MAPPINGS2:t_AE_SER.chkSAE) [1] Initial

2.* Follow-Up (MAPPINGS1:t_AE_SER.chkFU) Report [read- (MAPPINGS2:t_AE_SER.chkFU) only] [2] Follow-Up

RANDOMISATION 3. Did SAE occur (MAPPINGS1:t_AE_SER.rdcSAERAND) after initiation (MAPPINGS2:t_AE_SER.rdcSAERAND) of study [N] No medication? [Y] Yes

SAE Event Modified MedDRA MedDRA Failed Start Outcome Maximum Maximum Maximum Action Subject Relationship Duration Time to Sequence term synonym lower coding Date Intensity Grade Grade or Taken Withdrawn? of AE if Onset Number level term and Intensity < 24 code Time hours 4. [hidden] [hidden][hidden][hidden][hidden] [hidden][hidden] [hidden][hidden SERIOUS ADVERSE EVENT Entry

4.a* SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESEQ) (MAPPINGS2:t_AE_SER.AESEQ)

4.b Serious Adverse Event (MAPPINGS1:t_AE_SER.AETERM) A100 Diagnosis Only (if known) Otherwise Sign/Symptom (MAPPINGS2:t_AE_SER.AETERM)

* Modified term [hidden] (AE_CODE1:0.LogsRpts.AE_SER.sctSAE.itsSAE.itmAELLTCD.AELLTCD) 4.c A100 (AE_FAILED1:0.LogsRpts.AE_SER.sctSAE.itsSAE.itmAE_FAILED.calAE_FAILED) (AE_SYNONYM1:0.LogsRpts.AE_SER.sctSAE.itsSAE.itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE_SER.AEMODIFY) (MAPPINGS2:t_AE_SER.AEMODIFY)

MedDRA synonym [hidden] (MAPPINGS1:t_AE_SER.AEMEDSYN) (MAPPINGS2:t_AE_SER.AEMEDSYN)

MedDRA lower level term code [hidden] (MAPPINGS1:t_AE_SER.AELLTCD) (MAPPINGS2:t_AE_SER.AELLTCD)

Failed coding [hidden] (MAPPINGS1:t_AE_SER.calAE_FAILED) (MAPPINGS2:t_AE_SER.calAE_FAILED)

4.d Start Date and Time Req / Req / Req (2007-2009) (MAPPINGS1:t_AE_SER.AESTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_AE_SER.AESTDTTM) NReq : NReq 24-hour clock

4.e Outcome / End Date and Time (MAPPINGS1:t_AE_SER.AEOUTCD1) Hr:Min (00:00-23:59) (MAPPINGS2:t_AE_SER.AEOUTCD1) [1] Recovered/Resolved, provide End Date and Time Req / Req / Req (2007-2009) (MAPPINGS1:t_AE_SER.AEENDTTM1) (MAPPINGS2:t_AE_SER.AEENDTTM1) NReq : NReq 24-hour clock [2] Recovering/Resolving [3] Not recovered/Not resolved [4] Recovered/Resolved with sequelae, provide End Date and Time Req / Req / Req (2007-2009) (MAPPINGS1:t_AE_SER.AEENDTTM2) (MAPPINGS2:t_AE_SER.AEENDTTM2) NReq : NReq 24-hour clock [5] Fatal, record Date and Time of Death Req / Req / Req (2007-2010) (MAPPINGS1:t_AE_SER.AEENDTTM3) (MAPPINGS2:t_AE_SER.AEENDTTM3) NReq : NReq 24-hour clock

Maximum Intensity (MAPPINGS1:t_AE_SER.AESEVCD) Annotated Trial Design Page 98 of 166

4.f* (MAPPINGS2:t_AE_SER.AESEVCD) [1] Mild [2] Moderate [3] Severe [X] Not applicable

4.g* Maximum Grade [hidden] (MAPPINGS1:t_AE_SER.AETOXCD) (MAPPINGS2:t_AE_SER.AETOXCD) [1] Grade 1 [2] Grade 2 [3] Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable

4.h* Maximum Grade or Intensity [hidden] (MAPPINGS1:t_AE_SER.AETXHVCD) (MAPPINGS2:t_AE_SER.AETXHVCD) [1] Mild or Grade 1 [2] Moderate or Grade 2 [3] Severe or Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable

4.i Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE_SER.AEACTRCD) (MAPPINGS2:t_AE_SER.AEACTRCD) [1] Investigational product(s) withdrawn [2] Dose reduced [3] Dose increased [4] Dose not changed [5] Dose interrupted [X] Not applicable

4.j Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE_SER.AEWD) (MAPPINGS2:t_AE_SER.AEWD) [Y] Yes [N] No

4.k Is there a reasonable possibility that the AE may have been caused by the investigational product? (MAPPINGS1:t_AE_SER.AEREL) (MAPPINGS2:t_AE_SER.AEREL) [Y] Yes [N] No

4.l* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 ) (MAPPINGS1:t_AE_SER.AEDURHR) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE_SER.AEDURMIN) (MAPPINGS2:t_AE_SER.AEDURHR) (MAPPINGS2:t_AE_SER.AEDURMIN) Hr(s) Min(s)

4.m* Time to Onset Since Last Dose [hidden] xx (MAPPINGS1:t_AE_SER.AEONLDSH) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE_SER.AEONLDSM) (MAPPINGS2:t_AE_SER.AEONLDSH) (MAPPINGS2:t_AE_SER.AEONLDSM) Hr(s) Min(s)

4.n Was SAE caused by activities related to study participation (e.g. procedures)? (MAPPINGS1:t_AE_SER.rdcAESREL) (MAPPINGS2:t_AE_SER.rdcAESREL) [Y] Yes [N] No

4.o* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESER) (MAPPINGS2:t_AE_SER.AESER) [Y] Yes [N] No SERIOUSNESS Specify the reason for considering this an SAE. Check all that apply. 5. Seriousness? (MAPPINGS1:t_AE_SER.AESERDTH) (MAPPINGS2:t_AE_SER.AESERDTH) [A] Results in death (MAPPINGS1:t_AE_SER.AESERLIF) (MAPPINGS2:t_AE_SER.AESERLIF) [B] Is life-threatening (MAPPINGS1:t_AE_SER.AESERHOS) (MAPPINGS2:t_AE_SER.AESERHOS) [C] Requires hospitalisation or prolongation of existing hospitalisation (MAPPINGS1:t_AE_SER.AESERDIS) (MAPPINGS2:t_AE_SER.AESERDIS) [D] Results in disability/incapacity Annotated Trial Design Page 99 of 166

(MAPPINGS1:t_AE_SER.AESERCON) (MAPPINGS2:t_AE_SER.AESERCON) [E] Congenital anomaly/birth defect (MAPPINGS1:t_AE_SER.AESEROTH) (MAPPINGS2:t_AE_SER.AESEROTH) [F] Other, specify within general narrative comment

CM Sequence Drug Name Dose Unit Frequency Route Start Ongoing? Primary Drug Number Date Indication Type (Trade Name preferred) 6. [hidden] RELEVANT CONCOMITANT/TREATMENT MEDICATIONS Entry Include details of any medication that may have contributed to the SAE or was used to treat the SAE.

6.a* CM Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAECMSEQ) (MAPPINGS2:t_AE_SER.txtSAECMSEQ)

6.b Drug Name (MAPPINGS1:t_AE_SER.txtCMTERM) A100 (MAPPINGS2:t_AE_SER.txtCMTERM) (Trade Name preferred)

6.c* Dose xxxxxxxxx. (MAPPINGS1:t_AE_SER.txtSAECMDOS) (MAPPINGS2:t_AE_SER.txtSAECMDOS)

6.d* Unit Pulldown List 1 (MAPPINGS1:t_AE_SER.pdcCMUNIT) (MAPPINGS2:t_AE_SER.pdcCMUNIT)

6.e* Frequency Pulldown List 2 (MAPPINGS1:t_AE_SER.pdcSAECMFRQ) (MAPPINGS2:t_AE_SER.pdcSAECMFRQ)

6.f* Route Pulldown List 3 (MAPPINGS1:t_AE_SER.pdcCMROUTCD) (MAPPINGS2:t_AE_SER.pdcCMROUTCD)

6.g* Start Date Req/Unk / Req/Unk / Req/Unk (1970-2010) (MAPPINGS1:t_AE_SER.dtmSAECMSTD) (MAPPINGS2:t_AE_SER.dtmSAECMSTD)

6.h* Ongoing? (MAPPINGS1:t_AE_SER.rdcSAECMONG) (MAPPINGS2:t_AE_SER.rdcSAECMONG) [Y] Yes [N] No, specify End Date Req/Unk / Req/Unk / Req/Unk (1970- (MAPPINGS1:t_AE_SER.dtmSAECMEND) 2010) (MAPPINGS2:t_AE_SER.dtmSAECMEND)

6.i* Primary Indication A50 (MAPPINGS1:t_AE_SER.txtCMIND) (MAPPINGS2:t_AE_SER.txtCMIND)

6.j Drug Type Pulldown List 4 (MAPPINGS1:t_AE_SER.pdcCMDRGTYP) (MAPPINGS2:t_AE_SER.pdcCMDRGTYP)

MHx Specific Condition Name Date of Continuing? Sequence onset Number 7. [hidden] RELEVANT MEDICAL CONDITIONS/RISK FACTORS Entry Specify past or current medical disorders, allergies, surgeries, family or social history that may help explain the SAE

7.a* MHx Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtMHXSEQ) (MAPPINGS2:t_AE_SER.txtMHXSEQ)

7.b Specific Condition Name (MAPPINGS1:t_AE_SER.txtSAEMHTRM) A100 (MAPPINGS2:t_AE_SER.txtSAEMHTRM)

7.c* Date of onset Req/Unk / Req/Unk / Req (1970-2010) (MAPPINGS1:t_AE_SER.dtmMHSTDTM) (MAPPINGS2:t_AE_SER.dtmMHSTDTM)

7.d* Continuing? (MAPPINGS1:t_AE_SER.rdcMHCONT) (MAPPINGS2:t_AE_SER.rdcMHCONT) [Y] Yes [N] No, specify date of last occurrence Req/Unk / Req/Unk / Req (1970- (MAPPINGS1:t_AE_SER.dtmMHLSTOC) 2010) (MAPPINGS2:t_AE_SER.dtmMHLSTOC) [U] Unknown

* 8. Relevant A1000 Medical History / Risk Factors not noted above Annotated Trial Design Page 100 of 166

Lab Test Name Test Test Result Test Units Normal Normal Sequence Date Low High Number Range Range 9. [hidden] RELEVANT DIAGNOSTIC RESULTS Entry Provide details of any tests or procedures carried out to diagnose the SAE.

9.a* Lab Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAELBSEQ) (MAPPINGS2:t_AE_SER.txtSAELBSEQ)

9.b Test Name Pulldown List 5 (MAPPINGS1:t_AE_SER.pdcLBTST) (MAPPINGS2:t_AE_SER.pdcLBTST)

9.c Test Date Req/Unk / Req/Unk / Req (2007- (MAPPINGS1:t_AE_SER.dtmLABDTM) 2010) (MAPPINGS2:t_AE_SER.dtmLABDTM)

9.d Test Result A50 (MAPPINGS1:t_AE_SER.txtLABRES) (MAPPINGS2:t_AE_SER.txtLABRES)

9.e* Test Units A35 (MAPPINGS1:t_AE_SER.txtLABUNIT) (MAPPINGS2:t_AE_SER.txtLABUNIT)

9.f* Normal Low Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNLR) (MAPPINGS2:t_AE_SER.txtLABNLR)

9.g* Normal High Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNHR) (MAPPINGS2:t_AE_SER.txtLABNHR)

* 10. Relevant A1000 diagnostic results not noted above A1000

INVESTIGATIONAL PRODUCTS

11.* If (MAPPINGS1:t_AE_SER.rdcSAEIP) Investigational (MAPPINGS2:t_AE_SER.rdcSAEIP) product(s) [N] No stopped, did [Y] Yes the reported event(s) recur [U] Unknown at this time after further [X] Not applicable investigational product(s) were administered? GENERAL NARRATIVE COMMENTS Provide a brief narrative description of SAE, possible other causes of the event (e.g. lack of efficacy, withdrawal of investigational product, the disease under study or other medical conditions) and details of the treatment.

12. General A1000 narrative comments

A1000

NON CLINICAL

13.* Send (MAPPINGS1:t_AE_SER.chkSAESENDI) incomplete (MAPPINGS2:t_AE_SER.chkSAESENDI) SAE data to [3] Incomplete SAE GSK Safety [hidden]

14.* Receipt by Req / Req / Req (2007- (MAPPINGS1:t_AE_SER.dtmSAEDTM) GSK date 2010) (MAPPINGS2:t_AE_SER.dtmSAEDTM) [hidden] Req : Req 24-hour clock

15.* Was the event (MAPPINGS1:t_AE_SER.AESE1) serious? (MAPPINGS2:t_AE_SER.AESER) [hidden] [Y] Yes [N] No Annotated Trial Design Page 101 of 166

16.* SAE Sequence A5 (MAPPINGS1:t_AE_SER.AESE2) Number (MAPPINGS2:t_AE_SER.AESEQ) [hidden]

17.* Version A4 (MAPPINGS1:t_AE_SER.txtSAEVERSION) Number (MAPPINGS2:t_AE_SER.txtSAEVERSION) [hidden]

18.* Case ID A20 (MAPPINGS1:t_AE_SER.txtSAEID) [hidden] (MAPPINGS2:t_AE_SER.txtSAEID)

19.* Randomisation A255 (MAPPINGS1:t_AE_SER.txtSAERNDNO) Number (MAPPINGS2:t_AE_SER.txtSAERNDNO) [hidden]

20.* OCEANS Code A13 (MAPPINGS1:t_AE_SER.txtOCEANSCD) [hidden] (MAPPINGS2:t_AE_SER.txtOCEANSCD)

Email Flag (MAPPINGS1:t_AE_SER.calSAEEmailFlag) [hidden] (MAPPINGS2:t_AE_SER.calSAEEmailFlag)

* Item is not required

Form Design Note:

Version 05.04A - 18 OCT 2006

Item Design Notes:

Item No. Design Note

4.d Start Time is optional

4.e End Time is optional

4.f Optional item: This item may be hidden if either the "Maximum Grade" or "Maximum Grade or Intensity" item has been used. Grade 5 is optional.

4.g Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade or Intensity" item has been used Grade 5 is optional.

4.h Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade" item has been used Grade 5 is optional.

4.l If AE start and end time are used this item must be hidden.

4.m This item is optional

5. Optional Criterion G is an optional criterion and may be removed

13. This item is optional

Pulldown List 1: RefName Display Text Value Design Note estrSaeUnitACTU Actuation ACTU estrSaeUnitAMP Ampoule AMP estrSaeUnitAPP Application AP estrSaeUnitBOT Bottle BT estrSaeUnitCAP Capsule CAP estrSaeUnitCC Cubic centimeter CC estrSaeUnitGTT Drops 031 estrSaeUnitGM Gram 002 estrSaeUnitIU International units 025 estrSaeUnitIUKG International units per kilogram 028 estrSaeUnitIUML International units per millilitre IUML estrSaeUnitL Litre 011 Annotated Trial Design Page 102 of 166

estrSaeUnitLPM Litre per minute LM estrSaeUnitLOZ Lozenge LOZ estrSaeUnitMU Megaunits (million units) MEGU estrSaeUnitMCG Microgram (MCG) 004 estrSaeUnitUG Microgram (UG) 004 estrSaeUnitMCGKG Microgram/kilogram 008 estrSaeUnitMCGKGMIN Microgram/kilogram per minute MCG/KG/MIN estrSaeUnitMCGMIN Micrograms per minute MCG/MIN estrSaeUnitMCL Microlitre 013 estrSaeUnitMEQ Milliequivalent 029 estrSaeUnitMEQ24HR Milliequivalent per 24 hours MEQ24 estrSaeUnitMG Milligram 003 estrSaeUnitMGPER Milligrams percent MGPER estrSaeUnitMGHR Milligram per hour MGH estrSaeUnitMGKG Milligram/kilogram 007 estrSaeUnitMGKGHR Milligram/kilogram per hour MGKH estrSaeUnitMGKGMIN Milligram/kilogram per minute MGKM estrSaeUnitMGM2 Milligram/metre squared 009 estrSaeUnitMGML Milligram/millilitre MGML estrSaeUnitML Millilitre 012 estrSaeUnitMLHR Millilitre per hour MLH estrSaeUnitMLMIN Millilitre per minute MLM estrSaeUnitMMOL Millimole 023 estrSaeUnitMIU Million international units 027 estrSaeUnitMAC Minimum alveolar concentration MAC estrSaeUnitNEB Nebule NEB estrSaeUnitPATCH Patch PAT estrSaeUnitPer Percent 030 estrSaeUnitPUFF Puff PUFF estrSaeUnitSACH Sachet SAC estrSaeUnitSP Spray SPR estrSaeUnitSUPP Suppository SUP estrSaeUnitTBSP Tablespoon TBS estrSaeUnitTAB Tablet TAB estrSaeUnitTSP Teaspoon TSP estrSaeUnitUNIT Units UNT estrSaeUnitUNK Unknown U estrSaeUnitVIAL Vial VIA

Pulldown List 2: RefName Display Text Value Design Note estrSaeFreq2XWK 2 times per week 2W estrSaeFreq3XWK 3 times per week 3W estrSaeFreq4XWK 4 times per week 4W estrSaeFreq5XD 5 times per day 5D estrSaeFreq5XWK 5 times per week 5W estrSaeFreqAC AC AC estrSaeFreqBID BID 2D estrSaeFreqCINF Continuous infusion CO estrSaeFreqQ2WK Every 2 weeks FO estrSaeFreqQ3WK Every 3 weeks Q3WK Annotated Trial Design Page 103 of 166

estrSaeFreqQ3M Every 3 months Q3M estrSaeFreqQOD Every other day AD estrSaeFreqHS At Bedtime 1N estrSaeFreqQM Once a month MO estrSaeFreqQWK Once a week WE estrSaeFreqQD Once daily 1D estrSaeFreqONE Once only 1S estrSaeFreqPC PC PC estrSaeFreqPRN PRN PRN estrSaeFreqQ2H Q2H 12D estrSaeFreqQ3D Q3D Q3D estrSaeFreqQ4D Q4D Q4D estrSaeFreqQ4H Q4H 6D estrSaeFreqQ6H Q6H 4D estrSaeFreqQ8H Q8H 3D estrSaeFreqQ12H Q12H 2D estrSaeFreqQAM QAM 1M estrSaeFreqQH QH 24D estrSaeFreqQID QID 4D estrSaeFreqQPM QPM 1N estrSaeFreqTID TID 3D estrSaeFreqUNK Unknown U

Pulldown List 3: RefName Display Text Value Design Note estrSaeRouteOU Both eyes 047 estrSaeRouteEP Epidural 008 estrSaeRouteGTT Gastrostomy tube GT estrSaeRouteIH Inhalation 055 estrSaeRouteINJ Injection INJ estrSaeRouteIA Intra-arterial 013 estrSaeRouteIB Intra-bursa IBU estrSaeRouteIL Intralesional 026 estrSaeRouteIM Intramuscular 030 estrSaeRouteIN Intranasal 045 estrSaeRouteIO Intraocular 031 estrSaeRouteIOS Intraosteal IOS estrSaeRouteIP Intraperitoneal 033 estrSaeRouteIT Intrathecal 037 estrSaeRouteIU Intrauterine 015 estrSaeRouteIV Intravenous 042 estrSaeRouteNS Nasal 045 estrSaeRoutePO Oral 048 estrSaeRoutePR Rectal 054 estrSaeRouteSC Subcutaneous 058 estrSaeRouteSL Sublingual 060 estrSaeRouteTP Topical 061 estrSaeRouteTD Transdermal 062 estrSaeRouteUNK Unknown 065 estrSaeRouteVG Vaginal 067

