GSK Clinical Study Register

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1 In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

2 CONFIDENTIAL The GlaxoSmithKline group group of companies of companies Division: Worldwide Development Retention Category: GRS019 Information Type: Synoptic Clinical Study Report Control: Placebo or active-control (i.e., metformin, sulfonylurea, insulin). Title: Phase: 2008 Update to Integrated Clinical Trials (ICT - also known as CV modeling) analysis for AVANDIA (rosiglitazone maleate) IV Compound Number: BRL Effective Date: 23-MAR-2009 Description: In September 2004, a statistical analysis (cardiovascular [CV] modeling) of the rosiglitazone (RSG) Integrated Clinical Trials database (ICT) was conducted to estimate the risk (and associated confidence intervals; CI) of developing / exacerbating congestive heart failure and events associated with myocardial ischemia for RSG relative to active or placebo controls. This analysis was conducted on a cohort of subjects with type 2 diabetes mellitus (T2DM) enrolled in GlaxoSmithKline (GSK)-sponsored doubleblind, controlled, studies that utilized total daily doses of 4 milligrams (mg) or 8mg of RSG and had statistical analysis completed (SAC) on or before September 30, In August 2005, the analysis was updated with 5 additional studies, making a total of 42 studies with data from 14,237 subjects. As per the analysis plan, all studies in the ICT were centrally monitored (i.e., conducted and sponsored by GSK Research and Development [R&D] or by GSK United States Pharmaceutical Development) with patient-level electronic data centrally available for integration by the August 2005 cutoff. As part of GSKs ongoing review of clinical trials conducted using RSG worldwide, a further update to the ICT analysis was performed in December 2008 in order to include additional data from 10 studies that met the study design criteria for the previous ICT analyses and; therefore, could be integrated with the studies included in the previous analysis. Two of the studies (128 and 374) were completed by the August 2005 cut-off, but patient-level electronic data for these studies was not centrally available at that time because the studies were conducted and monitored by non-us local operating companies. The 8 remaining studies were not completed by the August 2005 cut off; 4 of these studies were conducted by GSK R&D, and 4 were conducted by non-u.s. local operating companies. Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited. 1 1

3 CONFIDENTIAL The GlaxoSmithKline group group of companies of companies This update was performed by integrating data from the additional 10 studies, involving an additional 2,758 subjects, with data from the 42 studies in the August 2005 analysis. The scope of this update focuses on the comparison of RSG relative to controls for events associated with myocardial ischemia and MACE (major adverse cardiovascular events; a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) - an endpoint not defined in the previous ICT. Specifically for myocardial ischemia, the scope of the analysis was to update the hazard ratio (HR; and associated CI) based on comparison between the pooled RSG and the pooled non-rsg groups as previously reported. A similar analysis was also performed for MACE. Subject: AVANDIA, Cardiovascular Events, Statistical Model, MACE (Major Adverse Cardiovascular Event), Myocardial Ischemia Author(s): GSK Internal Personnel - External Reviewer Initiation Date: Completion Date: Date of Report: 10-Sep Dec Mar-2009 Sponsor Signatory: (and Medical Officer) M.D., Ph.D. Senior Director, CVM MDC, Clinical GlaxoSmithKline This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. 2 2

4 Table of Contents Page Abbreviations Synopsis REFERENCES SAFETY DATA SOURCE FIGURES AND TABLES

5 CONFIDENTIAL Abbreviations ADOPT AE APPROACH CI CV GSK HR ICT INS MACE MET mg N or n PBO R&D RSG SAC SE SIM SU T2DM U.S. A Diabetes Outcome Progression Trial (GSK Study BRL049653/048) Adverse Event Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetic Patients with Cardiovascular History (GSK Study AVD100521) Confidence Interval Cardiovascular GlaxoSmithKline Hazard Ratio Integrated Clinical Trials Insulin Major adverse cardiovascular event Metformin milligram Number Placebo Research and Development Rosiglitazone Statistical Analysis Complete Standard Error Simvastatin Sulfonylurea Type 2 diabetes mellitus United States Trademark Information Trademarks of the GlaxoSmithKline group of companies AVANDIA Trademarks not owned by the GlaxoSmithKline group of companies None 4 4

6 CONFIDENTIAL Synopsis Study Number: Title: 2008 Update to Integrated Clinical Trials (ICT - also known as Cardiovascular [CV] modeling) analysis for AVANDIA (rosiglitazone maleate) Investigator(s) and Study Center(s): These analyses were conducted by internal GlaxoSmithKline (GSK) personnel using data from previously completed and reported GSK-sponsored double-blind, controlled studies. Publication(s): In process Study Period: GlaxoSmithKline-sponsored double-blind, controlled studies that had statistical analysis completed (SAC) on or before November 26, Phase of Development: Phase IV Objectives: The primary objectives were: to estimate the myocardial ischemia hazard ratio (HR; and associated confidence interval, CI) for rosiglitazone (RSG) relative to active or placebo control based on a statistical analysis of updated ICT data, which includes pooled data from the 42 studies in the previous ICT analysis plus data from 10 additional studies. to estimate the major adverse cardiovascular events (MACE; a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) HR (and associated CI) for RSG relative to active or placebo control based on a statistical analysis of updated ICT data. Methodology: An initial statistical analysis was conducted on the cohort of type 2 diabetes mellitus (T2DM) subjects enrolled in GSK-sponsored double-blind, controlled, studies that utilized total daily doses of 4 milligrams (mg) or 8mg of RSG and had statistical analysis completed (SAC) on or before September 30, Further statistical analysis was conducted on an updated integrated dataset, which contained 5 additional clinical studies that completed statistical analyses by an August 2005 cut-off, in order to assess the consistency of results with the initial analysis. The current 52-study analysis, conducted in December 2008, focuses on myocardial ischemic events and MACE (a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) and includes data from the 10 following studies (Table 1): 5 5

7 CONFIDENTIAL Table 1 Listing of 10 Studies Integrated into the Avandia ICT Analysis in December 2008 (by number of patients included in analysis) Study ID Control Number patients (RSG/Control) Location of Study BRL /376 PBO 40 (19/21) Global BRL /351 PBO 56 (27/29) Global BRL /128 1 PBO + SU 77 (39/38) Local Study -Taiwan AVD PBO + SU 149 (74/75) Local study Japan BRL /374 1 PBO + α-glucosidase inhibitor 169 (84/85) Local study Japan AVD INS+PBO 263 (132/131) Local study China AVS PBO + SIM 369 (276/93) R&D AVD PBO, pioglitazone 372 (159/213) Local study Japan AVM MET + SU 595 (294/301) Europe only AVD SU (Glipizide) 668 (331/337) Global Additional 10 Studies 2758 (1435/1323) 42 Studies 3 14,237 (8604/5633) All (52 Studies) 16,995 (10039/6956) 1. Completed prior to August 2005 cut off, but patient-level electronic data was not available for integration into the 42-study ICT. These studies were not centrally monitored. 2. Study included 4 monotherapy treatment arms: RSG 4mg + PBO, RSG 8mg + PBO, SIM 40mg + PBO, and SIM 80mg + PBO, and 4 fixed-dose combination treatment arms: RSG 4mg/SIM 40mg, RSG 4mg/SIM 80mg, RSG 8mg/SIM 40mg, and RSG 8mg/SIM 80mg. 3. See [GlaxoSmithKline Document Number ZM2005/00181/01] PBO = placebo, INS = insulin, SU = sulfonylurea, SIM = simvastatin, MET = metformin The analyses of interest using the updated ICT dataset include a re-estimate of the HR and CI for the comparison between the group of subjects who received RSG and the group of subjects who did not receive RSG; regardless of the RSG dose and/or other background medication(s). Assignment to the treatment groups represented in the comparisons was based on randomized treatment assignment. All randomized subjects were included in this analysis, except where there were alleged irregularities in data collection or a failed study audit (n=65 patients). Excluding these patients is consistent with the approach that was taken for safety summaries in reporting these studies to regulatory authorities. This analysis involved the safety endpoints of myocardial ischemia and MACE. A Cox proportional hazards model analysis was used to calculate the HR for RSG relative to non-rsg comparator (Control). Subjects who were randomized to RSG were pooled into one group and those randomized to Control (non-rsg) were pooled into another group. The model contained the term for pooled treatment but was not adjusted for other covariates. This analysis was performed by combining the patient-level data from the 10 additional studies with the pooled patient-level data from the previous 42 studies. Consistent with the overall estimate reported for the 42 study analysis, the updated analysis was not stratified by study. Although this required a stronger proportional hazards assumption than would be the case for a stratified analysis, it did permit followup time for patients in zero-event studies to be included in the event that this could affect the HR estimate. The stratified analysis would have allowed the underlying hazard function to be different between studies. 6 6

8 CONFIDENTIAL A summary of the event rate per 100 patient-years is also provided, by treatment group, and cumulative incidence plots, by treatment group, were generated. The ICT analysis combines patient-level data from short-term trials (i.e., a majority are 6 months in duration). The ICT is a hypothesis generating exercise requiring independent confirmation via long-term trials. Therefore, the long-term ADOPT (A Diabetes Outcome and Progression Trial) was not included in this update. The substantially greater follow-up in ADOPT (4 to 6 years) would have introduced clinical heterogeneity, limiting the interpretability of analyses from the integrated dataset [Thompson, 1991]. In addition, an exploratory analysis of the HRs and corresponding CIs for programmatically-derived myocardial ischemic adverse events (AEs) highlight substantial differences between ADOPT and the 42-study ICT analysis. This underscores the statistical heterogeneity that would further undermine interpretation of an ICT analysis that included ADOPT (see Adhoc 2184). Number of subjects: The data from the 42 studies from the previous ICT (14,237 subjects [8,604 RSG/5,633 Control]) and the 10 additional studies (2,758 subjects [1,435 RSG/1323 Control]) were integrated into this 52-study analysis (16,995 subjects [10,039 RSG/6,956 Control]). Diagnosis and main criteria for inclusion: Studies considered for inclusion in this statistical analysis were all GSK Research and Development (R&D) and United States (U.S.) Pharmaceuticals sponsored RSG studies in subjects, and studies included in supplemental New Drug Applications. Specific requirements for study inclusion in the statistical analysis are: The study must have included a control regimen (placebo or active) with a randomized design. The study population must have been adults who have T2DM. This is the population for which RSG is currently indicated. The study must have included data on either 4 milligrams (mg) or 8mg RSG doses. These are the total daily doses of RSG recommended for use in the treatment oft2dm. The study must have been double-blind. This minimizes potential differential reporting bias between RSG and Control groups. The study must have reached the SAC milestone prior to November 26, Safety Analysis Endpoints: Events of myocardial ischemia and MACE were the two categories of interest in these statistical analyses. The definition of an event of myocardial ischemia followed the methodology of the previous ICT analyses [GlaxoSmithKline Document Number ZM2005/00181/01]. [Cobitz, 2008] and [GlaxoSmithKline Document Number ZM2005/00181/01]. For the additional 10 studies listed in Table 1, identification of myocardial ischemia is described in Section 10.1 of the Summary Document Analysis Plan [GlaxoSmithKline Document Number ZM2008/00173/00]. 7 7