Annotated Trial Design Page 104 of 166

Pulldown List 4: RefName Display Text Value Design Note estrDRUGTYPE01 Concomitant 2 estrDRUGTYPE02 Treatment T estrDRUGTYPE03 Cause of SAE 1

Pulldown List 5: RefName Display Text Value Design Note estrSAELBTST01 Activated partial thromboplastin time Activated partial thromboplastin time estrSAELBTST02 Albumin Albumin estrSAELBTST03 Alkaline phosphatase Alkaline phosphatase estrSAELBTST04 Amylase Amylase estrSAELBTST05 Basophils Basophils estrSAELBTST06 Bicarbonate Bicarbonate estrSAELBTST07 Bilirubin Bilirubin estrSAELBTST08 Bilirubin direct Bilirubin direct estrSAELBTST09 Bilirubin total Bilirubin total estrSAELBTST10 Blood myoglobin Blood myoglobin estrSAELBTST11 Blood pH Blood pH estrSAELBTST12 Blood pressure Blood pressure estrSAELBTST13 Blood urea nitrogen Blood urea nitrogen estrSAELBTST14 Body temperature Body temperature estrSAELBTST15 Calcium Calcium estrSAELBTST16 CD4 lymphocytes CD4 lymphocytes estrSAELBTST17 CD8 lymphocytes CD8 lymphocytes estrSAELBTST18 Chloride Chloride estrSAELBTST19 Cholesterol total Cholesterol total estrSAELBTST20 C-reactive protein C-reactive protein estrSAELBTST21 Creatine Creatine estrSAELBTST22 Creatine phosphokinase Creatine phosphokinase estrSAELBTST23 Creatine phosphokinase MB Creatine phosphokinase MB estrSAELBTST24 Creatinine Creatinine estrSAELBTST25 Creatinine clearance Creatinine clearance estrSAELBTST26 Diastolic blood pressure Diastolic blood pressure estrSAELBTST27 Eosinophils Eosinophils estrSAELBTST28 Erythrocyte sedimentation rate Erythrocyte sedimentation rate estrSAELBTST29 Fasting blood glucose Fasting blood glucose estrSAELBTST30 FEV 1 FEV 1 estrSAELBTST31 Gamma-glutamyltransferase Gamma-glutamyltransferase estrSAELBTST32 Glutamic-oxaloacetic transferase Glutamic-oxaloacetic transferase estrSAELBTST33 Glutamic-pyruvate transaminase Glutamic-pyruvate transaminase estrSAELBTST34 HbA1c HbA1c estrSAELBTST35 HBV-DNA decreased HBV-DNA decreased estrSAELBTST36 HBV-DNA increased HBV-DNA increased estrSAELBTST37 Heart rate Heart rate estrSAELBTST38 Hematocrit Hematocrit estrSAELBTST39 Hemoglobin Hemoglobin estrSAELBTST40 High density lipoprotein High density lipoprotein estrSAELBTST41 HIV viral load HIV viral load estrSAELBTST42 INR INR estrSAELBTST43 Lactic dehydrogenase Lactic dehydrogenase Annotated Trial Design Page 105 of 166

estrSAELBTST44 Lipase Lipase estrSAELBTST45 Low density lipoprotein Low density lipoprotein estrSAELBTST46 Lymphocytes Lymphocytes estrSAELBTST47 Magnesium Magnesium estrSAELBTST48 Mean cell hemoglobin concentration Mean cell hemoglobin concentration estrSAELBTST49 Mean corpuscular hemoglobin Mean corpuscular hemoglobin estrSAELBTST50 Mean corpuscular volume Mean corpuscular volume estrSAELBTST51 Monocytes Monocytes estrSAELBTST52 Neutrophils Neutrophils estrSAELBTST53 Oxygen saturation Oxygen saturation estrSAELBTST54 pCO2 pCO2 estrSAELBTST55 pH pH estrSAELBTST56 Phosphate Phosphate estrSAELBTST57 Platelet count Platelet count estrSAELBTST58 pO2 pO2 estrSAELBTST59 Potassium Potassium estrSAELBTST60 Protein total Protein total estrSAELBTST61 Prothrombin time Prothrombin time estrSAELBTST62 Red blood cell count Red blood cell count estrSAELBTST63 Respiratory rate Respiratory rate estrSAELBTST64 Reticulocyte count Reticulocyte count estrSAELBTST65 Serum glucose Serum glucose estrSAELBTST66 Serum uric acid Serum uric acid estrSAELBTST67 Sodium Sodium estrSAELBTST68 Systolic blood pressure Systolic blood pressure estrSAELBTST69 Thrombin time Thrombin time estrSAELBTST70 Total lung capacity Total lung capacity estrSAELBTST71 Triglycerides Triglycerides estrSAELBTST72 Troponin Troponin estrSAELBTST73 Troponin I Troponin I estrSAELBTST74 Troponin T Troponin T estrSAELBTST75 Urine myoglobin Urine myoglobin estrSAELBTST76 Urine pH Urine pH estrSAELBTST77 Vital capacity Vital capacity estrSAELBTST78 White blood cell count White blood cell count

CDD: MAPPINGS1 Table: t_AE_SER Key Type: PATIENTVISIT Column Name Column Data Type Design Note chkSAE STRING(255) chkFU STRING(255) rdcSAERAND STRING(1) AESEQ STRING(5) - A5 AETERM STRING(100) - A100 AEMODIFY STRING(100) - A100 AEMEDSYN STRING(255) AELLTCD STRING(255) calAE_FAILED STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD1 STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM Annotated Trial Design Page 106 of 166

AEENDTTM3 DATE - DDMONYYYY HHMM AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 rdcAESREL STRING(1) AESER STRING(1) AESERDTH STRING(255) AESERLIF STRING(255) AESERHOS STRING(255) AESERDIS STRING(255) AESERCON STRING(255) AESEROTH STRING(255) txtSAECMSEQ STRING(4) - A4 txtCMTERM STRING(100) - A100 txtSAECMDOS FLOAT - F10.0 pdcCMUNIT STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 031, 002, 025, 028, IUML, 011, LM, LOZ, MEGU, 004, 004, 008, MCG/KG/MIN , MCG/MIN , 013, 029, MEQ24, 003, MGPER, MGH, 007, MGKH, MGKM, 009, MGML, 012, MLH, MLM, 023, 027, MAC, NEB, PAT, 030, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA pdcSAECMFRQ STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D , Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N, 3D, U pdcCMROUTCD STRING(255) - 047, 008, GT, 055, INJ, 013, IBU, 026, 030, 045, 031, IOS, 033, 037, 015, 042, 045, 048, 054, 058, 060, 061, 062, 065, 067 dtmSAECMSTD DATE - DDMONYYYY rdcSAECMONG STRING(1) dtmSAECMEND DATE - DDMONYYYY txtCMIND STRING(50) - A50 pdcCMDRGTYP STRING(255) - 2, T, 1 txtMHXSEQ STRING(4) - A4 txtSAEMHTRM STRING(100) - A100 dtmMHSTDTM DATE - DDMONYYYY rdcMHCONT STRING(1) dtmMHLSTOC DATE - DDMONYYYY txtSAELBSEQ STRING(4) - A4 pdcLBTST STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total, Blood myoglobin, Blood pH, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils, Oxygen saturation, pCO2, pH, Phosphate, Platelet count, pO2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count, Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine myoglobin, Urine pH, Vital capacity, White blood cell count dtmLABDTM DATE - DDMONYYYY txtLABRES STRING(50) - A50 txtLABUNIT STRING(35) - A35 txtLABNLR FLOAT - F8.0 txtLABNHR FLOAT - F8.0 rdcSAEIP STRING(1) chkSAESENDI STRING(255) dtmSAEDTM DATE - DDMONYYYY HHMM AESE1 STRING(1) AESE2 STRING(5) - A5 Annotated Trial Design Page 107 of 166

txtSAEVERSION STRING(4) - A4 txtSAEID STRING(20) - A20 txtSAERNDNO STRING(255) - A255 txtOCEANSCD STRING(13) - A13 calSAEEmailFlag STRING(255)

CDD: MAPPINGS2 Table: t_AE_SER Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note chkSAE STRING(255) chkFU STRING(255) rdcSAERAND STRING(1) AESEQ STRING(5) - A5 AETERM STRING(100) - A100 AEMODIFY STRING(100) - A100 AEMEDSYN STRING(255) AELLTCD STRING(255) calAE_FAILED STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD1 STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM AEENDTTM3 DATE - DDMONYYYY HHMM AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 rdcAESREL STRING(1) AESER STRING(1) AESERDTH STRING(255) AESERLIF STRING(255) AESERHOS STRING(255) AESERDIS STRING(255) AESERCON STRING(255) AESEROTH STRING(255) txtSAECMSEQ STRING(4) - A4 txtCMTERM STRING(100) - A100 txtSAECMDOS FLOAT - F10.0 pdcCMUNIT STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 031, 002, 025, 028, IUML, 011, LM, LOZ, MEGU, 004, 004, 008, MCG/KG/MIN , MCG/MIN , 013, 029, MEQ24, 003, MGPER, MGH, 007, MGKH, MGKM, 009, MGML, 012, MLH, MLM, 023, 027, MAC, NEB, PAT, 030, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA pdcSAECMFRQ STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D , Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N, 3D, U pdcCMROUTCD STRING(255) - 047, 008, GT, 055, INJ, 013, IBU, 026, 030, 045, 031, IOS, 033, 037, 015, 042, 045, 048, 054, 058, 060, 061, 062, 065, 067 dtmSAECMSTD DATE - DDMONYYYY rdcSAECMONG STRING(1) dtmSAECMEND DATE - DDMONYYYY txtCMIND STRING(50) - A50 Annotated Trial Design Page 108 of 166

pdcCMDRGTYP STRING(255) - 2, T, 1 txtMHXSEQ STRING(4) - A4 txtSAEMHTRM STRING(100) - A100 dtmMHSTDTM DATE - DDMONYYYY rdcMHCONT STRING(1) dtmMHLSTOC DATE - DDMONYYYY txtSAELBSEQ STRING(4) - A4 pdcLBTST STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total, Blood myoglobin, Blood pH, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils, Oxygen saturation, pCO2, pH, Phosphate, Platelet count, pO2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count, Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine myoglobin, Urine pH, Vital capacity, White blood cell count dtmLABDTM DATE - DDMONYYYY txtLABRES STRING(50) - A50 txtLABUNIT STRING(35) - A35 txtLABNLR FLOAT - F8.0 txtLABNHR FLOAT - F8.0 rdcSAEIP STRING(1) chkSAESENDI STRING(255) dtmSAEDTM DATE - DDMONYYYY HHMM txtSAEVERSION STRING(4) - A4 txtSAEID STRING(20) - A20 txtSAERNDNO STRING(255) - A255 txtOCEANSCD STRING(13) - A13 calSAEEmailFlag STRING(255)

Annotated Trial Design Page 109 of 166

IPC103711_SHZ : LOCAL LABORATORY (Lab Rpt) - Repeating Form # Date Fasted? Results 1

LOCAL LABORATORY If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page.

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_RPT.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_RPT.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_RPT.LBFAST) (MAPPINGS2:t_LAB_RPT.LBFAST) [Y] Yes [N] No

Laboratory Test Laboratory Test Result 3. Results Entry Record the results for each repeated test in the add entry section 3.a Laboratory Test (MAPPINGS1:t_LAB_RPT.rdcLBTESTCD) (MAPPINGS2:t_LAB_RPT.rdcLBTESTCD) [- Clinical Chemistry Pulldown List 1 (MAPPINGS1:t_LAB_RPT.LBTESTCD_CHEM) 98] (MAPPINGS2:t_LAB_RPT.LBTESTCD_CHEM) [- Haematology Pulldown List 2 (MAPPINGS1:t_LAB_RPT.LBTESTCD_HAEMA) 99] (MAPPINGS2:t_LAB_RPT.LBTESTCD_HAEMA) 3.b Laboratory Test Result (MAPPINGS1:t_LAB_RPT.rdcLBORRES) (MAPPINGS2:t_LAB_RPT.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_RPT.RSLTNUM) 97] (MAPPINGS2:t_LAB_RPT.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_RPT.RSLTCHAR) 98] (MAPPINGS2:t_LAB_RPT.RSLTCHAR) [- No result 99]

Form Design Note:

This form is optional and is to be used for phase 1 studies for unscheduled measurements

Section Design Notes:

Title Design Note

LOCAL LABORATORY Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

2. This item is optional

Pulldown List 1: RefName Display Text Value Design Note estrLBTESTCDCAlbum Albumin ALB_PLC estrLBTESTCDCAlk Alkaline Phosphatase ALP_PLC estrLBTESTCDCALT ALT ALT_PLC estrLBTESTCDCAST AST AST_PLC estrLBTESTCDCCA Calcium CA_PLC estrLBTESTCDCChlor Chloride CL_PLC estrLBTESTCDCCreat Creatinine CRT_PLC Annotated Trial Design Page 110 of 166

estrLBTESTCDCCK Creatinine Kinase CK_PLC estrLBTESTCDCCKMB Creatinine Kinase-MB CKMB_PLC estrLBTESTCDCCRP CRP CRP_PLC estrLBTESTCDCGGT GGT GGT_PLC estrLBTESTCDCGlucose Glucose GLUC_PLC estrLBTESTCDCLDH LDH LDH_PLC estrLBTESTCDCPot Potassium K_PLC estrLBTESTCDCSodium Sodium NA_PLC estrLBTESTCDCTotalBili Total Bilirubin BILT_PLC estrLBTESTCDCTotalProt Total Protein TP_PLC estrLBTESTCDCUrea Urea UREA_PLC estrLBTESTCDCUric Uric Acid URIC_PLC

Pulldown List 2: RefName Display Text Value Design Note estrLBTESTCDHBaso Basophils BASO_BLC estrLBTESTCDHEos Eosinophils EOS_BLC estrLBTESTCDHHaemaglob Haemoglobin HB_BLC estrLBTESTCDHHaemato Haematocrit HCT_BLC estrLBTESTCDHLymph Lymphocytes LYMPH_BLC estrLBTESTCDHMonos Monocytes MONO_BLC estrLBTESTCDHNeutro Neutrophils NEUT_BLC estrLBTESTCDHPlat Platelets PLT_BLC estrLBTESTCDHRBC RBC RBC_BLC estrLBTESTCDHWBC WBC WBC_BLC

CDD: MAPPINGS1 Table: t_LAB_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBTESTCD NUMERIC LBTESTCD_CHEM STRING(255) - ALB_PLC, ALP_PLC, ALT_PLC, AST_PLC, CA_PLC, CL_PLC, CRT_PLC, CK_PLC, CKMB_PLC, CRP_PLC, GGT_PLC, GLUC_PLC, LDH_PLC, K_PLC, NA_PLC, BILT_PLC, TP_PLC, UREA_PLC, URIC_PLC LBTESTCD_HAEMA STRING(255) - BASO_BLC, EOS_BLC, HB_BLC, HCT_BLC, LYMPH_BLC, MONO_BLC, NEUT_BLC, PLT_BLC, RBC_BLC, WBC_BLC rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBTESTCD NUMERIC LBTESTCD_CHEM STRING(255) - ALB_PLC, ALP_PLC, ALT_PLC, AST_PLC, CA_PLC, CL_PLC, CRT_PLC, CK_PLC, CKMB_PLC, CRP_PLC, GGT_PLC, GLUC_PLC, LDH_PLC, K_PLC, NA_PLC, BILT_PLC, TP_PLC, UREA_PLC, URIC_PLC LBTESTCD_HAEMA STRING(255) - BASO_BLC, EOS_BLC, HB_BLC, HCT_BLC, LYMPH_BLC, MONO_BLC, NEUT_BLC, PLT_BLC, RBC_BLC, WBC_BLC rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 111 of 166

IPC103711_SHZ : URINALYSIS - LOCAL (Lab U Rpt) - Repeating Form # Date Result of dipstick Results 1

Complete the Adverse Events (AE) form if clinically significant abnormalities meet the protocol definition for an AE. URINALYSIS - LOCAL

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_URIN_RPT.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_URIN_RPT.LBDTTM) Req : Req 24-hour clock

2. Result of dipstick (MAPPINGS1:t_LAB_URIN_RPT.RSLTCHARU_RPT) (MAPPINGS2:t_LAB_URIN_RPT.RSLTCHARU_RPT) [NR] No result [NEG] Negative [POS] (MAPPINGS1:t_LAB_URIN_RPT.rdcMICROSCOPY_Rpt) (MAPPINGS2:t_LAB_URIN_RPT.rdcMICROSCOPY_Rpt) Positive Was sedimentary microscopy performed? [N] No [Y] Yes, provide details of repeated tests in the add entry section below.

Laboratory Test Laboratory Test Result 3. Results Entry Record the results for each repeated test in the add entry section 3.a Laboratory Test (MAPPINGS1:t_LAB_URIN_RPT.rdcLBTESTCD_URIN) (MAPPINGS2:t_LAB_URIN_RPT.rdcLBTESTCD_URIN) [- Urine dipstick Pulldown List 1 (MAPPINGS1:t_LAB_URIN_RPT.LBTESTCD_UDIP) 98] (MAPPINGS2:t_LAB_URIN_RPT.LBTESTCD_UDIP) [- Urine microscopy Pulldown List 2 (MAPPINGS1:t_LAB_URIN_RPT.LBTESTCD_UMIC) 99] (MAPPINGS2:t_LAB_URIN_RPT.LBTESTCD_UMIC) 3.b Laboratory Test Result (MAPPINGS1:t_LAB_URIN_RPT.rdcLBORRES) (MAPPINGS2:t_LAB_URIN_RPT.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_URIN_RPT.RSLTNUM) 97] (MAPPINGS2:t_LAB_URIN_RPT.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_URIN_RPT.RSLTCHAR) 98] (MAPPINGS2:t_LAB_URIN_RPT.RSLTCHAR) [- No result 99]

Form Design Note:

Repeat Urinalysis

Section Design Notes:

Title Design Note

URINALYSIS - LOCAL Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Pulldown List 1: RefName Display Text Value Design Note estrLBTESTCDUDProtein Protein PROT_URG estrLBTESTCDUDGlucose Glucose GLUC_URG estrLBTESTCDUDKetones Ketones KETO_URG estrLBTESTCDUDBilirubin Bilirubin BIL_URG estrLBTESTCDUDBlood Blood BLD_URG estrLBTESTCDUDUrobilinogen Urobilinogen URO_URG estrLBTESTCDUDLeucocytes Leucocytes WBC_URG

Annotated Trial Design Page 112 of 166

Pulldown List 2: RefName Display Text Value Design Note estrLBTESTCDUMWBC White blood cells WBCM_URG estrLBTESTCDUMRBC Red blood cells RBCM_URG estrLBTESTCDUMHCasts Hyaline casts HCASTM_URG estrLBTESTCDUMGCasts Granular casts GCASTM_URG estrLBTESTCDUMCCasts Cellular casts CCASTM_URG

CDD: MAPPINGS1 Table: t_LAB_URIN_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM RSLTCHARU_RPT STRING(3) rdcMICROSCOPY_Rpt STRING(1) rdcLBTESTCD_URIN NUMERIC LBTESTCD_UDIP STRING(255) - PROT_URG, GLUC_URG, KETO_URG, BIL_URG, BLD_URG, URO_URG, WBC_URG LBTESTCD_UMIC STRING(255) - WBCM_URG, RBCM_URG, HCASTM_URG, GCASTM_URG, CCASTM_URG rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_URIN_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM RSLTCHARU_RPT STRING(3) rdcMICROSCOPY_Rpt STRING(1) rdcLBTESTCD_URIN NUMERIC LBTESTCD_UDIP STRING(255) - PROT_URG, GLUC_URG, KETO_URG, BIL_URG, BLD_URG, URO_URG, WBC_URG LBTESTCD_UMIC STRING(255) - WBCM_URG, RBCM_URG, HCASTM_URG, GCASTM_URG, CCASTM_URG rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 113 of 166

IPC103711_SHZ : 12-LEAD ECG (ECG Rpt) - Repeating Form # Date HR PR QRS QT QTC Method QTc Calc Result 1

12-LEAD ECG

1. Date and Time of ECG Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_RPT.EGDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_RPT.EGDTTM) Req : Req 24-hour clock

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_RPT.EGHR) (MAPPINGS2:t_ECG_RPT.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.PR__) (MAPPINGS2:t_ECG_RPT.PR__)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QRS__) (MAPPINGS2:t_ECG_RPT.QRS__)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QT__) (MAPPINGS2:t_ECG_RPT.QT__)

6. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QTC__) (MAPPINGS2:t_ECG_RPT.QTC__)

7. Method of QTc Calculation (MAPPINGS1:t_ECG_RPT.EGMTCLCD) (MAPPINGS2:t_ECG_RPT.EGMTCLCD) [1] Machine [2] Manual

8. Result of the ECG (MAPPINGS1:t_ECG_RPT.EGINTPCD) (MAPPINGS2:t_ECG_RPT.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available)

Form Design Note:

Repeat ECG

CDD: MAPPINGS1 Table: t_ECG_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1)

CDD: MAPPINGS2 Table: t_ECG_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1) Annotated Trial Design Page 114 of 166

Annotated Trial Design Page 115 of 166

IPC103711_SHZ : ECG ABNORMALITIES (ECG Abn) - Repeating Form # Lead used Date Result 1

12-LEAD ECG ABNORMALITIES 1. Lead used for measurement (MAPPINGS1:t_ECG_ABNORM.EGLEAD) (MAPPINGS2:t_ECG_ABNORM.EGLEAD) [1] 12 Lead ECG [2] Lead II [3] Holter ECG [4] Continuous Lead II [5] Telemetry [OT] Other lead

2. Date and Time of ECG Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_ABNORM.EGDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_ABNORM.EGDTTM) Req : Req 24-hour clock

3. Record clinically significant abnormalities A. Rhythm (check all that apply) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_AAA) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_AAA) [A1] Sinus bradycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_BBB) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_BBB) [A21] Sinus bradycardia (heart rate 40-50 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_CCC) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_CCC) [A22] Sinus bradycardia (heart rate 30-39 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_DDD) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_DDD) [A23] Sinus bradycardia (heart rate <30 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_EEE) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_EEE) [A3] Sinus pause (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_FFF) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_FFF) [A2] Sinus tachycardia (heart rate > 100 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_GGG) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_GGG) [A4] Ectopic supraventricular beats (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_HHH) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_HHH) [A20] Ectopic supraventricular rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_III) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_III) [A17] Wandering atrial pacemaker (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_JJJ) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_JJJ) [A26] Multifocal atrial tachycardia (wandering atrial pacemaker w/rate >100 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_KKK) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_KKK) [A6] Supraventricular tachycardia (heart rate>100 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_LLL) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_LLL) [A7] Atrial flutter (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_MMM) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_MMM) [A8] Atrial fibrillation (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_NNN) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_NNN) [A5] Junctional rhythm (heart rate<=100 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_OOO) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_OOO) [A25] Junctional rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_PPP) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_PPP) [A24] Junctional tachycardia (heart rate>100 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_QQQ) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_QQQ) [A9] Ectopic ventricular beats (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_RRR) Annotated Trial Design Page 116 of 166

(MAPPINGS2:t_ECG_ABNORM.RHYTHM1_RRR) [A12] Ventricular couplets (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_SSS) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_SSS) [A13] Bigeminy (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_TTT) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_TTT) [A28] Trigeminy (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_UUU) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_UUU) [A14] Electrical alternans (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_VVV) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_VVV) [A29] R on T phenomenon (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_WWW) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_WWW) [A18] Ventricular fibrillation (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_XXX) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_XXX) [A19] Idioventricular rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_YYY) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_YYY) [A10] Sustained ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_ZZZ) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_ZZZ) [A11] Non-sustained ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_GGG) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_GGG) [A32] Wide QRS tachycardia (diagnosis unknown) (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_AAA) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_AAA) [A27] Ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_BBB) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_BBB) [A30] Monomorphic ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_CCC) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_CCC) [A15] Torsades de Pointes (Polymorphic ventricular tachycardia with prolonged QT) (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_DDD) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_DDD) [A31] Polymorphic (sustained and non-sustained) ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_EEE) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_EEE) [A16] Artificial Pacemaker (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_FFF) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_FFF) [A99] Other abnormal rhythm, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHA) (MAPPINGS2:t_ECG_ABNORM.EGFOTHA) A200

B. P-Wave Morphology (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_AAA) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_AAA) [B1] Left atrial abnormality (P mitrale) (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_BBB) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_BBB) [B2] Right atrial abnormality (P pulmonale) (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_CCC) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_CCC) [B3] Right ventricular hypertrophy (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_DDD) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_DDD) [B5] Intraatrial conduction delay (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_EEE) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_EEE) [D14] Increased voltage consistent with left ventricular hypertrophy (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_FFF) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_FFF) [B99] Other morphology, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHB) (MAPPINGS2:t_ECG_ABNORM.EGFOTHB) A200 Annotated Trial Design Page 117 of 166

C. Conduction (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_AAA) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_AAA) [C1] First degree AV block (PR interval > 200msec) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_TTT) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_TTT) [C20] Short PR interval (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_BBB) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_BBB) [C2] Second degree AV block (Mobitz type 1) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_CCC) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_CCC) [C3] Second degree AV block (Mobitz type 2) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_DDD) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_DDD) [C16] 2:1 AV block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_EEE) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_EEE) [C4] Third degree AV block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_FFF) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_FFF) [C5] Left axis deviation (QRS axis more negative than -30 degrees) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_GGG) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_GGG) [C6] Right axis deviation (QRS axis more positive than +110 degrees) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_HHH) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_HHH) [C7] Incomplete right bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_III) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_III) [C13] Incomplete left bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_JJJ) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_JJJ) [C8] Right bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_KKK) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_KKK) [C14] Left anterior hemiblock (synonymous to left anterior fascicular block) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_LLL) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_LLL) [C15] Left posterior hemiblock (synonymous to left posterior fascicular block) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_MMM) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_MMM) [C9] Left bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_NNN) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_NNN) [C17] Bifascicular block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_OOO) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_OOO) [C10] Non-specific intraventricular conduction delay (QRS > 120 msec) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_PPP) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_PPP) [C11] Accessory pathway (Wolff-Parkinson White, Lown-Ganong-Levine) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_UUU) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_UUU) [C19] Prolonged QT interval (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_QQQ) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_QQQ) [C12] QT/QTc prolongation > 500 msec (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_RRR) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_RRR) [C18] AV dissociation (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_SSS) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_SSS) [C99] Other conduction, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHC) (MAPPINGS2:t_ECG_ABNORM.EGFOTHC) A200

D. Myocardial Infarction (MAPPINGS1:t_ECG_ABNORM.MI_AAA) (MAPPINGS2:t_ECG_ABNORM.MI_AAA) [D1] Myocardial infarction, old (MAPPINGS1:t_ECG_ABNORM.MI_BBB) (MAPPINGS2:t_ECG_ABNORM.MI_BBB) Annotated Trial Design Page 118 of 166

[D2] Myocardial infarction, anterior (MAPPINGS1:t_ECG_ABNORM.MI_CCC) (MAPPINGS2:t_ECG_ABNORM.MI_CCC) [D3] Myocardial infarction, lateral (MAPPINGS1:t_ECG_ABNORM.MI_DDD) (MAPPINGS2:t_ECG_ABNORM.MI_DDD) [D4] Myocardial infarction, posterior (MAPPINGS1:t_ECG_ABNORM.MI_EEE) (MAPPINGS2:t_ECG_ABNORM.MI_EEE) [D5] Myocardial infarction, inferior (MAPPINGS1:t_ECG_ABNORM.MI_FFF) (MAPPINGS2:t_ECG_ABNORM.MI_FFF) [D6] Myocardial infarction, septal (MAPPINGS1:t_ECG_ABNORM.MI_GGG) (MAPPINGS2:t_ECG_ABNORM.MI_GGG) [D20] Myocardial infarction, Non Q-wave (MAPPINGS1:t_ECG_ABNORM.MI_HHH) (MAPPINGS2:t_ECG_ABNORM.MI_HHH) [D98] Other myocardial infarction, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHD) (MAPPINGS2:t_ECG_ABNORM.EGFOTHD) A200

E. Depolarisation/Repolarisation (QRS-T) (MAPPINGS1:t_ECG_ABNORM.DEPO_AAA) (MAPPINGS2:t_ECG_ABNORM.DEPO_AAA) [D7] Non-specific ST-T changes (MAPPINGS1:t_ECG_ABNORM.DEPO_BBB) (MAPPINGS2:t_ECG_ABNORM.DEPO_BBB) [D19] J point elevation (MAPPINGS1:t_ECG_ABNORM.DEPO_CCC) (MAPPINGS2:t_ECG_ABNORM.DEPO_CCC) [D8] ST elevation (MAPPINGS1:t_ECG_ABNORM.DEPO_DDD) (MAPPINGS2:t_ECG_ABNORM.DEPO_DDD) [D21] ST-elevation - pericarditis (MAPPINGS1:t_ECG_ABNORM.DEPO_EEE) (MAPPINGS2:t_ECG_ABNORM.DEPO_EEE) [D9] ST depression (MAPPINGS1:t_ECG_ABNORM.DEPO_FFF) (MAPPINGS2:t_ECG_ABNORM.DEPO_FFF) [D10] U waves abnormal (MAPPINGS1:t_ECG_ABNORM.DEPO_GGG) (MAPPINGS2:t_ECG_ABNORM.DEPO_GGG) [D11] T wave inversion (MAPPINGS1:t_ECG_ABNORM.DEPO_HHH) (MAPPINGS2:t_ECG_ABNORM.DEPO_HHH) [D12] T wave peaked (MAPPINGS1:t_ECG_ABNORM.DEPO_III) (MAPPINGS2:t_ECG_ABNORM.DEPO_III) [D15] T waves flat (MAPPINGS1:t_ECG_ABNORM.DEPO_JJJ) (MAPPINGS2:t_ECG_ABNORM.DEPO_JJJ) [D16] T waves biphasic (MAPPINGS1:t_ECG_ABNORM.DEPO_KKK) (MAPPINGS2:t_ECG_ABNORM.DEPO_KKK) [D18] Notched T-waves (MAPPINGS1:t_ECG_ABNORM.DEPO_LLL) (MAPPINGS2:t_ECG_ABNORM.DEPO_LLL) [D13] Low QRS voltage (MAPPINGS1:t_ECG_ABNORM.DEPO_MMM) (MAPPINGS2:t_ECG_ABNORM.DEPO_MMM) [D17] T-wave flattening/inversion (MAPPINGS1:t_ECG_ABNORM.DEPO_NNN) (MAPPINGS2:t_ECG_ABNORM.DEPO_NNN) [D99] Other depolarisation/repolarisation, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHE) (MAPPINGS2:t_ECG_ABNORM.EGFOTHE) A200

Other abnormalities (MAPPINGS1:t_ECG_ABNORM.OTHER_AAA) (MAPPINGS2:t_ECG_ABNORM.OTHER_AAA) [E99] (MAPPINGS1:t_ECG_ABNORM.EGFOTHO) Annotated Trial Design Page 119 of 166

Enter comment (MAPPINGS2:t_ECG_ABNORM.EGFOTHO) A200

CDD: MAPPINGS1 Table: t_ECG_ABNORM Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGLEAD STRING(2) EGDTTM DATE - DDMONYYYY HHMM RHYTHM1_AAA STRING(255) RHYTHM1_BBB STRING(255) RHYTHM1_CCC STRING(255) RHYTHM1_DDD STRING(255) RHYTHM1_EEE STRING(255) RHYTHM1_FFF STRING(255) RHYTHM1_GGG STRING(255) RHYTHM1_HHH STRING(255) RHYTHM1_III STRING(255) RHYTHM1_JJJ STRING(255) RHYTHM1_KKK STRING(255) RHYTHM1_LLL STRING(255) RHYTHM1_MMM STRING(255) RHYTHM1_NNN STRING(255) RHYTHM1_OOO STRING(255) RHYTHM1_PPP STRING(255) RHYTHM1_QQQ STRING(255) RHYTHM1_RRR STRING(255) RHYTHM1_SSS STRING(255) RHYTHM1_TTT STRING(255) RHYTHM1_UUU STRING(255) RHYTHM1_VVV STRING(255) RHYTHM1_WWW STRING(255) RHYTHM1_XXX STRING(255) RHYTHM1_YYY STRING(255) RHYTHM1_ZZZ STRING(255) RHYTHM2_GGG STRING(255) RHYTHM2_AAA STRING(255) RHYTHM2_BBB STRING(255) RHYTHM2_CCC STRING(255) RHYTHM2_DDD STRING(255) RHYTHM2_EEE STRING(255) RHYTHM2_FFF STRING(255) EGFOTHA STRING(200) - A200 MORPHOLOGY_AAA STRING(255) MORPHOLOGY_BBB STRING(255) MORPHOLOGY_CCC STRING(255) MORPHOLOGY_DDD STRING(255) MORPHOLOGY_EEE STRING(255) MORPHOLOGY_FFF STRING(255) EGFOTHB STRING(200) - A200 CONDUCTION_AAA STRING(255) Annotated Trial Design Page 120 of 166

CONDUCTION_TTT STRING(255) CONDUCTION_BBB STRING(255) CONDUCTION_CCC STRING(255) CONDUCTION_DDD STRING(255) CONDUCTION_EEE STRING(255) CONDUCTION_FFF STRING(255) CONDUCTION_GGG STRING(255) CONDUCTION_HHH STRING(255) CONDUCTION_III STRING(255) CONDUCTION_JJJ STRING(255) CONDUCTION_KKK STRING(255) CONDUCTION_LLL STRING(255) CONDUCTION_MMM STRING(255) CONDUCTION_NNN STRING(255) CONDUCTION_OOO STRING(255) CONDUCTION_PPP STRING(255) CONDUCTION_UUU STRING(255) CONDUCTION_QQQ STRING(255) CONDUCTION_RRR STRING(255) CONDUCTION_SSS STRING(255) EGFOTHC STRING(200) - A200 MI_AAA STRING(255) MI_BBB STRING(255) MI_CCC STRING(255) MI_DDD STRING(255) MI_EEE STRING(255) MI_FFF STRING(255) MI_GGG STRING(255) MI_HHH STRING(255) EGFOTHD STRING(200) - A200 DEPO_AAA STRING(255) DEPO_BBB STRING(255) DEPO_CCC STRING(255) DEPO_DDD STRING(255) DEPO_EEE STRING(255) DEPO_FFF STRING(255) DEPO_GGG STRING(255) DEPO_HHH STRING(255) DEPO_III STRING(255) DEPO_JJJ STRING(255) DEPO_KKK STRING(255) DEPO_LLL STRING(255) DEPO_MMM STRING(255) DEPO_NNN STRING(255) EGFOTHE STRING(200) - A200 OTHER_AAA STRING(255) EGFOTHO STRING(200) - A200

CDD: MAPPINGS2 Table: t_ECG_ABNORM Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGLEAD STRING(2) Annotated Trial Design Page 121 of 166

EGDTTM DATE - DDMONYYYY HHMM RHYTHM1_AAA STRING(255) RHYTHM1_BBB STRING(255) RHYTHM1_CCC STRING(255) RHYTHM1_DDD STRING(255) RHYTHM1_EEE STRING(255) RHYTHM1_FFF STRING(255) RHYTHM1_GGG STRING(255) RHYTHM1_HHH STRING(255) RHYTHM1_III STRING(255) RHYTHM1_JJJ STRING(255) RHYTHM1_KKK STRING(255) RHYTHM1_LLL STRING(255) RHYTHM1_MMM STRING(255) RHYTHM1_NNN STRING(255) RHYTHM1_OOO STRING(255) RHYTHM1_PPP STRING(255) RHYTHM1_QQQ STRING(255) RHYTHM1_RRR STRING(255) RHYTHM1_SSS STRING(255) RHYTHM1_TTT STRING(255) RHYTHM1_UUU STRING(255) RHYTHM1_VVV STRING(255) RHYTHM1_WWW STRING(255) RHYTHM1_XXX STRING(255) RHYTHM1_YYY STRING(255) RHYTHM1_ZZZ STRING(255) RHYTHM2_GGG STRING(255) RHYTHM2_AAA STRING(255) RHYTHM2_BBB STRING(255) RHYTHM2_CCC STRING(255) RHYTHM2_DDD STRING(255) RHYTHM2_EEE STRING(255) RHYTHM2_FFF STRING(255) EGFOTHA STRING(200) - A200 MORPHOLOGY_AAA STRING(255) MORPHOLOGY_BBB STRING(255) MORPHOLOGY_CCC STRING(255) MORPHOLOGY_DDD STRING(255) MORPHOLOGY_EEE STRING(255) MORPHOLOGY_FFF STRING(255) EGFOTHB STRING(200) - A200 CONDUCTION_AAA STRING(255) CONDUCTION_TTT STRING(255) CONDUCTION_BBB STRING(255) CONDUCTION_CCC STRING(255) CONDUCTION_DDD STRING(255) CONDUCTION_EEE STRING(255) CONDUCTION_FFF STRING(255) CONDUCTION_GGG STRING(255) CONDUCTION_HHH STRING(255) Annotated Trial Design Page 122 of 166

CONDUCTION_III STRING(255) CONDUCTION_JJJ STRING(255) CONDUCTION_KKK STRING(255) CONDUCTION_LLL STRING(255) CONDUCTION_MMM STRING(255) CONDUCTION_NNN STRING(255) CONDUCTION_OOO STRING(255) CONDUCTION_PPP STRING(255) CONDUCTION_UUU STRING(255) CONDUCTION_QQQ STRING(255) CONDUCTION_RRR STRING(255) CONDUCTION_SSS STRING(255) EGFOTHC STRING(200) - A200 MI_AAA STRING(255) MI_BBB STRING(255) MI_CCC STRING(255) MI_DDD STRING(255) MI_EEE STRING(255) MI_FFF STRING(255) MI_GGG STRING(255) MI_HHH STRING(255) EGFOTHD STRING(200) - A200 DEPO_AAA STRING(255) DEPO_BBB STRING(255) DEPO_CCC STRING(255) DEPO_DDD STRING(255) DEPO_EEE STRING(255) DEPO_FFF STRING(255) DEPO_GGG STRING(255) DEPO_HHH STRING(255) DEPO_III STRING(255) DEPO_JJJ STRING(255) DEPO_KKK STRING(255) DEPO_LLL STRING(255) DEPO_MMM STRING(255) DEPO_NNN STRING(255) EGFOTHE STRING(200) - A200 OTHER_AAA STRING(255) EGFOTHO STRING(200) - A200

Annotated Trial Design Page 123 of 166

IPC103711_SHZ : VITAL SIGNS (VS Rpt) - Repeating Form # Actual BP HR Temperature 1

VITAL SIGNS

1. Actual date/time Req / Req / Req (2007-2009) (MAPPINGS1:t_VITALS_RPT.VSACTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_RPT.VSACTDTTM) Req : Req 24-hour clock

2. Blood pressure (MAPPINGS1:t_VITALS_RPT.rdcBPRpt) (MAPPINGS2:t_VITALS_RPT.rdcBPRpt) [ND] Not Done [Y] xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_RPT.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_RPT.DIABP) (MAPPINGS2:t_VITALS_RPT.SYSBP) (MAPPINGS2:t_VITALS_RPT.DIABP) (systolic/diastolic)

3. Heart rate (MAPPINGS1:t_VITALS_RPT.rdcHEART) (MAPPINGS2:t_VITALS_RPT.rdcHEART) [ND] Not Done [Y] xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_RPT.HEART) (MAPPINGS2:t_VITALS_RPT.HEART)