9 CONFIDENTIAL Identification of MACE for the 10 additional studies is described in Section 10.2 of the Summary Document Analysis Plan [GlaxoSmithKline Document Number ZM2008/00173/00]. In GSK study AVD (APPROACH; Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetic Patients with Cardiovascular History), MACE was a pre-defined secondary endpoint and a blinded endpoint committee reviewed all MACE that occurred during the study. Summary: Myocardial Ischemia The number of patients with at least one event of myocardial ischemia (n) and number of patients (N) for each of the 10 studies added to the ICT analysis are provided in Table 2. Table 2 Number and Percent of Patients with an Event of Myocardial Ischemia for the 10 Studies Added in December 2008 (All Randomized Subjects) RSG Control n/n % n/n % BRL /376 0/19 0 0/21 0 BRL /351 2/ / BRL /128 1/ /38 0 AVD /74 0 0/75 0 BRL /374 1/ /85 0 AVD / / AVS / /93 0 AVD / /213 0 AVM / / AVD (APPROACH) 42/ / Studies 50/ / Study 222/ / Data Source: Source Table U2.1 and Source Table U2.3. The myocardial ischemia HR for the 42-study ICT analysis, the 10 additional studies, and the combined 52-study ICT analysis are provided separately in Table 3. For the 10 additional studies, the incidence of myocardial ischemic events was generally higher than in the previous 42 studies, with a slightly higher incidence for the Control group compared to RSG. This higher incidence reflects the inclusion of the APPROACH study which was conducted in subjects at higher risk of cardiovascular events (i.e., patients with T2DM and established coronary artery disease; Table 2). When combined with the 42 studies, the overall incidence of myocardial ischemic events in the pooled 52-study ICT was low and similar for the RSG group (2.21%, 4.34 events per 100 patient-years) and the Control group (2.08%, 3.98 events per 100 patient-years), with no significant difference between groups (HR [95% CI to 1.354] p=0.383). 8 8

10 CONFIDENTIAL Table 3 Myocardial Ischemia Serious and Non-serious AEs: Results from Proportional Hazards Regression Analysis (All Randomized Subjects) Hazard Ratio 1 RSG Control HR (95% CI) p-value Events/ subjects (%) PY (Rate 100 PY) Events/ subjects (%) PY (Rate 100 PY) 42- Study (1.004, 1.685) /8604 (2.00) (4.15) 86/5633 (1.53) (3.21) 10 Studies (0.564, 1.198) /1435 (3.48) (5.12) 59/1323 (4.46) (6.12) 52- Study (0.890, 1.354) /10039 (2.21) (4.34) 145/6956 (2.08) (3.98) 1. Comparison is based on pooled RSG treatment group against non-rsg treatment group without covariates. 2. Values are for the 10 studies that were added to the ICT dataset in December 2008, only. Data Source: Source Table U2.1 Figure 1 shows the cumulative incidence (+/- standard error [SE]) plot of myocardial ischemia AEs for up to 2 years (720 days) for the overall All RSG vs. All Control population. Figure Cumulative Proportion with Event Time-to-Event Analysis 1 for Myocardial Ischemia Cumulative Incidence (+/- SE) Plot of Ischaemia AEs ALL RSG vs ALL Control RSG # of Subjects: # Subjects w/ Event: Control RSG (2.21%) Control (2.08%) Time since Randomisation (Days) Subjects at Risk RSG Control Studies AVD (331 RSG patients and 337 Control patients) and BRL49653/135 (116 RSG patients and 111 Control patients), also in the 42-study analysis, exposed subjects to RSG for 18 and 24 months, respectively. Data Source: Source Figure U

11 CONFIDENTIAL MACE The number of patients with at least one MACE event (n) and number of patients (N) for each of the 10 studies added to the ICT analysis are provided in Table 4: Table 4 Number and Percentage of Patients with a MACE Event for 10 Studies Added in December 2008 (All Randomized Subjects) RSG Control n/n % n/n % BRL /376 0/19 0 0/21 0 BRL /351 0/27 0 0/29 0 BRL /128 1/ /38 0 AVD /74 0 1/ BRL /374 0/84 0 0/85 0 AVD / / AVS / /93 0 AVD / /213 0 AVM / / AVD (APPROACH) 13/ / Studies 17/ / Study 80/ / Data Source: Source Table U2.2 and Source Table U2.4 The MACE HR for the 42-study ICT analysis, the 10 additional studies, and the combined 52-study ICT analysis are provided in Table 5. For the 52-study ICT, the incidence of MACE was low and similar for the RSG group (0.80%, 1.56 events per 100 patient-years) and the Control group (0.73%, 1.40 events per 100 patient-years), with no significant difference between groups (HR [95% CI to 1.593] p=0.525). The APPROACH study, which included MACE as a pre-defined secondary endpoint event, contributed a higher incidence rate than did the other studies (Table 4). Table 5 MACE: Results from Proportional Hazards Regression Analysis (All Randomized Subjects) Hazard Ratio 1 RSG Control HR (95% CI) p-value Events/ subjects (%) PY (Rate 100 PY) Events/ Subjects (%) PY (Rate 100 PY) 42- Study (0.712, 1.593) /8604 (0.73) (1.52) 38/5633 (0.67) (1.42) 10 Studies (0.628, 2.664) /1435 (1.18) (1.74) 13/1323 (0.98) (1.35) 52- Study (0.789, 1.593) /10039 (0.80) (1.56) 51/6956 (0.73) (1.40) 1. Comparison is based on pooled RSG treatment group against non-rsg treatment group without covariates. 2. Values are for the 10 studies that were added to the ICT dataset in December 2008, only. Data Source: Source Table U2.2 Figure 2 shows the cumulative incidence (+/- SE) plot of MACE for up to 2 years (720 days) for the overall All RSG vs. All Control population