4. Temperature (MAPPINGS1:t_VITALS_RPT.rdcTEMP) (MAPPINGS2:t_VITALS_RPT.rdcTEMP) [ND] Not Done [?] xxx.x °C (MAPPINGS1:t_VITALS_RPT.TEMPERATURE) (MAPPINGS2:t_VITALS_RPT.TEMPERATURE)

Form Design Note:

Repeat vital signs

CDD: MAPPINGS1 Table: t_VITALS_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM rdcBPRpt STRING(2) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 rdcHEART STRING(2) HEART NUMERIC - N3 rdcTEMP STRING(42) TEMPERATURE FLOAT - F5.1

CDD: MAPPINGS2 Table: t_VITALS_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM rdcBPRpt STRING(2) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 rdcHEART STRING(2) HEART NUMERIC - N3 rdcTEMP STRING(42) TEMPERATURE FLOAT - F5.1

Annotated Trial Design Page 124 of 166

IPC103711_SHZ : REPEAT PHARMACODYNAMICS - [Analyte and PD sample type] (PD Rpt) - Repeating Form # Date/time of sample 1

REPEAT PHARMACODYNAMICS

1. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_RPT.PDACTDTTM) (MAPPINGS2:t_PD_RPT.PDACTDTTM) Req : Req 24-hour clock

Form Design Note:

Rpt PD

CDD: MAPPINGS1 Table: t_PD_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note PDACTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_PD_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note PDACTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 125 of 166

IPC103711_SHZ : REPEAT PULMONARY FUNCTION TESTS (PFT Rpt) - Repeating Form # Date/time FEV1 FVC 1

REPEAT PULMONARY FUNCTION TESTS

1. Date/time of test Req / Req / Req (2007-2009) (MAPPINGS1:t_PFT_RPT.PFTDTTM) (MAPPINGS2:t_PFT_RPT.PFTDTTM) Req : Req 24-hour clock

2. FEV1 (3 readings) Reading (MAPPINGS1:t_PFT_RPT.FEV1A) Reading (MAPPINGS1:t_PFT_RPT.FEV1B) Reading (MAPPINGS1:t_PFT_RPT.FEV1C) 1 (MAPPINGS2:t_PFT_RPT.FEV1A) 2 (MAPPINGS2:t_PFT_RPT.FEV1B) 3 (MAPPINGS2:t_PFT_RPT.FEV1C) xxxx. L xxxx. L xxxx. L

3. FVC (3 readings) Reading (MAPPINGS1:t_PFT_RPT.FVCA) Reading (MAPPINGS1:t_PFT_RPT.FVCB) Reading (MAPPINGS1:t_PFT_RPT.FVCC) 1 (MAPPINGS2:t_PFT_RPT.FVCA) 2 (MAPPINGS2:t_PFT_RPT.FVCB) 3 (MAPPINGS2:t_PFT_RPT.FVCC) xxxx. L xxxx. L xxxx. L

Form Design Note:

Rpt PFT

CDD: MAPPINGS1 Table: t_PFT_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note PFTDTTM DATE - DDMONYYYY HHMM FEV1A FLOAT - F5.0 FEV1B FLOAT - F5.0 FEV1C FLOAT - F5.0 FVCA FLOAT - F5.0 FVCB FLOAT - F5.0 FVCC FLOAT - F5.0

CDD: MAPPINGS2 Table: t_PFT_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note PFTDTTM DATE - DDMONYYYY HHMM FEV1A FLOAT - F5.0 FEV1B FLOAT - F5.0 FEV1C FLOAT - F5.0 FVCA FLOAT - F5.0 FVCB FLOAT - F5.0 FVCC FLOAT - F5.0

Annotated Trial Design Page 126 of 166

IPC103711_SHZ : REPEAT PHARMACOKINETICS BLOOD - [drug name] (PK Rpt) - Repeating Form # Actual date/time 1

REPEAT PHARMACOKINETICS BLOOD

1. Actual date/time Req / Req / Req (2007-2009) (MAPPINGS1:t_PK_RPT.PKSTDTTM) (MAPPINGS2:t_PK_RPT.PKSTDTTM) Req : Req 24-hour clock

Form Design Note:

Repeat PK

CDD: MAPPINGS1 Table: t_PK_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note PKSTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_PK_RPT Key Type: PATIENTVISIT Column Name Column Data Type Design Note PKSTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 127 of 166

IPC103711_SHZ : Liver Event DOV (Liver DoV) DATE OF VISIT/ASSESSMENT

1. Date of visit/assessment Req / Req / Req (2007-2009) (MAPPINGS1:t_STATUS_LIVER_VISIT.DOV) (MAPPINGS2:t_STATUS_LIVER_VISIT.DOV)

LIVER EVENTS ASSESSMENT (If no liver event, tick 'No' and enter date of study conclusion/withdrawal above) 2. Have liver chemistry results reached or exceeded protocol-defined investigational product stopping criteria? (MAPPINGS1:t_STATUS_LIVER_VISIT.LVEVTANY) (MAPPINGS2:t_STATUS_LIVER_VISIT.LVEVTANY) [Y] Yes [N] No If Yes, stop investigational product, complete date stopped on Investigational Product form, contact GSK within 24 hours of occurrence, complete Liver Events Form and obtain the following tests: * PK blood sample within 24 hours of last dose (or 3x the investigational product half life or t1/2). * Hepatitis A: Hepatitis A IgM antibody. * Hepatitis B: Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). * Hepatitis C: Hepatitis C RNA. * Hepatitis E IgM antibody (if subject resides or has travelled in the past 3 months outside the USA or Canada). * Cytomegalovirus IgM antibody (CMV). * EBV (Epstein Barr viral capsid antigen IgM antibody) or if unavailable, obtain heterophile antibody or monospot testing.) * Bilirubin fractionation, if bilirubin >= 1.5xULN * CPK (serum creatine phosphokinase), * LDH (lactate dehydrogenase).

The following are only needed when ALT >=3xULN and bilirubin >=1.5xULN (>35% direct) * Anti-nuclear antibody * Anti-smooth muscle antibody * Type 1 anti-liver kidney microsomal antibodies (if available) * Liver Imaging (ultrasound, magnetic resonance, or computerised tomography)

3.* If Yes, complete the Liver Event forms displayed upon submission of this form [read-only] (MAPPINGS1:t_STATUS_LIVER_VISIT.DUMMYPROMPT) (MAPPINGS2:t_STATUS_LIVER_VISIT.DUMMYPROMPT)

* Item is not required

Section Design Notes:

Title Design Note

LIVER EVENTS ASSESSMENT (If no liver event, tick 'No' and enter date of study conclusion/withdrawal above) The text 'or' and 'or 5` nucleaotidase or Gammaglutamyltranspeptidase' is conditional text.

If Yes, stop investigational product, complete date stopped on Investigational Product form, contact GSK within 24 hours of occurrence, The following text 'protocol specified longer value to be inserted' is a prompt to the eCRF designer and should be complete Liver Events Form and obtain the following tests: replaced with the relevant text from the protocol.

Item Design Notes:

Item No. Design Note

3. This item must not be removed, as it is required in order to display the section Notes

CDD: MAPPINGS1 Table: t_STATUS_LIVER_VISIT Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY LVEVTANY STRING(1) DUMMYPROMPT STRING(255)

CDD: MAPPINGS2 Table: t_STATUS_LIVER_VISIT Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY LVEVTANY STRING(1) DUMMYPROMPT STRING(255)

Annotated Trial Design Page 128 of 166

IPC103711_SHZ : LIVER EVENTS (LIVER EVENTS) 1. Which liver chemistry result reached or exceeded protocol-defined (MAPPINGS1:t_RUCAM.RUORRSCD1A) investigational product stopping criteria? (MAPPINGS2:t_RUCAM.RUORRSCD1A) [1] ALT (alanine aminotransferase) Check all that apply (MAPPINGS1:t_RUCAM.RUORRSCD2A) (MAPPINGS2:t_RUCAM.RUORRSCD2A) [2] AST (aspartate aminotransferase) (MAPPINGS1:t_RUCAM.RUORRSCD3A) (MAPPINGS2:t_RUCAM.RUORRSCD3A) [3] Total bilirubin (MAPPINGS1:t_RUCAM.RUORRSCD4A) (MAPPINGS2:t_RUCAM.RUORRSCD4A) [4] Alkaline phosphatase (MAPPINGS1:t_RUCAM.RUORRSCD5A) (MAPPINGS2:t_RUCAM.RUORRSCD5A) [5] 5` nucleotidase (MAPPINGS1:t_RUCAM.RUORRSCD6A) (MAPPINGS2:t_RUCAM.RUORRSCD6A) [6] Gammaglutamyltranspeptidase (MAPPINGS1:t_RUCAM.RUORRSCDOT1) (MAPPINGS2:t_RUCAM.RUORRSCDOT1) [OT] Other

Record the details of any Adverse Events or exacerbations of Adverse Events on the Non-Serious Adverse Event Form or the Serious Adverse Event form. Exacerbations of Adverse Events include increases in frequency and severity. It is particularly important to record any significant hypotension immediately prior to or concomitant with ALT elevation.

It is particularly important to record any gallbladder or biliary disease, or pancreatitis, that occurred during the study. 2. Is the subject age 55 or older? (MAPPINGS1:t_RUCAM.RUORRSCD2) (MAPPINGS2:t_RUCAM.RUORRSCD2) [Y] Yes [N] No

3. If female, is the subject pregnant? (MAPPINGS1:t_RUCAM.RUORRSCD3) (MAPPINGS2:t_RUCAM.RUORRSCD3) [Y] Yes ensure Pregnancy Notification Form has been completed. [N] No [X] Not applicable

4. Were any diagnostic imaging tests of the liver or hepatobiliary system (MAPPINGS1:t_RUCAM.RUORRSCD4) performed (such as liver ultrasound, computerised tomography or CAT scan, (MAPPINGS2:t_RUCAM.RUORRSCD4) magnetic resonance imaging or MRI, or endoscopic retrograde [Y] Yes. If Yes, were the results normal? (MAPPINGS1:t_RUCAM.RUORRSCD5) cholangiopancreatography, or other)? (MAPPINGS2:t_RUCAM.RUORRSCD5) [Y] Yes If No, record the details on the Non-Serious Adverse Events form or Serious Adverse Event form. [N] No [N] No

5. Were any liver biopsies performed? (MAPPINGS1:t_RUCAM.RUORRSCD6) (MAPPINGS2:t_RUCAM.RUORRSCD6) [Y] Yes complete Liver Biopsy form. [N] No

6. Does the subject use herbals, complementary or alternative medicines, food (MAPPINGS1:t_RUCAM.RUORRSCD7) supplements (vitamins) or illicit drugs? (MAPPINGS2:t_RUCAM.RUORRSCD7) [Y] Yes record on the appropriate Concomitant Medication form. [N] No

7. Did the subject fast or undergo significant dietary change in the past week? (MAPPINGS1:t_RUCAM.RUORRSCD8) (MAPPINGS2:t_RUCAM.RUORRSCD8) [Y] Yes [N] No

Evaluation interval code [hidden] (MAPPINGS1:t_RUCAM.EVLINTCD) (MAPPINGS2:t_RUCAM.EVLINTCD)

Form Design Note:

IDSL Version 01.02A 24 AUG 06

Item Design Notes:

Item No. Design Note Annotated Trial Design Page 129 of 166

1. Codes 5 and 6 are conditional

itmEVLINTCD1L Item will be calculated by InForm.

CDD: MAPPINGS1 Table: t_RUCAM Key Type: PATIENTVISIT Column Name Column Data Type Design Note RUORRSCD1A STRING(255) RUORRSCD2A STRING(255) RUORRSCD3A STRING(255) RUORRSCD4A STRING(255) RUORRSCD5A STRING(255) RUORRSCD6A STRING(255) RUORRSCDOT1 STRING(255) RUORRSCD2 STRING(1) RUORRSCD3 STRING(1) RUORRSCD4 STRING(1) RUORRSCD5 STRING(1) RUORRSCD6 STRING(1) RUORRSCD7 STRING(1) RUORRSCD8 STRING(1) EVLINTCD STRING(255)

CDD: MAPPINGS2 Table: t_RUCAM Key Type: PATIENTVISIT Column Name Column Data Type Design Note RUORRSCD1A STRING(255) RUORRSCD2A STRING(255) RUORRSCD3A STRING(255) RUORRSCD4A STRING(255) RUORRSCD5A STRING(255) RUORRSCD6A STRING(255) RUORRSCDOT1 STRING(255) RUORRSCD2 STRING(1) RUORRSCD3 STRING(1) RUORRSCD4 STRING(1) RUORRSCD5 STRING(1) RUORRSCD6 STRING(1) RUORRSCD7 STRING(1) RUORRSCD8 STRING(1) EVLINTCD STRING(255)

Annotated Trial Design Page 130 of 166

IPC103711_SHZ : INVESTIGATIONAL PRODUCT (LIVER) (LIVER IP) Time period to the onset of ALT >= 2x Upper Limit Normal (ULN)

Notes: - Although stopping criteria is ALT >= 3x ULN, GSK are interested in capturing ALT >= 2x ULN to assess the probabilty of drug relatedness of liver event. - Only complete dates for the treatment period applicable to the onset of ALT >= 2x ULN. If the liver event occurred during treatment period record start and stop date of investigational product for that treatment period. 1. Start Date Investigational Product (MAPPINGS1:t_EXPOSURE_LIVER.rdcEXSTDT) (MAPPINGS2:t_EXPOSURE_LIVER.rdcEXSTDT) [- Req/Unk / Req/Unk / Req/Unk (2007-2009) (MAPPINGS1:t_EXPOSURE_LIVER.EXSTDT) 99] (MAPPINGS2:t_EXPOSURE_LIVER.EXSTDT) [- Not applicable 98] 2. End Date Investigational Product (MAPPINGS1:t_EXPOSURE_LIVER.rdcEXENDT) (MAPPINGS2:t_EXPOSURE_LIVER.rdcEXENDT) [- Req/Unk / Req/Unk / Req/Unk (2007-2009) (MAPPINGS1:t_EXPOSURE_LIVER.EXENDT) 99] (MAPPINGS2:t_EXPOSURE_LIVER.EXENDT) [- Not applicable 98] If the liver event occurred after treatment period record start and stop date of investigational product for the most recent period prior to the liver event. 3. Start Date Investigational Product (MAPPINGS1:t_EXPOSURE_LIVER.rdcEXSTDT) (MAPPINGS2:t_EXPOSURE_LIVER.rdcEXSTDT) [- Req/Unk / Req/Unk / Req/Unk (2007-2009) (MAPPINGS1:t_EXPOSURE_LIVER.EXSTDT) 99] (MAPPINGS2:t_EXPOSURE_LIVER.EXSTDT) [- Not applicable 98] 4. End Date Investigational Product (MAPPINGS1:t_EXPOSURE_LIVER.rdcEXENDT) (MAPPINGS2:t_EXPOSURE_LIVER.rdcEXENDT) [- Req/Unk / Req/Unk / Req/Unk (2007-2009) (MAPPINGS1:t_EXPOSURE_LIVER.EXENDT) 99] (MAPPINGS2:t_EXPOSURE_LIVER.EXENDT) [- Not applicable 98]

Form Design Note:

IDSL Version 01.03A - 11Jan07

CDD: MAPPINGS1 Table: t_EXPOSURE_LIVER Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note rdcEXSTDT STRING(3) EXSTDT DATE - DDMONYYYY rdcEXENDT STRING(3) EXENDT DATE - DDMONYYYY

CDD: MAPPINGS2 Table: t_EXPOSURE_LIVER Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note rdcEXSTDT STRING(3) EXSTDT DATE - DDMONYYYY rdcEXENDT STRING(3) EXENDT DATE - DDMONYYYY

Annotated Trial Design Page 131 of 166

IPC103711_SHZ : PHARMACOKINETICS (LIVER PK) An unscheduled PK blood sample must be obtained within 24 hours of last dose (or 3x the investigational product half-life or t1/2; protocol specified longer value to be inserted). 1. Was a pharmacokinetic blood sample obtained? (MAPPINGS1:t_PK_LIVER.rdcPKLIVER) (MAPPINGS2:t_PK_LIVER.rdcPKLIVER) [Y] Yes, date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_PK_LIVER.PKSTDTTM2) (MAPPINGS2:t_PK_LIVER.PKSTDTTM2) Req : Req 24-hour clock

If Yes, date and time of last investigational product dose prior to PK sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PK_LIVER.EXSTDTTM1) (MAPPINGS2:t_PK_LIVER.EXSTDTTM1) Req : Req 24-hour clock Sample Identifier/Sample Number A17 (MAPPINGS1:t_PK_LIVER.PKSMPID) (MAPPINGS2:t_PK_LIVER.PKSMPID) [N] No

Form Design Note:

IDSL Version 02.00A 16 JAN 07

Section Design Notes:

Title Design Note

An unscheduled PK blood sample must be obtained within 24 hours of last dose (or 3x the investigational product half-life or t1/2; The following text 'protocol specified longer value to be inserted' is a prompt for the eCRF designer and should be replaced protocol specified longer value to be inserted). with the relevant text from the protocol.

Item Design Notes:

Item No. Design Note

1. Sample Identifier and Sample Number are conditional. The study team must choose one for inclusion on the eCRF form.

CDD: MAPPINGS1 Table: t_PK_LIVER Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcPKLIVER STRING(1) PKSTDTTM2 DATE - DDMONYYYY HHMM EXSTDTTM1 DATE - DDMONYYYY HHMM PKSMPID STRING(17) - A17

CDD: MAPPINGS2 Table: t_PK_LIVER Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcPKLIVER STRING(1) PKSTDTTM2 DATE - DDMONYYYY HHMM EXSTDTTM1 DATE - DDMONYYYY HHMM PKSMPID STRING(17) - A17

Annotated Trial Design Page 132 of 166

IPC103711_SHZ : MEDICAL CONDITIONS (LIVER MEDHX) LIVER DISEASE MEDICAL CONDITIONS 1. Acute Viral Hepatitis A (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

2. Chronic Hepatitis B (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

3. Chronic Hepatitis C (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

4. Cytomegalovirus Hepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

5. Epstein Barr Virus Infectious Mononucleosis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

6. Herpes Simplex Hepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

7. Alcoholic Liver Disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

8. Non-alcoholic Steatohepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

9. Fatty Liver (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

10. Hepatic Cirrhosis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

11. Hemochromatosis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

12. Autoimmune Hepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition Annotated Trial Design Page 133 of 166

13. Gallbladder disease or biliary disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition DRUG RELATED LIVER DISEASE CONDITIONS (All drugs including Investigational Product) 14. Drug related liver disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

Sequence Number Specific Condition Modified MedDRA MedDRA Failed Status Term Synonym lower coding level term code 15. [hidden] [hidden][hidden][hidden][hidden] OTHER LIVER DISEASE CONDITIONS Entry

15.a* Sequence Number [hidden] xxxx (MAPPINGS1:t_MEDHIST_A_LIVER.MHSEQ) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSEQ)

15.b Specific Condition (MAPPINGS1:t_MEDHIST_A_LIVER.MHTERM) A100 (MAPPINGS2:t_MEDHIST_A_LIVER.MHTERM)

* Modified Term [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.MHMODIFY) 15.c A100 (MAPPINGS2:t_MEDHIST_A_LIVER.MHMODIFY)

MedDRA Synonym [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.MHMEDSYN) (MAPPINGS2:t_MEDHIST_A_LIVER.MHMEDSYN)

MedDRA lower level term code [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.MHLLTCD) (MAPPINGS2:t_MEDHIST_A_LIVER.MHLLTCD)

Failed coding [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.calMH_FAILED) (MAPPINGS2:t_MEDHIST_A_LIVER.calMH_FAILED)

15.d Status (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD1) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD1) [1] Current [2] Past OTHER MEDICAL CONDITIONS 16. Drug Allergies (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

17. Rheumatoid Arthritis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

18. Psoriasis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

19. Thyroid Disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

20. Inflammatory Bowel Disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

21. Lupus (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) Annotated Trial Design Page 134 of 166

(MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

22. Sjogren's Syndrome (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

23. Vitiligo (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2) (MAPPINGS2:t_MEDHIST_A_LIVER.MHSTATCD2) [1] Current [2] Past [5] No Medical Condition

* Item is not required

Form Design Note:

IDSL Version 01.01A 07 AUG 06

CDD: MAPPINGS1 Table: t_MEDHIST_A_LIVER Key Type: PATIENTTOITEM Column Name Column Data Type Design Note MHSTATCD2 STRING(1) MHSEQ NUMERIC - N4 MHTERM STRING(100) - A100 MHMODIFY STRING(100) - A100 MHMEDSYN STRING(255) MHLLTCD STRING(255) calMH_FAILED STRING(255) MHSTATCD1 STRING(1)

CDD: MAPPINGS2 Table: t_MEDHIST_A_LIVER Key Type: PATIENTTOITEM Column Name Column Data Type Design Note MHSTATCD2 STRING(1) MHSEQ NUMERIC - N4 MHTERM STRING(100) - A100 MHMODIFY STRING(100) - A100 MHMEDSYN STRING(255) MHLLTCD STRING(255) calMH_FAILED STRING(255) MHSTATCD1 STRING(1)

Annotated Trial Design Page 135 of 166

IPC103711_SHZ : ALCOHOL INTAKE (LIVER ALCOHOL) ALCOHOL INTAKE 1. Does the subject consume alcohol? (MAPPINGS1:t_SUBUSE_AL_LIVER.SUAL1) (MAPPINGS2:t_SUBUSE_AL_LIVER.SUAL1) [N] No [Y] Yes, record the average number of units of alcohol consumed per week (MAPPINGS1:t_SUBUSE_AL_LIVER.SUALUNWK1) xxx.xx (MAPPINGS2:t_SUBUSE_AL_LIVER.SUALUNWK1)

Substance Use Type [hidden] (MAPPINGS1:t_SUBUSE_AL_LIVER.SUTYPCD1) (MAPPINGS2:t_SUBUSE_AL_LIVER.SUTYPCD1)

Form Design Note:

IDSL Version 01.02A 18 OCT 06

Item Design Notes:

Item No. Design Note

itmSUTYPCD1 This item will be calculated by InForm.

CDD: MAPPINGS1 Table: t_SUBUSE_AL_LIVER Key Type: PATIENTVISIT Column Name Column Data Type Design Note SUAL1 STRING(1) SUALUNWK1 FLOAT - F6.2 SUTYPCD1 STRING(255)

CDD: MAPPINGS2 Table: t_SUBUSE_AL_LIVER Key Type: PATIENTVISIT Column Name Column Data Type Design Note SUAL1 STRING(1) SUALUNWK1 FLOAT - F6.2 SUTYPCD1 STRING(255)

Annotated Trial Design Page 136 of 166

IPC103711_SHZ : LIVER IMAGING (IMAGING) - Repeating Form # Date of hepatic or What method was Are images Indicate the Indicate the Grade the diffuse and/or Ascites Are Focal Hepatic Lesions Gallstones or Biliary ductal Portal/Hepatic vein liver imaging test used for this imaging technically liver size liver texture geographic fatty infiltrate of present characterisable? gallbladder lesions? lesions? abnormalities? test? adequate? the liver 1

Date of hepatic or liver imaging test

1. Date of hepatic or liver imaging test Req / Req / Req (2007-2016) (MAPPINGS1:t_LIMAGING.LIDT) (MAPPINGS2:t_LIMAGING.LIDT)

What method was used for this imaging test? 2. What method was used for this imaging test? (MAPPINGS1:t_LIMAGING.LIMETHCD1) (MAPPINGS2:t_LIMAGING.LIMETHCD1) [1] Ultrasound - transabdominal [2] Ultrasound - endoscopic [3] Magnetic Resonance Imaging (MRI) [4] Computerised Tomography (CT) [5] Endoscopic Retrograde Cholangiopancreatography (ERCP) [6] Positron Emission Tomography (PET) [7] Positron Emission Tomography/Computerised Tomography (PET/CT) [OT] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIMETHSP) (MAPPINGS2:t_LIMAGING.LIMETHSP)

Are images technically adequate? 3. Are images technically adequate? (MAPPINGS1:t_LIMAGING.IMGADQCD1) (MAPPINGS2:t_LIMAGING.IMGADQCD1) [1] Optimal [2] Readable, but not optimal [3] Not readable [OT] Other, specify: A200 (MAPPINGS1:t_LIMAGING.IMGADQSP) (MAPPINGS2:t_LIMAGING.IMGADQSP)

Indicate the liver size 4. Indicate the liver size (MAPPINGS1:t_LIMAGING.LIORRSCDA1) (MAPPINGS2:t_LIMAGING.LIORRSCDA1) [A1] Normal size [A2] Hypertrophy (or enlarged) [A3] Atrophy (or smaller than normal) [A4] Segmental hypertrophy [A99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPA99) (MAPPINGS2:t_LIMAGING.LIORRSSPA99)

Indicate the liver texture 5. Indicate the liver texture (MAPPINGS1:t_LIMAGING.LIORRSCDB1) (MAPPINGS2:t_LIMAGING.LIORRSCDB1) [B1] Normal [B2] Heterogenous [B3] Suggestive of fibrosis [B4] Nodular or suggestive of cirrhosis [B99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPB99) (MAPPINGS2:t_LIMAGING.LIORRSSPB99)

Grade the diffuse and/or geographic fatty infiltrate of the liver 6. Grade the diffuse and/or geographic fatty infiltrate of the liver (MAPPINGS1:t_LIMAGING.LIORRSCDC1) (MAPPINGS2:t_LIMAGING.LIORRSCDC1) [C1] Not applicable - no fatty infiltration [C2] Mild (<=25%) [C3] Moderate (>25% to <75%) [C4] Severe (>=75%) [C99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPC99) (MAPPINGS2:t_LIMAGING.LIORRSSPC99)

Ascites present 7. Ascites present (MAPPINGS1:t_LIMAGING.LIORRSCDD1) (MAPPINGS2:t_LIMAGING.LIORRSCDD1) [D1] None present [D2] Yes - small amount Annotated Trial Design Page 137 of 166

[D3] Yes - moderate or severe amount [D99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPD99) (MAPPINGS2:t_LIMAGING.LIORRSSPD99)

Are Focal Hepatic Lesions characterisable? 8. Are Focal Hepatic Lesions characterisable? (MAPPINGS1:t_LIMAGING.LIORRSCDE0) (MAPPINGS2:t_LIMAGING.LIORRSCDE0) [E0] Not applicable - no hepatic lesions [E] Check all that apply (MAPPINGS1:t_LIMAGING.LIORRSCDE1) (MAPPINGS2:t_LIMAGING.LIORRSCDE1) [E1] Solid (MAPPINGS1:t_LIMAGING.LIORRSCDE2) (MAPPINGS2:t_LIMAGING.LIORRSCDE2) [E2] Cystic (MAPPINGS1:t_LIMAGING.LIORRSCDE3) (MAPPINGS2:t_LIMAGING.LIORRSCDE3) [E3] Hemangioma (MAPPINGS1:t_LIMAGING.LIORRSCDE4) (MAPPINGS2:t_LIMAGING.LIORRSCDE4) [E4] Focal Nodular Hyperplasia (MAPPINGS1:t_LIMAGING.LIORRSCDE99) (MAPPINGS2:t_LIMAGING.LIORRSCDE99) [E99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPE99) (MAPPINGS2:t_LIMAGING.LIORRSSPE99)

Gallstones or gallbladder lesions? 9. Gallstones or gallbladder lesions? (MAPPINGS1:t_LIMAGING.LIORRSCDF0) (MAPPINGS2:t_LIMAGING.LIORRSCDF0) [F0] None [F] Check all that apply (MAPPINGS1:t_LIMAGING.LIORRSCDF1) (MAPPINGS2:t_LIMAGING.LIORRSCDF1) [F1] Gallstones (MAPPINGS1:t_LIMAGING.LIORRSCDF2) (MAPPINGS2:t_LIMAGING.LIORRSCDF2) [F2] Gallbladder polyp(s) (MAPPINGS1:t_LIMAGING.LIORRSCDF3) (MAPPINGS2:t_LIMAGING.LIORRSCDF3) [F3] Sludge (MAPPINGS1:t_LIMAGING.LIORRSCDF4) (MAPPINGS2:t_LIMAGING.LIORRSCDF4) [F4] Gallbladder wall thickening/oedema (MAPPINGS1:t_LIMAGING.LIORRSCDF5) (MAPPINGS2:t_LIMAGING.LIORRSCDF5) [F5] Gallbladder wall gas (MAPPINGS1:t_LIMAGING.LIORRSCDF6) (MAPPINGS2:t_LIMAGING.LIORRSCDF6) [F6] Cholecystitis (MAPPINGS1:t_LIMAGING.LIORRSCDF7) (MAPPINGS2:t_LIMAGING.LIORRSCDF7) [F7] Gallbladder wall calcification (MAPPINGS1:t_LIMAGING.LIORRSCDF8) (MAPPINGS2:t_LIMAGING.LIORRSCDF8) [F8] Gallbladder mass (MAPPINGS1:t_LIMAGING.LIORRSCDF99) (MAPPINGS2:t_LIMAGING.LIORRSCDF99) [F99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPF99) (MAPPINGS2:t_LIMAGING.LIORRSSPF99)

Biliary ductal lesions? 10. Biliary ductal lesions? (MAPPINGS1:t_LIMAGING.LIORRSCDG0) (MAPPINGS2:t_LIMAGING.LIORRSCDG0) [G0] None [G] Check all that apply (MAPPINGS1:t_LIMAGING.LIORRSCDG1) (MAPPINGS2:t_LIMAGING.LIORRSCDG1) [G1] Intrahepatic ductal dilation (focal involving the right hepatic lobe) (MAPPINGS1:t_LIMAGING.LIORRSCDG2) (MAPPINGS2:t_LIMAGING.LIORRSCDG2) [G2] Intrahepatic ductal dilation (focal involving the left hepatic lobe) (MAPPINGS1:t_LIMAGING.LIORRSCDG3) (MAPPINGS2:t_LIMAGING.LIORRSCDG3) Annotated Trial Design Page 138 of 166

[G3] Intrahepatic ductal dilation (focal involving both right and left hepatic lobes) (MAPPINGS1:t_LIMAGING.LIORRSCDG4) (MAPPINGS2:t_LIMAGING.LIORRSCDG4) [G4] Extrahepatic ductal dilation (MAPPINGS1:t_LIMAGING.LIORRSCDG5) (MAPPINGS2:t_LIMAGING.LIORRSCDG5) [G5] Diffuse ductal dilation (involving both intrahepatic and extrahepatic ducts) (MAPPINGS1:t_LIMAGING.LIORRSCDG6) (MAPPINGS2:t_LIMAGING.LIORRSCDG6) [G6] Acute Cholangitis (MAPPINGS1:t_LIMAGING.LIORRSCDG7) (MAPPINGS2:t_LIMAGING.LIORRSCDG7) [G7] Primary sclerosing cholangitis (MAPPINGS1:t_LIMAGING.LIORRSCDG8) (MAPPINGS2:t_LIMAGING.LIORRSCDG8) [G8] Choledocholithiasis (gallstone in duct) (MAPPINGS1:t_LIMAGING.LIORRSCDG9) (MAPPINGS2:t_LIMAGING.LIORRSCDG9) [G9] Ductal filling defect(s), other than gallstone (MAPPINGS1:t_LIMAGING.LIORRSCDG10) (MAPPINGS2:t_LIMAGING.LIORRSCDG10) [G10] Ductal wall thickening or oedema (MAPPINGS1:t_LIMAGING.LIORRSCDG11) (MAPPINGS2:t_LIMAGING.LIORRSCDG11) [G11] Choledochal cyst (MAPPINGS1:t_LIMAGING.LIORRSCDG12) (MAPPINGS2:t_LIMAGING.LIORRSCDG12) [G12] Ductal mass (MAPPINGS1:t_LIMAGING.LIORRSCDG13) (MAPPINGS2:t_LIMAGING.LIORRSCDG13) [G13] Extrinsic mass compressing bile duct(s) (MAPPINGS1:t_LIMAGING.LIORRSCDG99) (MAPPINGS2:t_LIMAGING.LIORRSCDG99) [G99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPG99) (MAPPINGS2:t_LIMAGING.LIORRSSPG99)

Portal/Hepatic vein abnormalities? 11. Portal/Hepatic vein abnormalities? (MAPPINGS1:t_LIMAGING.LIORRSCDH0) (MAPPINGS2:t_LIMAGING.LIORRSCDH0) [H0] None [H] Check all that apply (MAPPINGS1:t_LIMAGING.LIORRSCDH1) (MAPPINGS2:t_LIMAGING.LIORRSCDH1) [H1] Portal vein enlargement (MAPPINGS1:t_LIMAGING.LIORRSCDH2) (MAPPINGS2:t_LIMAGING.LIORRSCDH2) [H2] Hepatic vein enlargement (MAPPINGS1:t_LIMAGING.LIORRSCDH3) (MAPPINGS2:t_LIMAGING.LIORRSCDH3) [H3] Nonocclusive portal vein thrombosis (MAPPINGS1:t_LIMAGING.LIORRSCDH4) (MAPPINGS2:t_LIMAGING.LIORRSCDH4) [H4] Occlusive portal vein thrombosis - bland (MAPPINGS1:t_LIMAGING.LIORRSCDH5) (MAPPINGS2:t_LIMAGING.LIORRSCDH5) [H5] Hepatic vein thrombosis - bland (MAPPINGS1:t_LIMAGING.LIORRSCDH6) (MAPPINGS2:t_LIMAGING.LIORRSCDH6) [H6] Occlusive portal vein thrombosis - malignant (MAPPINGS1:t_LIMAGING.LIORRSCDH7) (MAPPINGS2:t_LIMAGING.LIORRSCDH7) [H7] Hepatic vein thrombosis - malignant (MAPPINGS1:t_LIMAGING.LIORRSCDH8) (MAPPINGS2:t_LIMAGING.LIORRSCDH8) [H8] Involvement of the main portal vein (MAPPINGS1:t_LIMAGING.LIORRSCDH9) (MAPPINGS2:t_LIMAGING.LIORRSCDH9) [H9] Involvement of the right portal vein (MAPPINGS1:t_LIMAGING.LIORRSCDH10) (MAPPINGS2:t_LIMAGING.LIORRSCDH10) [H10] Involvement of the left portal vein (MAPPINGS1:t_LIMAGING.LIORRSCDH11) (MAPPINGS2:t_LIMAGING.LIORRSCDH11) [H11] Budd-Chiari syndrome Annotated Trial Design Page 139 of 166

(MAPPINGS1:t_LIMAGING.LIORRSCDH99) (MAPPINGS2:t_LIMAGING.LIORRSCDH99) [H99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPH99) (MAPPINGS2:t_LIMAGING.LIORRSSPH99)

Form Design Note:

IDSL Version 01.02A 05 OCT 06

CDD: MAPPINGS1 Table: t_LIMAGING Key Type: PATIENTVISIT Column Name Column Data Type Design Note LIDT DATE - DDMONYYYY LIMETHCD1 STRING(2) LIMETHSP STRING(200) - A200 IMGADQCD1 STRING(2) IMGADQSP STRING(200) - A200 LIORRSCDA1 STRING(3) LIORRSSPA99 STRING(200) - A200 LIORRSCDB1 STRING(3) LIORRSSPB99 STRING(200) - A200 LIORRSCDC1 STRING(3) LIORRSSPC99 STRING(200) - A200 LIORRSCDD1 STRING(3) LIORRSSPD99 STRING(200) - A200 LIORRSCDE0 STRING(2) LIORRSCDE1 STRING(255) LIORRSCDE2 STRING(255) LIORRSCDE3 STRING(255) LIORRSCDE4 STRING(255) LIORRSCDE99 STRING(255) LIORRSSPE99 STRING(200) - A200 LIORRSCDF0 STRING(2) LIORRSCDF1 STRING(255) LIORRSCDF2 STRING(255) LIORRSCDF3 STRING(255) LIORRSCDF4 STRING(255) LIORRSCDF5 STRING(255) LIORRSCDF6 STRING(255) LIORRSCDF7 STRING(255) LIORRSCDF8 STRING(255) LIORRSCDF99 STRING(255) LIORRSSPF99 STRING(200) - A200 LIORRSCDG0 STRING(2) LIORRSCDG1 STRING(255) LIORRSCDG2 STRING(255) LIORRSCDG3 STRING(255) LIORRSCDG4 STRING(255) LIORRSCDG5 STRING(255) LIORRSCDG6 STRING(255) LIORRSCDG7 STRING(255) LIORRSCDG8 STRING(255) LIORRSCDG9 STRING(255) Annotated Trial Design Page 140 of 166

LIORRSCDG10 STRING(255) LIORRSCDG11 STRING(255) LIORRSCDG12 STRING(255) LIORRSCDG13 STRING(255) LIORRSCDG99 STRING(255) LIORRSSPG99 STRING(200) - A200 LIORRSCDH0 STRING(2) LIORRSCDH1 STRING(255) LIORRSCDH2 STRING(255) LIORRSCDH3 STRING(255) LIORRSCDH4 STRING(255) LIORRSCDH5 STRING(255) LIORRSCDH6 STRING(255) LIORRSCDH7 STRING(255) LIORRSCDH8 STRING(255) LIORRSCDH9 STRING(255) LIORRSCDH10 STRING(255) LIORRSCDH11 STRING(255) LIORRSCDH99 STRING(255) LIORRSSPH99 STRING(200) - A200

CDD: MAPPINGS2 Table: t_LIMAGING Key Type: PATIENTVISIT Column Name Column Data Type Design Note LIDT DATE - DDMONYYYY LIMETHCD1 STRING(2) LIMETHSP STRING(200) - A200 IMGADQCD1 STRING(2) IMGADQSP STRING(200) - A200 LIORRSCDA1 STRING(3) LIORRSSPA99 STRING(200) - A200 LIORRSCDB1 STRING(3) LIORRSSPB99 STRING(200) - A200 LIORRSCDC1 STRING(3) LIORRSSPC99 STRING(200) - A200 LIORRSCDD1 STRING(3) LIORRSSPD99 STRING(200) - A200 LIORRSCDE0 STRING(2) LIORRSCDE1 STRING(255) LIORRSCDE2 STRING(255) LIORRSCDE3 STRING(255) LIORRSCDE4 STRING(255) LIORRSCDE99 STRING(255) LIORRSSPE99 STRING(200) - A200 LIORRSCDF0 STRING(2) LIORRSCDF1 STRING(255) LIORRSCDF2 STRING(255) LIORRSCDF3 STRING(255) LIORRSCDF4 STRING(255) LIORRSCDF5 STRING(255) LIORRSCDF6 STRING(255) LIORRSCDF7 STRING(255) Annotated Trial Design Page 141 of 166

LIORRSCDF8 STRING(255) LIORRSCDF99 STRING(255) LIORRSSPF99 STRING(200) - A200 LIORRSCDG0 STRING(2) LIORRSCDG1 STRING(255) LIORRSCDG2 STRING(255) LIORRSCDG3 STRING(255) LIORRSCDG4 STRING(255) LIORRSCDG5 STRING(255) LIORRSCDG6 STRING(255) LIORRSCDG7 STRING(255) LIORRSCDG8 STRING(255) LIORRSCDG9 STRING(255) LIORRSCDG10 STRING(255) LIORRSCDG11 STRING(255) LIORRSCDG12 STRING(255) LIORRSCDG13 STRING(255) LIORRSCDG99 STRING(255) LIORRSSPG99 STRING(200) - A200 LIORRSCDH0 STRING(2) LIORRSCDH1 STRING(255) LIORRSCDH2 STRING(255) LIORRSCDH3 STRING(255) LIORRSCDH4 STRING(255) LIORRSCDH5 STRING(255) LIORRSCDH6 STRING(255) LIORRSCDH7 STRING(255) LIORRSCDH8 STRING(255) LIORRSCDH9 STRING(255) LIORRSCDH10 STRING(255) LIORRSCDH11 STRING(255) LIORRSCDH99 STRING(255) LIORRSSPH99 STRING(200) - A200