12 CONFIDENTIAL Figure Cumulative Proportion with Event Time-to-Event 1 Analysis for MACE Cumulative Incidence (+/- SE) Plot of MACE ALL RSG vs ALL Control RSG # of Subjects: # Subjects w/ Event: Control RSG (0.80%) Control (0.73%) Time since Randomisation (Days) Subjects at Risk RSG Control Studies AVD (331 RSG patients and 337 Control patients) and BRL49653/135 (116 RSG patients and 11 Control patients), also in the 42 study analysis, exposed subjects to RSG for 18 and 24 months, respectively. Data Source: Source Figure U

13 CONFIDENTIAL Conclusions: Results from the analyses of the updated integrated dataset of 52 studies were generally similar to those of the previous 42-study dataset. Across the pooled treatment regimens evaluated in this 52-study ICT analysis, which encompasses 16,995 subjects in controlled double-blind studies, the incidence of events of myocardial ischemia in the RSG and Control treatment regimens was generally low. The MACE endpoint (composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) provides a generally accepted composite measure of overall cardiovascular mortality and morbidity in terms of serious and irreversible events. MACE events occurred infrequently in the ICT datasets with little difference between RSG and Control. The result of the analysis of the 52-study dataset is consistent with an analysis of the 42-study dataset. Of the 10 trials added, the APPROACH trial contributed the majority of events of myocardial ischemia (95 of 109 [87.2%] events) and MACE (22 of 30 [73.3%] of events) as expected given its higher-risk study population (i.e., patients with T2DM and established coronary artery disease). Previous analysis of the 42-study ICT included 46 events of myocardial ischemia from active-controlled trials, which did not show a significant increase in the risk of events of myocardial ischemia with RSG compared to active-controls (HR [95% CI to 1.584] p=0.9751); [GlaxoSmithKline Document Number ZM2005/00181/01], Adhoc Table ). APPROACH, which contributes 95 myocardial ischemic events (42/331 [12.69%] for RSG and 53/337 [15.73%] for Control) to the 52-study ICT analysis, also did not show a significant increase in risk of myocardial ischemic events with RSG compared to active controls. Only one event of myocardial ischemia was contributed by each of the two trials (BRL /128 and BRL /374) that had completed prior to the August 2005 cut-off for the 42-study ICT but did not have patient-level electronic data available at that time. Both of these events were in the RSG arms, but are not expected to have substantively affected the HR of the previous 42-study ICT analysis. The results of the analysis of the 52-study dataset are consistent with the results of the analysis of the 42-study dataset with regard to the risk of an event of myocardial ischemia. This 52-study ICT analysis remains hypothesis generating and independent long-term, randomized, clinical trials are necessary to further evaluate the cardiovascular safety of RSG. Date of Report: 23-Mar

14 CONFIDENTIAL REFERENCES Cobitz, A., Zambanini, A., Sowell, M., Heise, M., Louridas, B., McMorn, S., Semigran, M., and Koch, G. A retrospective evaluation of congestive heart failure and myocardial ischemic events in patients with type 2 diabetes mellitus enrolled in 42 short-term, double-blind, randomized clinical studies with RSG. Pharmacoepidemiology and drug safety. 2008;17: GlaxoSmithKline Document Number ZM2005/00181/01. AVANDIA Cardiovascular Event Modeling Project. Report Date 16-JUL GlaxoSmithKline Document Number ZM2008/00173/00. Summary Document Analysis Plan for AVANDIA Cardiovascular Event Modeling Update. Report Date 09-DEC Thompson, S.G. and Pocock, S.J. Can meta-analysis be trusted?. Lancet. 1991;338:

15 Safety Data Source Figures and Tables Page FIGURE U2.1 Cumulative Incidence (+/- SE) Plot of Ischaemia AEs. All RSG vs All Control. 52 Studies FIGURE U2.2 Cumulative Incidence (+/- SE) Plot of MACE. All RSG vs All Control. 52 Studies FIGURE Adhoc Normal Posterior Density Assuming Noninformative Prior. Endpoint = Ischaemia; Control= Non-RSG TABLE U2.1 Myocardial Ischaemia Serious and Non-serious AEs:. Results from Proportional Hazards Regression Analysis. All Randomized Patients TABLE U2.2 MACE (CV Mortality, Myocardial Infarction SAE, Stroke SAE):. Results from Proportional Hazards Regression Analysis. All Randomized Patients TABLE U2.3 Summary of Patient and Myocardial Ischaemia Serious and Non-serious Event Counts by Study and Treatment Group. 52 Studies. All Randomized Patients TABLE U2.4 Summary of Patient and MACE (CV Mortality, Myocardial Infarction SAE, Stroke SAE) Event Counts by Study and Treatment Group. 52 Studies. All Randomized Patients TABLE Statistical Analysis of Myocardial Ischemia AEs:. Results from Proportional Hazards Regression Analysis (by Type of Study). All Randomized Patients (42 ICT Studies)