Annotated Trial Design Page 142 of 166

IPC103711_SHZ : LIVER BIOPSY (BIOPSY) - Repeating Form # Date of Biopsy Final Liver Description of Liver Liver Cell or Hepatocyte or Liver Cell Liver or Portal Tract Bile Portal Liver Parasites Histologic Staining or liver size Diagnosis Architecture Cells or Hepatocytes Hepatocyte Inclusions Nuclear Abnormalities Lobular Inflammation Ducts Veins Infections or Ova Additional Studies biopsy or Vacuoles Infiltrates Obtained 1

Date of liver biopsy

1. Date of liver biopsy Req / Req / Req (2006-2016) (MAPPINGS1:t_LBIOPSY.LPDT) (MAPPINGS2:t_LBIOPSY.LPDT)

Biopsy size

2. Approximate size of liver biopsy xx mm (MAPPINGS1:t_LBIOPSY.BIOPSZ) (MAPPINGS2:t_LBIOPSY.BIOPSZ)

3.* Biopsy size unit [hidden] MM Final Diagnosis 4. Final Diagnosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA0NOR) (MAPPINGS2:t_LBIOPSY.LPORRSCDA0NOR) [A0] Normal [AAA] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDA1) (MAPPINGS2:t_LBIOPSY.LPORRSCDA1) [A1] Acute hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA2) (MAPPINGS2:t_LBIOPSY.LPORRSCDA2) [A2] Chronic hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA3) (MAPPINGS2:t_LBIOPSY.LPORRSCDA3) [A3] Cholestatic hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA4) (MAPPINGS2:t_LBIOPSY.LPORRSCDA4) [A4] Drug-induced cholestasis (MAPPINGS1:t_LBIOPSY.LPORRSCDA5) (MAPPINGS2:t_LBIOPSY.LPORRSCDA5) [A5] Acute viral hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA6) (MAPPINGS2:t_LBIOPSY.LPORRSCDA6) [A6] Chronic viral hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA7) (MAPPINGS2:t_LBIOPSY.LPORRSCDA7) [A7] Drug-induced hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA8) (MAPPINGS2:t_LBIOPSY.LPORRSCDA8) [A8] Autoimmune hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA9) (MAPPINGS2:t_LBIOPSY.LPORRSCDA9) [A9] Bridging necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA10) (MAPPINGS2:t_LBIOPSY.LPORRSCDA10) [A10] Submassive hepatic necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA11) (MAPPINGS2:t_LBIOPSY.LPORRSCDA11) [A11] Massive hepatic necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA12) (MAPPINGS2:t_LBIOPSY.LPORRSCDA12) [A12] Steatosis - microvesicular (MAPPINGS1:t_LBIOPSY.LPORRSCDA13) (MAPPINGS2:t_LBIOPSY.LPORRSCDA13) [A13] Steatosis - macrovesicular (MAPPINGS1:t_LBIOPSY.LPORRSCDA14) (MAPPINGS2:t_LBIOPSY.LPORRSCDA14) [A14] Steatosis - mixed (MAPPINGS1:t_LBIOPSY.LPORRSCDA15) (MAPPINGS2:t_LBIOPSY.LPORRSCDA15) [A15] Non-alcoholic steatohepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA16) (MAPPINGS2:t_LBIOPSY.LPORRSCDA16) [A16] Alcoholic hepatitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA17) (MAPPINGS2:t_LBIOPSY.LPORRSCDA17) Annotated Trial Design Page 143 of 166

[A17] Hepatic granulomas (MAPPINGS1:t_LBIOPSY.LPORRSCDA18) (MAPPINGS2:t_LBIOPSY.LPORRSCDA18) [A18] Sarcoidosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA19) (MAPPINGS2:t_LBIOPSY.LPORRSCDA19) [A19] Fibrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA20) (MAPPINGS2:t_LBIOPSY.LPORRSCDA20) [A20] Cirrhosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA21) (MAPPINGS2:t_LBIOPSY.LPORRSCDA21) [A21] Primary biliary cirrhosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA22) (MAPPINGS2:t_LBIOPSY.LPORRSCDA22) [A22] Primary sclerosing cholangitis (MAPPINGS1:t_LBIOPSY.LPORRSCDA23) (MAPPINGS2:t_LBIOPSY.LPORRSCDA23) [A23] Autoimmune overlap syndrome (MAPPINGS1:t_LBIOPSY.LPORRSCDA24) (MAPPINGS2:t_LBIOPSY.LPORRSCDA24) [A24] Hemochromatosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA25) (MAPPINGS2:t_LBIOPSY.LPORRSCDA25) [A25] Alpha-1-antitrypsin deficiency (MAPPINGS1:t_LBIOPSY.LPORRSCDA26) (MAPPINGS2:t_LBIOPSY.LPORRSCDA26) [A26] Wilson's disease (MAPPINGS1:t_LBIOPSY.LPORRSCDA27) (MAPPINGS2:t_LBIOPSY.LPORRSCDA27) [A27] Veno-occlusive disease (MAPPINGS1:t_LBIOPSY.LPORRSCDA28) (MAPPINGS2:t_LBIOPSY.LPORRSCDA28) [A28] Budd-Chiari syndrome (MAPPINGS1:t_LBIOPSY.LPORRSCDA29) (MAPPINGS2:t_LBIOPSY.LPORRSCDA29) [A29] Neoplasia (MAPPINGS1:t_LBIOPSY.LPORRSCDA99) (MAPPINGS2:t_LBIOPSY.LPORRSCDA99) [A99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPA99) (MAPPINGS2:t_LBIOPSY.LPORRSSPA99)

Liver Architecture 5. Liver Architecture (MAPPINGS1:t_LBIOPSY.LPORRSCDB1NORM) (MAPPINGS2:t_LBIOPSY.LPORRSCDB1NORM) [B1] Normal [BBB] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDB2) (MAPPINGS2:t_LBIOPSY.LPORRSCDB2) [B2] Bridging fibrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB3) (MAPPINGS2:t_LBIOPSY.LPORRSCDB3) [B3] Diffuse fibrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB4) (MAPPINGS2:t_LBIOPSY.LPORRSCDB4) [B4] Nodular regenerative hyperplasia (MAPPINGS1:t_LBIOPSY.LPORRSCDB5) (MAPPINGS2:t_LBIOPSY.LPORRSCDB5) [B5] Congenital hepatic fibrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB6) (MAPPINGS2:t_LBIOPSY.LPORRSCDB6) [B6] Cirrhosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB7) (MAPPINGS2:t_LBIOPSY.LPORRSCDB7) [B7] Centrilobular congestion (MAPPINGS1:t_LBIOPSY.LPORRSCDB8) (MAPPINGS2:t_LBIOPSY.LPORRSCDB8) [B8] Endophlebitis (MAPPINGS1:t_LBIOPSY.LPORRSCDB9) (MAPPINGS2:t_LBIOPSY.LPORRSCDB9) [B9] Veno-occlusive disease (MAPPINGS1:t_LBIOPSY.LPORRSCDB10) (MAPPINGS2:t_LBIOPSY.LPORRSCDB10) [B10] Canalicular cholestasis Annotated Trial Design Page 144 of 166

(MAPPINGS1:t_LBIOPSY.LPORRSCDB11) (MAPPINGS2:t_LBIOPSY.LPORRSCDB11) [B11] Apoptosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB12) (MAPPINGS2:t_LBIOPSY.LPORRSCDB12) [B12] Focal (or spotty or mild) hepatocellular necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB13) (MAPPINGS2:t_LBIOPSY.LPORRSCDB13) [B13] Interface hepatitis (periportal hepatitis or piecemeal necrosis) (MAPPINGS1:t_LBIOPSY.LPORRSCDB14) (MAPPINGS2:t_LBIOPSY.LPORRSCDB14) [B14] Ischaemic necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB15) (MAPPINGS2:t_LBIOPSY.LPORRSCDB15) [B15] Centrolobular (Zone 3) necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB16) (MAPPINGS2:t_LBIOPSY.LPORRSCDB16) [B16] Focal coagulative necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB17) (MAPPINGS2:t_LBIOPSY.LPORRSCDB17) [B17] Centrolobular (Zone 3) coagulative necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB18) (MAPPINGS2:t_LBIOPSY.LPORRSCDB18) [B18] Bridging hepatocellular necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB19) (MAPPINGS2:t_LBIOPSY.LPORRSCDB19) [B19] Massive or panlobular hepatocellular necrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDB20) (MAPPINGS2:t_LBIOPSY.LPORRSCDB20) [B20] Dysplasia (MAPPINGS1:t_LBIOPSY.LPORRSCDB21) (MAPPINGS2:t_LBIOPSY.LPORRSCDB21) [B21] Neoplasia (MAPPINGS1:t_LBIOPSY.LPORRSCDB99) (MAPPINGS2:t_LBIOPSY.LPORRSCDB99) [B99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPB99) (MAPPINGS2:t_LBIOPSY.LPORRSSPB99)

Description of Liver Cells or Hepatocytes 6. Description of Liver Cells or Hepatocytes (MAPPINGS1:t_LBIOPSY.LPORRSCDC0NOR) (MAPPINGS2:t_LBIOPSY.LPORRSCDC0NOR) [C0] Normal [CCC] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDC1) (MAPPINGS2:t_LBIOPSY.LPORRSCDC1) [C1] Ballooning (MAPPINGS1:t_LBIOPSY.LPORRSCDC2) (MAPPINGS2:t_LBIOPSY.LPORRSCDC2) [C2] Acidophilic (MAPPINGS1:t_LBIOPSY.LPORRSCDC3) (MAPPINGS2:t_LBIOPSY.LPORRSCDC3) [C3] Pseudoxanthomatous (MAPPINGS1:t_LBIOPSY.LPORRSCDC4) (MAPPINGS2:t_LBIOPSY.LPORRSCDC4) [C4] Multinucleated giant hepatocytes (MAPPINGS1:t_LBIOPSY.LPORRSCDC99) (MAPPINGS2:t_LBIOPSY.LPORRSCDC99) [C99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPC99) (MAPPINGS2:t_LBIOPSY.LPORRSSPC99)

Liver Cell or Hepatocyte Inclusions or Vacuoles 7. Liver Cell or Hepatocyte Inclusions or Vacuoles (MAPPINGS1:t_LBIOPSY.LPORRSCDDONOINC) (MAPPINGS2:t_LBIOPSY.LPORRSCDDONOINC) [D0] No inclusions [DDD] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDD1) (MAPPINGS2:t_LBIOPSY.LPORRSCDD1) [D1] Macrovesicular steatosis (MAPPINGS1:t_LBIOPSY.LPORRSCDD2) (MAPPINGS2:t_LBIOPSY.LPORRSCDD2) [D2] Microvesicular steatosis (MAPPINGS1:t_LBIOPSY.LPORRSCDD3) (MAPPINGS2:t_LBIOPSY.LPORRSCDD3) [D3] Bile accumulation Annotated Trial Design Page 145 of 166

(MAPPINGS1:t_LBIOPSY.LPORRSCDD4) (MAPPINGS2:t_LBIOPSY.LPORRSCDD4) [D4] Diastase-resistant, PAS-positive cytoplasmic inclusions (MAPPINGS1:t_LBIOPSY.LPORRSCDD5) (MAPPINGS2:t_LBIOPSY.LPORRSCDD5) [D5] Alpha-1-antitrypsin inclusions (MAPPINGS1:t_LBIOPSY.LPORRSCDD6) (MAPPINGS2:t_LBIOPSY.LPORRSCDD6) [D6] Megamitochondria (MAPPINGS1:t_LBIOPSY.LPORRSCDD7) (MAPPINGS2:t_LBIOPSY.LPORRSCDD7) [D7] Mallory bodies (MAPPINGS1:t_LBIOPSY.LPORRSCDD8) (MAPPINGS2:t_LBIOPSY.LPORRSCDD8) [D8] "Ground Glass" inclusions (MAPPINGS1:t_LBIOPSY.LPORRSCDD9) (MAPPINGS2:t_LBIOPSY.LPORRSCDD9) [D9] Lipofuscin pigment (MAPPINGS1:t_LBIOPSY.LPORRSCDD10) (MAPPINGS2:t_LBIOPSY.LPORRSCDD10) [D10] Hemosiderin granules (MAPPINGS1:t_LBIOPSY.LPORRSCDD11) (MAPPINGS2:t_LBIOPSY.LPORRSCDD11) [D11] Orcein-positive cytoplasmin granules (MAPPINGS1:t_LBIOPSY.LPORRSCDD12) (MAPPINGS2:t_LBIOPSY.LPORRSCDD12) [D12] Protoporphyrin crystals (birefringent under polarised light) (MAPPINGS1:t_LBIOPSY.LPORRSCDD13) (MAPPINGS2:t_LBIOPSY.LPORRSCDD13) [D13] Uroporphyrin crystals (red fluorescence under ultraviolet light) (MAPPINGS1:t_LBIOPSY.LPORRSCDD99) (MAPPINGS2:t_LBIOPSY.LPORRSCDD99) [D99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPD99) (MAPPINGS2:t_LBIOPSY.LPORRSSPD99)

Hepatocyte or Liver Cell Nuclear Abnormalities 8. Hepatocyte or Liver Cell Nuclear Abnormalities (MAPPINGS1:t_LBIOPSY.LPORRSCDE0NONE) (MAPPINGS2:t_LBIOPSY.LPORRSCDE0NONE) [E0] None [EEE] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDE1) (MAPPINGS2:t_LBIOPSY.LPORRSCDE1) [E1] Hepatocellular mitosis (MAPPINGS1:t_LBIOPSY.LPORRSCDE2) (MAPPINGS2:t_LBIOPSY.LPORRSCDE2) [E2] Binucleated or multinucleated hepatocytes (MAPPINGS1:t_LBIOPSY.LPORRSCDE3) (MAPPINGS2:t_LBIOPSY.LPORRSCDE3) [E3] CMV inclusion bodies (MAPPINGS1:t_LBIOPSY.LPORRSCDE4) (MAPPINGS2:t_LBIOPSY.LPORRSCDE4) [E4] HSV inclusions (MAPPINGS1:t_LBIOPSY.LPORRSCDE5) (MAPPINGS2:t_LBIOPSY.LPORRSCDE5) [E5] Varicella inclusions (MAPPINGS1:t_LBIOPSY.LPORRSCDE99) (MAPPINGS2:t_LBIOPSY.LPORRSCDE99) [E99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPE99) (MAPPINGS2:t_LBIOPSY.LPORRSSPE99)

Liver or Lobular Infiltrates 9. Liver or Lobular Infiltrates (MAPPINGS1:t_LBIOPSY.LPORRSCDF0NONE) (MAPPINGS2:t_LBIOPSY.LPORRSCDF0NONE) [F0] None [FFF] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDF1) (MAPPINGS2:t_LBIOPSY.LPORRSCDF1) [F1] Eosinophils (MAPPINGS1:t_LBIOPSY.LPORRSCDF2) (MAPPINGS2:t_LBIOPSY.LPORRSCDF2) [F2] Lymphocytes (MAPPINGS1:t_LBIOPSY.LPORRSCDF3) (MAPPINGS2:t_LBIOPSY.LPORRSCDF3) [F3] Plasma cells Annotated Trial Design Page 146 of 166

(MAPPINGS1:t_LBIOPSY.LPORRSCDF4) (MAPPINGS2:t_LBIOPSY.LPORRSCDF4) [F4] Neutrophils (MAPPINGS1:t_LBIOPSY.LPORRSCDF5) (MAPPINGS2:t_LBIOPSY.LPORRSCDF5) [F5] Macrophages and proliferating Kupffer cells (MAPPINGS1:t_LBIOPSY.LPORRSCDF6) (MAPPINGS2:t_LBIOPSY.LPORRSCDF6) [F6] Granulomas (MAPPINGS1:t_LBIOPSY.LPORRSCDF99) (MAPPINGS2:t_LBIOPSY.LPORRSCDF99) [F99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPF99) (MAPPINGS2:t_LBIOPSY.LPORRSSPF99)

Portal Tract Inflammation 10. Portal Tract Inflammation (MAPPINGS1:t_LBIOPSY.LPORRSCDG0NONE) (MAPPINGS2:t_LBIOPSY.LPORRSCDG0NONE) [G0] None [GGG] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDG1) (MAPPINGS2:t_LBIOPSY.LPORRSCDG1) [G1] Eosinophils (MAPPINGS1:t_LBIOPSY.LPORRSCDG2) (MAPPINGS2:t_LBIOPSY.LPORRSCDG2) [G2] Lymphoid aggregates and/or follicles (MAPPINGS1:t_LBIOPSY.LPORRSCDG3) (MAPPINGS2:t_LBIOPSY.LPORRSCDG3) [G3] Plasma cells (MAPPINGS1:t_LBIOPSY.LPORRSCDG4) (MAPPINGS2:t_LBIOPSY.LPORRSCDG4) [G4] Neutrophils (MAPPINGS1:t_LBIOPSY.LPORRSCDG5) (MAPPINGS2:t_LBIOPSY.LPORRSCDG5) [G5] Histocytes and macrophages (MAPPINGS1:t_LBIOPSY.LPORRSCDG99) (MAPPINGS2:t_LBIOPSY.LPORRSCDG99) [G99] Other, specify A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPG99) (MAPPINGS2:t_LBIOPSY.LPORRSSPG99)

Bile Ducts 11. Bile Ducts (MAPPINGS1:t_LBIOPSY.LPORRSCDH0NOR) (MAPPINGS2:t_LBIOPSY.LPORRSCDH0NOR) [H0] Normal [HHH] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDH1) (MAPPINGS2:t_LBIOPSY.LPORRSCDH1) [H1] Proliferation of bile ducts (bile ductular reaction) (MAPPINGS1:t_LBIOPSY.LPORRSCDH2) (MAPPINGS2:t_LBIOPSY.LPORRSCDH2) [H2] Dilation, degeneration or disruption of portal bile ducts (MAPPINGS1:t_LBIOPSY.LPORRSCDH3) (MAPPINGS2:t_LBIOPSY.LPORRSCDH3) [H3] Paucity of bile ducts (MAPPINGS1:t_LBIOPSY.LPORRSCDH4) (MAPPINGS2:t_LBIOPSY.LPORRSCDH4) [H4] Periductal fibrosis (MAPPINGS1:t_LBIOPSY.LPORRSCDH99) (MAPPINGS2:t_LBIOPSY.LPORRSCDH99) [H99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPH99) (MAPPINGS2:t_LBIOPSY.LPORRSSPH99)

Portal Veins 12. Portal Veins (MAPPINGS1:t_LBIOPSY.LPORRSCDI0NOR) (MAPPINGS2:t_LBIOPSY.LPORRSCDI0NOR) [I0] Normal [III] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDI1) (MAPPINGS2:t_LBIOPSY.LPORRSCDI1) [I1] Pyelophlebitis (MAPPINGS1:t_LBIOPSY.LPORRSCDI2) (MAPPINGS2:t_LBIOPSY.LPORRSCDI2) [I2] Thrombosis, sclerosis or occlusion of portal vein (MAPPINGS1:t_LBIOPSY.LPORRSCDI3) Annotated Trial Design Page 147 of 166

(MAPPINGS2:t_LBIOPSY.LPORRSCDI3) [I3] Neoplastic invasion of portal vein (MAPPINGS1:t_LBIOPSY.LPORRSCDI4) (MAPPINGS2:t_LBIOPSY.LPORRSCDI4) [I4] Granulomatous compression of portal vein (MAPPINGS1:t_LBIOPSY.LPORRSCDI99) (MAPPINGS2:t_LBIOPSY.LPORRSCDI99) [I99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPI99) (MAPPINGS2:t_LBIOPSY.LPORRSSPI99)