16 15 Cumulative Proportion with Event RSG # of Subjects: # Subjects w/ Event: Figure U2.1 Cumulative Incidence (+/- SE) Plot of Ischaemia AEs Control ALL RSG vs ALL Control RSG (2.21%) Control (2.08%) Time since Randomization (Days) Subjects at Risk RSG Control CONFIDENTIAL

17 16 Cumulative Proportion with Event RSG # of Subjects: # Subjects w/ Event: Figure U2.2 Cumulative Incidence (+/- SE) Plot of MACE Control ALL RSG vs ALL Control RSG (0.80%) Control (0.73%) Time since Randomization (Days) Subjects at Risk RSG Control CONFIDENTIAL

18 Adhoc 2184 Figure 1 Normal Posterior Density Assuming Noninformative Prior Endpoint=Ischaemia; Control=Non-RSG Study ADOPT ICT Hazard Ratio CONFIDENTIAL

19 Adhoc 2184 Figure 2 Normal Posterior Density Assuming Noninformative Prior Endpoint=MACE; Control=Non-RSG Study ADOPT ICT Hazard Ratio CONFIDENTIAL

20 Adhoc 2184 Figure 3 Lognormal Posterior Density Assuming Noninformative Prior Endpoint=Ischaemia; Control=Non-RSG Study ADOPT ICT Hazard Ratio, Log scale CONFIDENTIAL

21 Adhoc 2184 Figure 4 Lognormal Posterior Density Assuming Noninformative Prior Endpoint=MACE; Control=Non-RSG Study ADOPT ICT Hazard Ratio, Log scale CONFIDENTIAL

22 1 Table U2.1 Myocardial Ischaemia Serious and Non-serious AEs: Results from Proportional Hazards Regression Analysis All Randomized Patients Hazard Ratio RSG Control Treatment Comparison Rate/ Rate/ All RSG vs Non-RSG HR 95% CI p_value events/pats PY (%) 100PY events/pats PY (%) 100PY Studies (1.004, 1.685) / (2.00%) / (1.53%) Additional Studies (0.564, 1.198) / (3.48%) / (4.46%) 6.12 All 52 Studies (0.890, 1.354) / (2.21%) / (2.08%) Note: Comparison is based on pooled RSG treatment group against non-rsg treatment group without covariate. All Randomized Patients = Randomized patients with at least one dose of study medication. CONFIDENTIAL

23 1 Table U2.2 MACE (CV Mortality, Myocardial Infarction SAE, Stroke SAE): Results from Proportional Hazards Regression Analysis All Randomized Patients Hazard Ratio RSG Control Treatment Comparison Rate/ Rate/ All RSG vs Non-RSG HR 95% CI p_value events/pats PY (%) 100PY events/pats PY (%) 100PY Studies (0.712, 1.593) / (0.73%) / (0.67%) Additional Studies (0.628, 2.664) / (1.18%) / (0.98%) 1.35 All 52 Studies (0.789, 1.593) / (0.80%) / (0.73%) Note: Comparison is based on pooled RSG treatment group against non-rsg treatment group without covariate. All Randomized Patients = Randomized patients with at least one dose of study medication. CONFIDENTIAL

24 1 23 Table U2.3 Summary of Patient and Myocardial Ischaemia Serious and Non-serious Event Counts by Study and Treatment Group 52 Studies All Randomized Patients Non-RSG RSG Rate/ Rate/ Data Status Study events/pats % PY 100PY events/pats % PY 100PY Studies All 86/ 5633 (1.53%) / 8604 (2.00%) / 69 (0.00%) / 74 (2.70%) / 176 (2.27%) / 357 (2.80%) / 198 (3.03%) / 190 (2.63%) / 207 (2.42%) / 391 (3.58%) / 185 (1.62%) / 774 (1.68%) / 63 (3.17%) / 30 (0.00%) / 51 (0.00%) / 101 (0.99%) / 106 (1.89%) / 203 (0.99%) / 107 (0.00%) / 212 (2.36%) / 17 (5.88%) / 16 (0.00%) / 139 (0.72%) / 138 (4.35%) / 75 (0.00%) / 149 (0.67%) / 109 (0.92%) / 213 (2.35%) / 116 (0.86%) / 232 (1.29%) / 96 (3.13%) / 196 (3.06%) / 115 (0.87%) / 116 (5.17%) / 96 (1.04%) / 191 (1.57%) / 58 (3.45%) / 56 (3.57%) / 110 (0.91%) / 437 (0.69%) / 276 (1.45%) / 561 (1.60%) / 111 (8.11%) / 116 (9.48%) / 142 (1.41%) / 148 (2.70%) / 185 (3.24%) / 204 (1.96%) / 71 (0.00%) / 65 (0.00%) / 124 (0.81%) / 121 (0.83%) / 242 (0.83%) / 231 (2.60%) / 88 (2.27%) / 89 (5.62%) / 172 (0.00%) / 168 (1.79%) / 114 (5.26%) / 110 (8.18%) / 58 (0.00%) / 116 (0.00%) / 75 (1.33%) / 70 (0.00%) / 384 (0.52%) / 382 (1.31%) / 14 (0.00%) / 58 (0.00%) / 195 (1.54%) / 196 (1.53%) / 95 (2.11%) / 99 (1.01%) / 212 (1.89%) / 209 (1.91%) / 30 (13.33%) / 31 (16.13%) / 24 (0.00%) / 25 (4.00%) /002 0/ 280 (0.00%) / 289 (1.73%) /003 0/ 272 (0.00%) / 254 (1.57%) All Randomized Patients = Randomized patients with at least one dose of study medication. CONFIDENTIAL

25 2 24 Table U2.3 Summary of Patient and Myocardial Ischaemia Serious and Non-serious Event Counts by Study and Treatment Group 52 Studies All Randomized Patients Non-RSG RSG Rate/ Rate/ Data Status Study events/pats % PY 100PY events/pats % PY 100PY Studies /007 2/ 154 (1.30%) / 314 (0.96%) /004 2/ 222 (0.90%) / 672 (0.30%) New All 59/ 1323 (4.46%) / 1435 (3.48%) / 38 (0.00%) / 39 (2.56%) / 131 (2.29%) / 132 (0.00%) / 29 (3.45%) / 27 (7.41%) / 85 (0.00%) / 84 (1.19%) /376 0/ 21 (0.00%) / 19 (0.00%) AVD / 337 (15.73%) / 331 (12.69%) AVD / 213 (0.00%) / 159 (0.00%) AVD / 75 (0.00%) / 74 (0.00%) AVM / 301 (0.66%) / 294 (0.68%) AVS / 93 (0.00%) / 276 (0.72%) Total 145/ 6956 (2.08%) /10039 (2.21%) All Randomized Patients = Randomized patients with at least one dose of study medication. CONFIDENTIAL

26 1 25 Table U2.4 Summary of Patient and MACE (CV Mortality, Myocardial Infarction SAE, Stroke SAE) Event Counts by Study and Treatment Group 52 Studies All Randomized Patients Non-RSG RSG Rate/ Rate/ Data Status Study events/pats % PY 100PY events/pats % PY 100PY Studies All 38/ 5633 (0.67%) / 8604 (0.73%) / 69 (0.00%) / 74 (1.35%) / 176 (1.70%) / 357 (0.84%) / 198 (1.01%) / 190 (0.53%) / 207 (0.48%) / 391 (0.51%) / 185 (1.08%) / 774 (0.52%) / 63 (0.00%) / 30 (0.00%) / 51 (0.00%) / 101 (0.00%) / 106 (0.94%) / 203 (0.49%) / 107 (0.00%) / 212 (1.89%) / 17 (0.00%) / 16 (0.00%) / 139 (2.88%) / 138 (3.62%) / 75 (0.00%) / 149 (0.67%) / 109 (0.92%) / 213 (0.47%) / 116 (0.00%) / 232 (0.86%) / 96 (1.04%) / 196 (1.02%) / 115 (0.00%) / 116 (0.86%) / 96 (0.00%) / 191 (0.52%) / 58 (0.00%) / 56 (1.79%) / 110 (0.00%) / 437 (0.23%) / 276 (0.72%) / 561 (0.18%) / 111 (4.50%) / 116 (1.72%) / 142 (0.70%) / 148 (3.38%) / 185 (3.24%) / 204 (0.49%) / 71 (0.00%) / 65 (0.00%) / 124 (0.00%) / 121 (0.83%) / 242 (0.00%) / 231 (0.87%) / 88 (1.14%) / 89 (1.12%) / 172 (0.58%) / 168 (1.19%) / 114 (5.26%) / 110 (7.27%) / 58 (0.00%) / 116 (0.00%) / 75 (0.00%) / 70 (0.00%) / 384 (0.00%) / 382 (0.79%) / 14 (7.14%) / 58 (0.00%) / 195 (0.00%) / 196 (0.51%) / 95 (0.00%) / 99 (0.00%) / 212 (0.00%) / 209 (0.00%) / 30 (0.00%) / 31 (3.23%) / 24 (0.00%) / 25 (0.00%) /002 0/ 280 (0.00%) / 289 (0.69%) /003 0/ 272 (0.00%) / 254 (0.39%) All Randomized Patients = Randomized patients with at least one dose of study medication. CONFIDENTIAL

27 2 26 Table U2.4 Summary of Patient and MACE (CV Mortality, Myocardial Infarction SAE, Stroke SAE) Event Counts by Study and Treatment Group 52 Studies All Randomized Patients Non-RSG RSG Rate/ Rate/ Data Status Study events/pats % PY 100PY events/pats % PY 100PY Studies /007 0/ 154 (0.00%) / 314 (0.32%) /004 0/ 222 (0.00%) / 672 (0.00%) New All 13/ 1323 (0.98%) / 1435 (1.18%) / 38 (0.00%) / 39 (2.56%) / 131 (0.76%) / 132 (0.00%) / 29 (0.00%) / 27 (0.00%) / 85 (0.00%) / 84 (0.00%) /376 0/ 21 (0.00%) / 19 (0.00%) AVD / 337 (2.67%) / 331 (3.93%) AVD / 213 (0.00%) / 159 (0.00%) AVD / 75 (1.33%) / 74 (0.00%) AVM / 301 (0.66%) / 294 (0.68%) AVS / 93 (0.00%) / 276 (0.36%) Total 51/ 6956 (0.73%) /10039 (0.80%) All Randomized Patients = Randomized patients with at least one dose of study medication. CONFIDENTIAL