Liver Infections 13. Liver Infections (MAPPINGS1:t_LBIOPSY.LPORRSCDJ0NOR) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ0NOR) [J0] Normal [JJJ] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDJ1) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ1) [J1] Leishmaniasis donovani (MAPPINGS1:t_LBIOPSY.LPORRSCDJ2) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ2) [J2] Plasmodium falciparum (MAPPINGS1:t_LBIOPSY.LPORRSCDJ3) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ3) [J3] Toxoplasmosis (MAPPINGS1:t_LBIOPSY.LPORRSCDJ4) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ4) [J4] Cryptococcus neoformans (MAPPINGS1:t_LBIOPSY.LPORRSCDJ5) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ5) [J5] Histoplasma capsulatum (MAPPINGS1:t_LBIOPSY.LPORRSCDJ6) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ6) [J6] Mycobacterium tuberculois (MAPPINGS1:t_LBIOPSY.LPORRSCDJ7) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ7) [J7] Other mycobacterial species (MAPPINGS1:t_LBIOPSY.LPORRSCDJ99) (MAPPINGS2:t_LBIOPSY.LPORRSCDJ99) [J99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPJ99) (MAPPINGS2:t_LBIOPSY.LPORRSSPJ99)

Parasites or Ova 14. Parasites or Ova (MAPPINGS1:t_LBIOPSY.LPORRSCDK0NONE) (MAPPINGS2:t_LBIOPSY.LPORRSCDK0NONE) [K0] None [KKK] Check all that apply (MAPPINGS1:t_LBIOPSY.LPORRSCDK1) (MAPPINGS2:t_LBIOPSY.LPORRSCDK1) [K1] Schistosome and/or ova (MAPPINGS1:t_LBIOPSY.LPORRSCDK2) (MAPPINGS2:t_LBIOPSY.LPORRSCDK2) [K2] Ascaris and/or ova (MAPPINGS1:t_LBIOPSY.LPORRSCDK3) (MAPPINGS2:t_LBIOPSY.LPORRSCDK3) [K3] Toxocara and/or ova (MAPPINGS1:t_LBIOPSY.LPORRSCDK4) (MAPPINGS2:t_LBIOPSY.LPORRSCDK4) [K4] Echinococcus cysts (MAPPINGS1:t_LBIOPSY.LPORRSCDK5) (MAPPINGS2:t_LBIOPSY.LPORRSCDK5) [K5] Hepatic capillariasis worms and/or ova (MAPPINGS1:t_LBIOPSY.LPORRSCDK99) (MAPPINGS2:t_LBIOPSY.LPORRSCDK99) [K99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPK99) (MAPPINGS2:t_LBIOPSY.LPORRSSPK99)

Histologic Staining or Additional Studies Obtained 15. Histologic Staining or Additional Studies Obtained (MAPPINGS1:t_LBIOPSY.LPORRSCDL1) (MAPPINGS2:t_LBIOPSY.LPORRSCDL1) [L1] Haematoxylin and eosin (or H & E) (MAPPINGS1:t_LBIOPSY.LPORRSCDL2) (MAPPINGS2:t_LBIOPSY.LPORRSCDL2) [L2] Masson (MAPPINGS1:t_LBIOPSY.LPORRSCDL3) Annotated Trial Design Page 148 of 166

(MAPPINGS2:t_LBIOPSY.LPORRSCDL3) [L3] Toluidine blue or Giemsa (MAPPINGS1:t_LBIOPSY.LPORRSCDL4) (MAPPINGS2:t_LBIOPSY.LPORRSCDL4) [L4] Prussian blue (MAPPINGS1:t_LBIOPSY.LPORRSCDL5) (MAPPINGS2:t_LBIOPSY.LPORRSCDL5) [L5] Periodic Acidic Schiff (PAS), with or without diastase (MAPPINGS1:t_LBIOPSY.LPORRSCDL6) (MAPPINGS2:t_LBIOPSY.LPORRSCDL6) [L6] Oil red O (MAPPINGS1:t_LBIOPSY.LPORRSCDL7) (MAPPINGS2:t_LBIOPSY.LPORRSCDL7) [L7] Congo red (MAPPINGS1:t_LBIOPSY.LPORRSCDL8) (MAPPINGS2:t_LBIOPSY.LPORRSCDL8) [L8] Hall's stain (MAPPINGS1:t_LBIOPSY.LPORRSCDL9) (MAPPINGS2:t_LBIOPSY.LPORRSCDL9) [L9] Gridley's stain (MAPPINGS1:t_LBIOPSY.LPORRSCDL10) (MAPPINGS2:t_LBIOPSY.LPORRSCDL10) [L10] Rhodanine (copper) (MAPPINGS1:t_LBIOPSY.LPORRSCDL11) (MAPPINGS2:t_LBIOPSY.LPORRSCDL11) [L11] Rubeanic acid (copper) (MAPPINGS1:t_LBIOPSY.LPORRSCDL12) (MAPPINGS2:t_LBIOPSY.LPORRSCDL12) [L12] Orcein, aldehyde fuchsin or Victoria blue (MAPPINGS1:t_LBIOPSY.LPORRSCDL13) (MAPPINGS2:t_LBIOPSY.LPORRSCDL13) [L13] Electron microscopy (MAPPINGS1:t_LBIOPSY.LPORRSCDL14) (MAPPINGS2:t_LBIOPSY.LPORRSCDL14) [L14] Hepatitis A immunostains positive (MAPPINGS1:t_LBIOPSY.LPORRSCDL15) (MAPPINGS2:t_LBIOPSY.LPORRSCDL15) [L15] Hepatitis B core antigen or hepatitis B surface antibody immunostains positive (MAPPINGS1:t_LBIOPSY.LPORRSCDL16) (MAPPINGS2:t_LBIOPSY.LPORRSCDL16) [L16] Hepatitis D immunostains (MAPPINGS1:t_LBIOPSY.LPORRSCDL17) (MAPPINGS2:t_LBIOPSY.LPORRSCDL17) [L17] Other immunostains (MAPPINGS1:t_LBIOPSY.LPORRSCDL99) (MAPPINGS2:t_LBIOPSY.LPORRSCDL99) [L99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPL99) (MAPPINGS2:t_LBIOPSY.LPORRSSPL99)

* Item is not required

Form Design Note:

IDSL Version 01.02A 05 OCT 06

CDD: MAPPINGS1 Table: t_LBIOPSY Key Type: PATIENTVISIT Column Name Column Data Type Design Note LPDT DATE - DDMONYYYY BIOPSZ NUMERIC - N2 LPORRSCDA0NOR STRING(3) LPORRSCDA1 STRING(255) LPORRSCDA2 STRING(255) LPORRSCDA3 STRING(255) LPORRSCDA4 STRING(255) LPORRSCDA5 STRING(255) LPORRSCDA6 STRING(255) LPORRSCDA7 STRING(255) Annotated Trial Design Page 149 of 166

LPORRSCDA8 STRING(255) LPORRSCDA9 STRING(255) LPORRSCDA10 STRING(255) LPORRSCDA11 STRING(255) LPORRSCDA12 STRING(255) LPORRSCDA13 STRING(255) LPORRSCDA14 STRING(255) LPORRSCDA15 STRING(255) LPORRSCDA16 STRING(255) LPORRSCDA17 STRING(255) LPORRSCDA18 STRING(255) LPORRSCDA19 STRING(255) LPORRSCDA20 STRING(255) LPORRSCDA21 STRING(255) LPORRSCDA22 STRING(255) LPORRSCDA23 STRING(255) LPORRSCDA24 STRING(255) LPORRSCDA25 STRING(255) LPORRSCDA26 STRING(255) LPORRSCDA27 STRING(255) LPORRSCDA28 STRING(255) LPORRSCDA29 STRING(255) LPORRSCDA99 STRING(255) LPORRSSPA99 STRING(200) - A200 LPORRSCDB1NORM STRING(3) LPORRSCDB2 STRING(255) LPORRSCDB3 STRING(255) LPORRSCDB4 STRING(255) LPORRSCDB5 STRING(255) LPORRSCDB6 STRING(255) LPORRSCDB7 STRING(255) LPORRSCDB8 STRING(255) LPORRSCDB9 STRING(255) LPORRSCDB10 STRING(255) LPORRSCDB11 STRING(255) LPORRSCDB12 STRING(255) LPORRSCDB13 STRING(255) LPORRSCDB14 STRING(255) LPORRSCDB15 STRING(255) LPORRSCDB16 STRING(255) LPORRSCDB17 STRING(255) LPORRSCDB18 STRING(255) LPORRSCDB19 STRING(255) LPORRSCDB20 STRING(255) LPORRSCDB21 STRING(255) LPORRSCDB99 STRING(255) LPORRSSPB99 STRING(200) - A200 LPORRSCDC0NOR STRING(3) LPORRSCDC1 STRING(255) LPORRSCDC2 STRING(255) LPORRSCDC3 STRING(255) Annotated Trial Design Page 150 of 166

LPORRSCDC4 STRING(255) LPORRSCDC99 STRING(255) LPORRSSPC99 STRING(200) - A200 LPORRSCDDONOINC STRING(3) LPORRSCDD1 STRING(255) LPORRSCDD2 STRING(255) LPORRSCDD3 STRING(255) LPORRSCDD4 STRING(255) LPORRSCDD5 STRING(255) LPORRSCDD6 STRING(255) LPORRSCDD7 STRING(255) LPORRSCDD8 STRING(255) LPORRSCDD9 STRING(255) LPORRSCDD10 STRING(255) LPORRSCDD11 STRING(255) LPORRSCDD12 STRING(255) LPORRSCDD13 STRING(255) LPORRSCDD99 STRING(255) LPORRSSPD99 STRING(200) - A200 LPORRSCDE0NONE STRING(3) LPORRSCDE1 STRING(255) LPORRSCDE2 STRING(255) LPORRSCDE3 STRING(255) LPORRSCDE4 STRING(255) LPORRSCDE5 STRING(255) LPORRSCDE99 STRING(255) LPORRSSPE99 STRING(200) - A200 LPORRSCDF0NONE STRING(3) LPORRSCDF1 STRING(255) LPORRSCDF2 STRING(255) LPORRSCDF3 STRING(255) LPORRSCDF4 STRING(255) LPORRSCDF5 STRING(255) LPORRSCDF6 STRING(255) LPORRSCDF99 STRING(255) LPORRSSPF99 STRING(200) - A200 LPORRSCDG0NONE STRING(3) LPORRSCDG1 STRING(255) LPORRSCDG2 STRING(255) LPORRSCDG3 STRING(255) LPORRSCDG4 STRING(255) LPORRSCDG5 STRING(255) LPORRSCDG99 STRING(255) LPORRSSPG99 STRING(200) - A200 LPORRSCDH0NOR STRING(3) LPORRSCDH1 STRING(255) LPORRSCDH2 STRING(255) LPORRSCDH3 STRING(255) LPORRSCDH4 STRING(255) LPORRSCDH99 STRING(255) LPORRSSPH99 STRING(200) - A200 Annotated Trial Design Page 151 of 166

LPORRSCDI0NOR STRING(3) LPORRSCDI1 STRING(255) LPORRSCDI2 STRING(255) LPORRSCDI3 STRING(255) LPORRSCDI4 STRING(255) LPORRSCDI99 STRING(255) LPORRSSPI99 STRING(200) - A200 LPORRSCDJ0NOR STRING(3) LPORRSCDJ1 STRING(255) LPORRSCDJ2 STRING(255) LPORRSCDJ3 STRING(255) LPORRSCDJ4 STRING(255) LPORRSCDJ5 STRING(255) LPORRSCDJ6 STRING(255) LPORRSCDJ7 STRING(255) LPORRSCDJ99 STRING(255) LPORRSSPJ99 STRING(200) - A200 LPORRSCDK0NONE STRING(3) LPORRSCDK1 STRING(255) LPORRSCDK2 STRING(255) LPORRSCDK3 STRING(255) LPORRSCDK4 STRING(255) LPORRSCDK5 STRING(255) LPORRSCDK99 STRING(255) LPORRSSPK99 STRING(200) - A200 LPORRSCDL1 STRING(255) LPORRSCDL2 STRING(255) LPORRSCDL3 STRING(255) LPORRSCDL4 STRING(255) LPORRSCDL5 STRING(255) LPORRSCDL6 STRING(255) LPORRSCDL7 STRING(255) LPORRSCDL8 STRING(255) LPORRSCDL9 STRING(255) LPORRSCDL10 STRING(255) LPORRSCDL11 STRING(255) LPORRSCDL12 STRING(255) LPORRSCDL13 STRING(255) LPORRSCDL14 STRING(255) LPORRSCDL15 STRING(255) LPORRSCDL16 STRING(255) LPORRSCDL17 STRING(255) LPORRSCDL99 STRING(255) LPORRSSPL99 STRING(200) - A200

CDD: MAPPINGS2 Table: t_LBIOPSY Key Type: PATIENTVISIT Column Name Column Data Type Design Note LPDT DATE - DDMONYYYY BIOPSZ NUMERIC - N2 LPORRSCDA0NOR STRING(3) LPORRSCDA1 STRING(255) Annotated Trial Design Page 152 of 166

LPORRSCDA2 STRING(255) LPORRSCDA3 STRING(255) LPORRSCDA4 STRING(255) LPORRSCDA5 STRING(255) LPORRSCDA6 STRING(255) LPORRSCDA7 STRING(255) LPORRSCDA8 STRING(255) LPORRSCDA9 STRING(255) LPORRSCDA10 STRING(255) LPORRSCDA11 STRING(255) LPORRSCDA12 STRING(255) LPORRSCDA13 STRING(255) LPORRSCDA14 STRING(255) LPORRSCDA15 STRING(255) LPORRSCDA16 STRING(255) LPORRSCDA17 STRING(255) LPORRSCDA18 STRING(255) LPORRSCDA19 STRING(255) LPORRSCDA20 STRING(255) LPORRSCDA21 STRING(255) LPORRSCDA22 STRING(255) LPORRSCDA23 STRING(255) LPORRSCDA24 STRING(255) LPORRSCDA25 STRING(255) LPORRSCDA26 STRING(255) LPORRSCDA27 STRING(255) LPORRSCDA28 STRING(255) LPORRSCDA29 STRING(255) LPORRSCDA99 STRING(255) LPORRSSPA99 STRING(200) - A200 LPORRSCDB1NORM STRING(3) LPORRSCDB2 STRING(255) LPORRSCDB3 STRING(255) LPORRSCDB4 STRING(255) LPORRSCDB5 STRING(255) LPORRSCDB6 STRING(255) LPORRSCDB7 STRING(255) LPORRSCDB8 STRING(255) LPORRSCDB9 STRING(255) LPORRSCDB10 STRING(255) LPORRSCDB11 STRING(255) LPORRSCDB12 STRING(255) LPORRSCDB13 STRING(255) LPORRSCDB14 STRING(255) LPORRSCDB15 STRING(255) LPORRSCDB16 STRING(255) LPORRSCDB17 STRING(255) LPORRSCDB18 STRING(255) LPORRSCDB19 STRING(255) LPORRSCDB20 STRING(255) LPORRSCDB21 STRING(255) Annotated Trial Design Page 153 of 166

LPORRSCDB99 STRING(255) LPORRSSPB99 STRING(200) - A200 LPORRSCDC0NOR STRING(3) LPORRSCDC1 STRING(255) LPORRSCDC2 STRING(255) LPORRSCDC3 STRING(255) LPORRSCDC4 STRING(255) LPORRSCDC99 STRING(255) LPORRSSPC99 STRING(200) - A200 LPORRSCDDONOINC STRING(3) LPORRSCDD1 STRING(255) LPORRSCDD2 STRING(255) LPORRSCDD3 STRING(255) LPORRSCDD4 STRING(255) LPORRSCDD5 STRING(255) LPORRSCDD6 STRING(255) LPORRSCDD7 STRING(255) LPORRSCDD8 STRING(255) LPORRSCDD9 STRING(255) LPORRSCDD10 STRING(255) LPORRSCDD11 STRING(255) LPORRSCDD12 STRING(255) LPORRSCDD13 STRING(255) LPORRSCDD99 STRING(255) LPORRSSPD99 STRING(200) - A200 LPORRSCDE0NONE STRING(3) LPORRSCDE1 STRING(255) LPORRSCDE2 STRING(255) LPORRSCDE3 STRING(255) LPORRSCDE4 STRING(255) LPORRSCDE5 STRING(255) LPORRSCDE99 STRING(255) LPORRSSPE99 STRING(200) - A200 LPORRSCDF0NONE STRING(3) LPORRSCDF1 STRING(255) LPORRSCDF2 STRING(255) LPORRSCDF3 STRING(255) LPORRSCDF4 STRING(255) LPORRSCDF5 STRING(255) LPORRSCDF6 STRING(255) LPORRSCDF99 STRING(255) LPORRSSPF99 STRING(200) - A200 LPORRSCDG0NONE STRING(3) LPORRSCDG1 STRING(255) LPORRSCDG2 STRING(255) LPORRSCDG3 STRING(255) LPORRSCDG4 STRING(255) LPORRSCDG5 STRING(255) LPORRSCDG99 STRING(255) LPORRSSPG99 STRING(200) - A200 LPORRSCDH0NOR STRING(3) Annotated Trial Design Page 154 of 166

LPORRSCDH1 STRING(255) LPORRSCDH2 STRING(255) LPORRSCDH3 STRING(255) LPORRSCDH4 STRING(255) LPORRSCDH99 STRING(255) LPORRSSPH99 STRING(200) - A200 LPORRSCDI0NOR STRING(3) LPORRSCDI1 STRING(255) LPORRSCDI2 STRING(255) LPORRSCDI3 STRING(255) LPORRSCDI4 STRING(255) LPORRSCDI99 STRING(255) LPORRSSPI99 STRING(200) - A200 LPORRSCDJ0NOR STRING(3) LPORRSCDJ1 STRING(255) LPORRSCDJ2 STRING(255) LPORRSCDJ3 STRING(255) LPORRSCDJ4 STRING(255) LPORRSCDJ5 STRING(255) LPORRSCDJ6 STRING(255) LPORRSCDJ7 STRING(255) LPORRSCDJ99 STRING(255) LPORRSSPJ99 STRING(200) - A200 LPORRSCDK0NONE STRING(3) LPORRSCDK1 STRING(255) LPORRSCDK2 STRING(255) LPORRSCDK3 STRING(255) LPORRSCDK4 STRING(255) LPORRSCDK5 STRING(255) LPORRSCDK99 STRING(255) LPORRSSPK99 STRING(200) - A200 LPORRSCDL1 STRING(255) LPORRSCDL2 STRING(255) LPORRSCDL3 STRING(255) LPORRSCDL4 STRING(255) LPORRSCDL5 STRING(255) LPORRSCDL6 STRING(255) LPORRSCDL7 STRING(255) LPORRSCDL8 STRING(255) LPORRSCDL9 STRING(255) LPORRSCDL10 STRING(255) LPORRSCDL11 STRING(255) LPORRSCDL12 STRING(255) LPORRSCDL13 STRING(255) LPORRSCDL14 STRING(255) LPORRSCDL15 STRING(255) LPORRSCDL16 STRING(255) LPORRSCDL17 STRING(255) LPORRSCDL99 STRING(255) LPORRSSPL99 STRING(200) - A200

Annotated Trial Design Page 155 of 166

IPC103711_SHZ : PGx-PHARMACOGENETIC RESEARCH CONSENT (PGx Consent) PGx-PHARMACOGENETIC RESEARCH CONSENT 1. Has informed consent been obtained for PGx-Pharmacogenetic research? (MAPPINGS1:t_GENPRO_CONSENT.GPCNS) (MAPPINGS2:t_GENPRO_CONSENT.GPCNS) [Y] Yes, record: Date informed consent obtained for PGx-Pharmacogenetic research Req / Req / Req (2007-2009) (MAPPINGS1:t_GENPRO_CONSENT.GPCNSDT) (MAPPINGS2:t_GENPRO_CONSENT.GPCNSDT) (MAPPINGS1:t_GENPRO_CONSENT.GPSMPCOL) (MAPPINGS2:t_GENPRO_CONSENT.GPSMPCOL) Has a blood sample been collected for PGx-pharmacogenetic (DNA) research? [N] No [Y] Yes, record date sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_GENPRO_CONSENT.GPSMPDT) (MAPPINGS2:t_GENPRO_CONSENT.GPSMPDT) [N] (MAPPINGS1:t_GENPRO_CONSENT.GPCNRSCD) (MAPPINGS2:t_GENPRO_CONSENT.GPCNRSCD) No, check reason [1] Subject declined [2] Subject not asked by Investigator [Z] Other, specify (MAPPINGS1:t_GENPRO_CONSENT.GPCNSOTH) (MAPPINGS2:t_GENPRO_CONSENT.GPCNSOTH) A100

Form Design Note:

This form should only exist once in the study and is conditional upon inclusion of Pharmacogenetics in the protocol.

CDD: MAPPINGS1 Table: t_GENPRO_CONSENT Key Type: PATIENTVISIT Column Name Column Data Type Design Note GPCNS STRING(1) GPCNSDT DATE - DDMONYYYY GPSMPCOL STRING(1) GPSMPDT DATE - DDMONYYYY GPCNRSCD STRING(1) GPCNSOTH STRING(100) - A100

CDD: MAPPINGS2 Table: t_GENPRO_CONSENT Key Type: PATIENTVISIT Column Name Column Data Type Design Note GPCNS STRING(1) GPCNSDT DATE - DDMONYYYY GPSMPCOL STRING(1) GPSMPDT DATE - DDMONYYYY GPCNRSCD STRING(1) GPCNSOTH STRING(100) - A100

Annotated Trial Design Page 156 of 166

IPC103711_SHZ : PHARMACOGENETIC (PGx) RESEARCH WITHDRAWAL OF CONSENT (PGx Withdraw) WITHDRAWAL OF CONSENT FOR PGx (DNA) SAMPLE DESTRUCTION 1. Has subject withdrawn consent for PGx research? (MAPPINGS1:t_GENPRO_WD.GPCNSWD) (MAPPINGS2:t_GENPRO_WD.GPCNSWD) [N] No [Y] Yes, date informed consent withdrawn NReq / NReq / NReq (2007-2009) (MAPPINGS1:t_GENPRO_WD.GPCNSWDT) (MAPPINGS2:t_GENPRO_WD.GPCNSWDT)

2. Has a request been made for sample destruction? (MAPPINGS1:t_GENPRO_WD.GPDSREQ) (MAPPINGS2:t_GENPRO_WD.GPDSREQ) [N] No [Y] (MAPPINGS1:t_GENPRO_WD.GPDSRSCD) (MAPPINGS2:t_GENPRO_WD.GPDSRSCD) Yes, check reason [3] Subject withdrew consent for PGx [2] Screen failure [Z] Other, specify (MAPPINGS1:t_GENPRO_WD.GPDSOTH) (MAPPINGS2:t_GENPRO_WD.GPDSOTH) A100

Form Design Note:

IDSL Version 02.00A - 05 OCT 06. This form will be dynamically created when Q1, Has a blood sample been collected is Yes. Form is conditional upon inclusion of Pharmacogenetics in protocol. DNA in section title can be removed. Sample type to be stated.

Section Design Notes:

Title Design Note

WITHDRAWAL OF CONSENT FOR PGx (DNA) SAMPLE DESTRUCTION FOR PGx (DNA) is optional

Item Design Notes:

Item No. Design Note

2. Screen failure is an optional choice. Please replace 'insert sample type' with the appropriate sample type as specified in the protocol.

CDD: MAPPINGS1 Table: t_GENPRO_WD Key Type: PATIENTVISIT Column Name Column Data Type Design Note GPCNSWD STRING(1) GPCNSWDT DATE - DDMONYYYY GPDSREQ STRING(1) GPDSRSCD STRING(1) GPDSOTH STRING(100) - A100

CDD: MAPPINGS2 Table: t_GENPRO_WD Key Type: PATIENTVISIT Column Name Column Data Type Design Note GPCNSWD STRING(1) GPCNSWDT DATE - DDMONYYYY GPDSREQ STRING(1) GPDSRSCD STRING(1) GPDSOTH STRING(100) - A100

Annotated Trial Design Page 157 of 166

IPC103711_SHZ : VISIT REPORTS (VRP) VISIT REPORTS

1.* This section is not implemented for your study (MAPPINGS1:t_VISITREPORT.NOTAVAIL_CC) (MAPPINGS2:t_VISITREPORT.NOTAVAIL_CC)

* Item is not required

CDD: MAPPINGS1 Table: t_VISITREPORT Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255)

CDD: MAPPINGS2 Table: t_VISITREPORT Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255)

Annotated Trial Design Page 158 of 166

IPC103711_SHZ : Reg Docs (REG) Reg Docs

1.* This section is not implemented for your study (MAPPINGS1:t_REGDOCS.NOTAVAIL_CC) (MAPPINGS2:t_REGDOCS.NOTAVAIL_CC)

* Item is not required

CDD: MAPPINGS1 Table: t_REGDOCS Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255)

CDD: MAPPINGS2 Table: t_REGDOCS Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255)

Annotated Trial Design Page 159 of 166

IPC103711_SHZ : VITAL SIGNS (VS) EARLY WITHDRAWAL

1. Actual date/time Req / Req / Req (2007-2009) (MAPPINGS1:t_VITALS_X1_A.VSACTDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_VITALS_X1_A.VSACTDTTM) Req : Req 24-hour clock

2. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X1_A.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X1_A.DIABP) (MAPPINGS2:t_VITALS_X1_A.SYSBP) (MAPPINGS2:t_VITALS_X1_A.DIABP) (systolic/diastolic)

3. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X1_A.HEART) (MAPPINGS2:t_VITALS_X1_A.HEART)

4. Temperature xx.x °C (MAPPINGS1:t_VITALS_X1_A.TEMP) (MAPPINGS2:t_VITALS_X1_A.TEMP)

Form Design Note:

Bench vitals (x1) clone A

Item Design Notes:

Item No. Design Note

4. Item is optional

CDD: MAPPINGS1 Table: t_VITALS_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1

CDD: MAPPINGS2 Table: t_VITALS_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 TEMP FLOAT - F4.1

Annotated Trial Design Page 160 of 166

IPC103711_SHZ : 12-LEAD ECG (ECG) EARLY WITHDRAWAL

1. Date and Time of ECG Req / Req / Req (2007-2009) (MAPPINGS1:t_ECG_X1_A.EGDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_ECG_X1_A.EGDTTM) Req : Req 24-hour clock

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X1_A.EGHR) (MAPPINGS2:t_ECG_X1_A.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.PR__) (MAPPINGS2:t_ECG_X1_A.PR__)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QRS__) (MAPPINGS2:t_ECG_X1_A.QRS__)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QT__) (MAPPINGS2:t_ECG_X1_A.QT__)

6. QTc Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QTC__) (MAPPINGS2:t_ECG_X1_A.QTC__)

7. Method of QTc Calculation (MAPPINGS1:t_ECG_X1_A.EGMTCLCD) (MAPPINGS2:t_ECG_X1_A.EGMTCLCD) [1] Machine [2] Manual

8. Result of the ECG (MAPPINGS1:t_ECG_X1_A.EGINTPCD) (MAPPINGS2:t_ECG_X1_A.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE) [4] No result (not available)

Form Design Note:

Bench ECG (x1) clone A

CDD: MAPPINGS1 Table: t_ECG_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1)

CDD: MAPPINGS2 Table: t_ECG_X1_A Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR__ FLOAT - F6.0 QRS__ FLOAT - F6.0 QT__ FLOAT - F6.0 QTC__ FLOAT - F6.0 EGMTCLCD STRING(1) EGINTPCD STRING(1)

Annotated Trial Design Page 161 of 166

1. Date and time sample taken Req / Req / Req (2007-2009) (MAPPINGS1:t_LAB_CHEM_D.LBDTTM) Hr:Min (00:00-23:59) (MAPPINGS2:t_LAB_CHEM_D.LBDTTM) Req : Req 24-hour clock

2. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM_D.LBFAST) (MAPPINGS2:t_LAB_CHEM_D.LBFAST) [Y] Yes [N] No

3. ALT (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 4. AST (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 5. Total Bilirubin (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 6. Glucose (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 7. GGT (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 8. Total Protein (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 9. Albumin (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] Annotated Trial Design Page 162 of 166

10. Potassium (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 11. Sodium (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 12. Chloride (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 13. Urea (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 14. Creatinine (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 15. Uric Acid (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 16. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 17. Globulin (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 18. Phosphate (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) Annotated Trial Design Page 163 of 166

[- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99] 19. Bicarbonate (MAPPINGS1:t_LAB_CHEM_D.rdcLBORRES) (MAPPINGS2:t_LAB_CHEM_D.rdcLBORRES) [- Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM_D.RSLTNUM) 97] (MAPPINGS2:t_LAB_CHEM_D.RSLTNUM) [- Character result: A20 (MAPPINGS1:t_LAB_CHEM_D.RSLTCHAR) 98] (MAPPINGS2:t_LAB_CHEM_D.RSLTCHAR) [- No result 99]

Form Design Note:

Bench Lab Chem Clone B

Section Design Notes:

Title Design Note

CLINICAL CHEMISTRY Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

2. This item is optional

CDD: MAPPINGS1 Table: t_LAB_CHEM_D Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

CDD: MAPPINGS2 Table: t_LAB_CHEM_D Key Type: PATIENTTOITEM Column Name Column Data Type Design Note LBDTTM DATE - DDMONYYYY HHMM LBFAST STRING(1) rdcLBORRES STRING(3) RSLTNUM FLOAT - F13.0 RSLTCHAR STRING(20) - A20

Annotated Trial Design Page 164 of 166

IPC103711_SHZ : PULMONARY FUNCTION TESTS (PFT)

1. Date/time of test Req / Req / Req (2007-2009) (MAPPINGS1:t_PFT_X1_D.PFTDTTM) (MAPPINGS2:t_PFT_X1_D.PFTDTTM) Req : Req 24-hour clock

2. FEV1 xxxx. L (MAPPINGS1:t_PFT_X1_D.FEV1) (MAPPINGS2:t_PFT_X1_D.FEV1)

Form Design Note:

Bench PFT (x1) clone D

CDD: MAPPINGS1 Table: t_PFT_X1_D Key Type: PATIENTVISIT Column Name Column Data Type Design Note PFTDTTM DATE - DDMONYYYY HHMM FEV1 FLOAT - F5.0

CDD: MAPPINGS2 Table: t_PFT_X1_D Key Type: PATIENTVISIT Column Name Column Data Type Design Note PFTDTTM DATE - DDMONYYYY HHMM FEV1 FLOAT - F5.0

Annotated Trial Design Page 165 of 166

IPC103711_SHZ : PHARMACODYNAMICS - (BIOMARKER) EARLY WITHDRAWAL

1. Date/time of sample Req / Req / Req (2007-2009) (MAPPINGS1:t_PD_X1_C.PDACTDTTM) (MAPPINGS2:t_PD_X1_C.PDACTDTTM) Req : Req 24-hour clock

Form Design Note:

Bench PD (x1) clone C

CDD: MAPPINGS1 Table: t_PD_X1_C Key Type: PATIENTVISIT Column Name Column Data Type Design Note PDACTDTTM DATE - DDMONYYYY HHMM

CDD: MAPPINGS2 Table: t_PD_X1_C Key Type: PATIENTVISIT Column Name Column Data Type Design Note PDACTDTTM DATE - DDMONYYYY HHMM

Annotated Trial Design Page 166 of 166

CRB Electronic Signature Affidavit By my dated signature below, I, [First Name] [Last Name], verify that all case report form pages accurately display the results of the examinations, tests, evaluations and treatments performed on this patient.

Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature.

To this I do attest by supplying my user name and password and clicking the button marked Submit below.

CRF Electronic Signature Affidavit By my dated signature below, I, [First Name] [Last Name], verify that this case report form accurately displays the results of the examinations, tests, evaluations and treatments noted within.

To this I do attest by supplying my user name and password and clicking the button marked Submit below.

CONFIDENTIAL IPC103711

LIST OF INVESTIGATORS AND IECS/IRBS FOR IPC103711 (GM2008/00234/00)

Investigator Investigator/ Site no. Hospital/ Institution and IEC/IRB Committee Chair and Name of Address Committee

Germany.

CONFIDENTIAL 1 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711

1 This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

CONFIDENTIAL GM2008/00234/00 IPC103711

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Randomization Code

1 Protocol: IPC103711 Page 1 of 2 Population: All Subjects Listing 6 Listing of Actual and Planned Treatments

Randomised Actual Subject Treatment Treatment Discrepancy ------GSK256066 87.5mcg 066 87.5mcg QD GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 87.5mcg 066 87.5mcg QD Placebo Placebo GSK256066 25mcg 066 25mcg QD GSK256066 87.5mcg 066 87.5mcg QD

GSK256066 87.5mcg 066 87.5mcg QD CONFIDENTIAL Placebo Placebo GSK256066 25mcg 066 25mcg QD Placebo Placebo

2 GSK256066 87.5mcg 066 87.5mcg QD GSK256066 25mcg 066 25mcg QD GSK256066 87.5mcg 066 87.5mcg QD GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 87.5mcg 066 87.5mcg QD GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 87.5mcg 066 87.5mcg QD GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 87.5mcg 066 87.5mcg QD GM2008/00234/00 GSK256066 87.5mcg 066 87.5mcg QD GSK256066 25mcg 066 25mcg QD

Placebo Placebo IPC103711 GSK256066 25mcg 066 25mcg QD Placebo Placebo GSK256066 87.5mcg 066 87.5mcg QD Protocol: IPC103711 Page 2 of 2 Population: All Subjects Listing 6 Listing of Actual and Planned Treatments

Randomised Actual Subject Treatment Treatment Discrepancy ------GSK256066 87.5mcg 066 87.5mcg QD Placebo Placebo GSK256066 25mcg 066 25mcg QD GSK256066 25mcg 066 25mcg QD CONFIDENTIAL 3 GM2008/00234/00 GM2008/00234/00 IPC103711 IPC103711 CONFIDENTIAL GM2008/00234/00 IPC103711

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ICH Data Listings

Page Listing - ICH 1 Listing of Reasons for Withdrawal (All Subjects Population). . 3 Listing - ICH 2 Listing of Subjects With Inclusion/Exclusion Criteria Deviations (All Subjects Population) ...... 4 Listing - ICH 3 Listing of Subjects for Whom the Treatment Blind was Broken (All Subjects Population)...... 5 Listing - ICH 4 Listing of Demographic Characteristics (All Subjects Population) ...... 6 Listing - ICH 5 Listing of Concomitant Medications by Generic Term (All Subjects Population) ...... 8 Listing - ICH 6 Listing of Actual and Planned Treatments (All Subjects Population) ...... 12 Listing - ICH 7 Listing of Exposure Data (All Subjects Population) ...... 14 Listing - ICH 8 Listing of All Adverse Events (All Subjects Population)...... 32 Listing - ICH 9 Listing of Subject Numbers for Individual Adverse Events (All Subjects Population) ...... 52 Listing - ICH 10 Listing of Serious Adverse Events (All Subjects Population). 57 Listing - ICH 11 Listing of Adverse Events Leading to Withdrawal from Study (All Subjects Population) ...... 58 Listing - ICH 12 Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance (All Subjects Population) ...... 59 Listing - ICH 13 Listing of ECG Values of Potential Clinical Importance (All Subjects Population) ...... 65 Listing - ICH 14 Listing of Abnormal ECG findings (All Subjects Population) . 68 Listing - ICH 15 Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance (All Subjects Population) ...... 96 Listing - ICH 16 Listing of All Clinical Chemistry Laboratory Data for Subjects with Abnormalities of Potential Clinical Importance (All Subjects Population) ...... 102 Listing - ICH 17 Listing of Haematology Abnormalities of Potential Clinical Importance (All Subjects Population) ...... 209

1 CONFIDENTIAL GM2008/00234/00 IPC103711

Listing - ICH 18 Listing of All Haematology Laboratory Data for Subjects with Abnormalities of Potential Clinical Importance (All Subjects Population) ...... 210 Listing - ICH 19 Listing of Abnormal Urinalysis Data (All Subjects Population) ...... 211 Listing - ICH 20 Listing of Vital Signs of Potential Clinical Importance (All Subjects Population) ...... 224 Listing - ICH 21 Listing of All Vital Signs for Subjects with Values of Potential Clinical Importance (All Subjects Population) ...... 225

2 This section contained data from each individual patient, rather than in aggregate. They have been excluded 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 Clinical Study Register. CONFIDENTIAL GM2008/00234/00 IPC103711

Other Data Listings

Page Listing - Other 1 Listing of % Predicted FEV1 and FEV1/FVC Ratio Data at Screening (All Subjects Population) ...... 3 Listing - Other 2 Relationship between ATC Level 1, Ingredient and Verbatim Text (All Subjects Population) ...... 8 Listing - Other 3 Listing of BAL Inflammatory Cell Data: Total Cell Count /mL and Percentage (Per-protocol Population) ...... 10 Listing - Other 4 Raw Statistical Analysis SAS Output of Total Cell Count Data (x10^6/mL) by Inflammatory Cell Type (Per-protocol Population). . 22 Listing - Other 5 Raw SAS Output for the Statistical Analysis of Percentage Cell Count Data by Inflammatory Cell Type (All Subjects Population) . . . 137 Listing - Other 6 Listing of BAL Monocyte Data (Per-protocol Population) . . . 227 Listing - Other 7 Listing of BAL Protein Expression Data (pg/mL) on Day 7 (Per-protocol Population) ...... 232 Listing - Other 8 Raw SAS Output for the Statistical Analysis of BAL Protein Expression Data (pg/mL) (Per-protocol Population) ...... 252 Listing - Other 9 Listing of Serum Protein Expression Data (Per-protocol Population) ...... 364 Listing - Other 10 Raw SAS Output for the Statistical Analysis of Serum Protein Expression Data (ng/mL) (Per-protocol Population) ...... 374 Listing - Other 11 Listing of Clinically Significant Holter Abnormalities (All Subjects Population) ...... 412 Listing - Other 12 Relationship between System Organ Class and Verbatim Text (All Subjects Population) ...... 413 Listing - Other 13 Listing of All Clinical Chemistry Laboratory Data for Subjects with AEs of Interest (All Subjects Population) ...... 415 Listing - Other 14 Listing of All ECG Values for Subjects with Adverse Events of Interest (All Subjects Population) ...... 503 Listing - Other 15 Listing of Laboratory Reference Ranges (All Subjects Population) ...... 510 Listing - Other 16 Listing of All Vital Signs for Subjects with AEs of interest (All Subjects Population) ...... 515

1 CONFIDENTIAL GM2008/00234/00 IPC103711

Listing - Other 17 Listing of Spirometry Data (All Subjects Population) . . . . . 521 Listing - Other 18 Listing of Raw and Urea-Corrected GSK256066 BAL (Supernatant) Pharmacokinetic Concentration-Time Data (PK Concentration Population)...... 540 Listing - Other 20 Listing of Raw and Urea-Corrected GSK614917 BAL (Supernatant) Pharmacokinetic Concentration-Time Data (PK Concentration Population)...... 544 Listing - Other 19 Listing of Raw and Urea-Corrected GSK256066 BAL (Pellet) Pharmacokinetic Concentration-Time Data (PK Concentration Population) ...... 548 Listing - Other 21 Listing of Raw and Urea-Corrected GSK614917 BAL (Pellet) Pharmacokinetic Concentration-Time Data (PK Concentration Population) ...... 552