28 1 Adhoc Table Statistical Analysis of Myocardial Ischemia AEs: Results from Proportional Hazards Regression Analysis (by Type of Study) All Randomized Patients (42 ICT Studies) Hazard Ratio RSG Control Rate/ Rate/ Treatment Comparison HR 95% CI p_value events/pats PY (%) 100PY events/pats PY (%) 100PY Placebo Control Only#: (1.217, 2.317) / (2.02%) / (1.25%) 2.87 RSG vs. Control Active and Comb.*: (0.641, 1.584) / (1.90%) / (2.29%) 3.86 RSG vs. Control 27 Note: The treatment comparison is based on a proportional hazards regression model adjusting for number of major cardiovascular risk factors as a covariate. See Table a for supporting SAS statistical output. # Include studies 006, 011, 015, 024, 044, 082, 083, 085, 090, 094, 095, 096, 098, 127, 132, 134, 135, 136, 140, 143, 145, 147, 162, 234, 284, 325, 347, /002 and /003. * Include studies 020, 137, 282, 369, 025, 079, 093, 211, 311, 334, 352, /007 and /004. CONFIDENTIAL

29 CONFIDENTIAL ZM2008/00173/00 The GlaxoSmithKline group of companies Division: Worldwide Development Retention Category: GRS019 Information Type: Summary Document Analysis Plan Title: Summary Document Analysis Plan for Avandia Cardiovascular Event Modeling Update Compound Number: BRL Effective Date: 09-DEC-2008 Description: The hazard ratio estimate and corresponding confidence interval for myocardial ischaemia as well as major adverse cardiovascular event (MACE) from the pooled Integrated Clinical Trial (ICT) database will be updated with additional data from 10 studies. Subject: Avandia, Cardiovascular Events, Statistical Model, Myocardial Ischaemia, MACE Author: Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited 1

30 CONFIDENTIAL ZM2008/00173/00 TABLE OF CONTENTS PAGE ABBREVIATIONS INTRODUCTION OBJECTIVE(S) STUDIES TO BE INCORPORATED INTO THE ICT PLANNED STATISTICAL ANALYSES ANALYSIS POPULATIONS TREATMENT COMPARISONS GENERAL CONSIDERATIONS FOR DATA ANALYSES DATA HANDLING CONVENTIONS SUMMARY POPULATION SAFETY ANALYSES ENDPOINTS Myocardial Ischaemia Myocardial Ischaemia Determination Based on Serious AEs Myocardial Ischaemia Determination Based on Non- Serious AEs Major Adverse Cardiovascular Event (MACE) Determination of MACE for All Studies Except APPROACH Determination of MACE for APPROACH REFERENCES

31 CONFIDENTIAL ZM2008/00173/00 ABBREVIATIONS ADOPT AE APPROACH CHF CRF CV CTR ECG FDC GSK HR ICT LLT MACE MedDRA NDA RSG R&D SAE SU USP WHO A Diabetes Outcome Progression Trial Adverse Event Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients with Cardiovascular History Congestive Heart Failure Case Report Form Cardiovascular Clinical Trial Registry Electrocardiogram Fixed Dose Combination GlaxoSmithKline Hazard Ratio Integrated Clinical Trial Lower Level Term Major Adverse Cardiovascular Events Medical Dictionary for Regulatory Activities New Drug Application Rosiglitazone Research & Development Serious Adverse Event Sulfonylurea United States Pharmaceuticals World Health Organization Trademark Information Trademarks of the GlaxoSmithKline group of companies AVANDIA AVANDAMET Trademarks not owned by the GlaxoSmithKline group of companies None 3

32 CONFIDENTIAL ZM2008/00173/00 1. INTRODUCTION In 2005, a statistical analysis (CV modelling) of the Avandia Integrated Clinical Trial database (ICT), consisting of data from 42 GSK clinical trials, was conducted to estimate the risk (and associated confidence interval) of developing / exacerbating congestive heart failure (CHF) and events associated with myocardial ischaemia for rosiglitazone relative to active or placebo control. The 42 trials were determined based on fully documented criteria established in advance of their integration, based on a data cut-off date of August 2005 and the studies were centrally monitored (either R&D or USPsponsored) with patient level electronic data centrally available for integration. During a review of clinical trials conducted with rosiglitazone worldwide (undertaken to support a remedial review for NDA , July 2008), it was noted that 2 studies (128 and 374) completed prior to August 2005, described in Table 1, met the design criteria for inclusion into the ICT. Although patient level electronic data had not been centrally available for integration at the time of the ICT analysis, both of these studies were conducted by non-us local operating companies, but were not centrally monitored. In addition, 8 other studies, described in Table 1, met the ICT inclusion criteria but had data available after the Aug 2005 cut off; 4 of these studies were conducted by GSK Research & Development (R&D), and 4 were conducted by non-us local operating companies. Since these 10 studies met the design criteria for the ICT analysis, it was determined that the data from these studies should be integrated with the previous studies. An update to the CV modelling analysis will be performed using the additional data from these 10 studies. The scope of the updated analysis will focus on the effect of rosiglitazone relative to control on events associated with myocardial ischaemia and MACE (major adverse cardiovascular events; composite of cardiovascular death, nonfatal myocardial infarction, or non-fatal stroke; defined in Section 10.2), which is an endpoint not defined in the previous ICT. Specifically for myocardial ischaemia, the scope of the analysis will be to update the hazard ratio estimate (and confidence interval) based on comparison between the pooled RSG and the pooled non-rsg groups as reported in the GSK Clinical Trial Registry (CTR). A similar analysis will be performed for MACE. 2. OBJECTIVE(S) The primary objectives are: to estimate the myocardial ischaemia hazard ratio (and associated confidence interval) for rosiglitazone relative to active or placebo control based on a statistical analysis of an updated integrated clinical trial data. The HR based on the previous ICT was reported in the CTR and an updated estimate will be calculated using the pooled data from the previous ICT as well as data from 10 additional studies. to estimate the MACE hazard ratio (and associated confidence interval) for rosiglitazone relative to active or placebo control based on a statistical analysis of an updated integrated clinical trial data. 4

33 CONFIDENTIAL ZM2008/00173/00 3. STUDIES TO BE INCORPORATED INTO THE ICT The requirements for inclusion in the original ICT are described in the ICT Statistical Analysis Plan [Cobitz, 2005] and in particular required that they be double-blind. This analysis will incorporate the following double-blind studies listed in Table 1 into the previous ICT. Table 1 Studies to be Included Study RSG Regimen Control RSG Notes TDD* 128 RSG+SU Placebo+SU 4 mg Local study in Taiwan 374 RSG+αglucosidase Placebo+αglucosidase 4 mg Local study in Japan inhibitor inhibitor AVM Avandamet Metformin+SU 4 8 mg EU study with Central R&D monitoring 376 RSG Placebo 4 mg Central R&D funded AVS RSG; Simvastatin 4 8 mg Central R&D funded RSG+Simvastatin FDC AVD RSG+Insulin Insulin 4 mg Local study in China AVD RSG Placebo; Pioglitazone 4 8 mg Local study in Japan AVD RSG+SU Placebo+SU 4 mg Local study in Japan 351 RSG Placebo 4 8 mg Central R&D funded AVD RSG Glipizide(SU) 4 8 mg APPROACH; Central R&D funded *TDD=Total daily dose Since the ICT is comprised of predominantly short-term studies used to generate hypotheses, which can be independently tested in long-term trials; the long-term ADOPT study will not be included in this update. The substantially greater follow-up in the ADOPT study (4 to 6 years) would introduce clinical heterogeneity, limiting the interpretability of analyses from the integrated dataset [Thompson, 1991]. In addition, an exploratory data analysis of the hazard ratios and corresponding confidence intervals for programmatically-derived myocardial ischaemia AEs highlight substantial difference between ADOPT and the previous ICT, underscoring statistical heterogeneity that would further undermine interpretation should ADOPT be included. 4. PLANNED STATISTICAL ANALYSES Analysis of the event myocardial ischaemia AEs and SAEs and MACE (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) will be performed with additional data from 10 studies. Derivation of these endpoints is described in Section 10. The analysis of interest using the updated ICT database will include re-estimating the HR estimate for the comparison between the group taking rosiglitazone (RSG) and the group not taking RSG regardless of the RSG dose and other background medication. 5

34 CONFIDENTIAL ZM2008/00173/00 Assignment to the treatment groups represented in the comparisons above will be based on randomized treatment assignment. This analysis is identical to the one performed to generate the myocardial ischaemia hazard ratio and confidence interval for comparing RSG and non-rsg groups as reported in the CTR. The planned analyses involve the safety endpoints myocardial ischaemia and MACE, which are defined in Section 10.1 and Section 10.2, respectively. A Cox proportional hazards model analysis will be used to calculate the hazard ratio for RSG relative to non- RSG comparator. Subjects who were randomized to RSG will be pooled into one group and those randomized to control will be pooled into another group. The model will contain the term for pooled treatment but will not be adjusted for other covariates. This analysis will be performed by combining the raw data from the 10 additional studies and the previous ICT data. Consistent with the overall estimate reported in the CTR, the updated analysis will not be stratified by study. Although this requires a stronger proportional hazards assumption than would be the case for a stratified analysis, it does permit follow-up time for patients in zero-event studies to be included in the event that this could affect the hazard ratio estimate. A summary of the event rate per 100 patient-year will also be provided by treatment group. Cumulative incidence plots by treatment group will be generated. 5. ANALYSIS POPULATIONS All randomized patients will be included in the planned analysis. The exception to this is that data will be excluded from centers where there were alleged irregularities in data collection or which failed a study audit (n=65 patients). Excluding these patients is consistent with the approach that was taken for safety summaries in reporting of these studies to regulatory authorities. 6. TREATMENT COMPARISONS Treatment comparisons using the updated ICT data will be between the pooled RSG group and the pooled non-rsg group. 7. GENERAL CONSIDERATIONS FOR DATA ANALYSES The analysis will be limited in scope compared to the previous CV modelling exercise as the intent is to update the myocardial ischaemia hazard ratio point estimate and corresponding confidence interval reported in the CTR. As the objective is to update a previously-reported estimate, the planned statistical analysis will be identical to the one performed to obtain the previous estimate. 6

35 8. DATA HANDLING CONVENTIONS CONFIDENTIAL ZM2008/00173/00 Data handling conventions used for the analysis of the previous ICT will be followed as applicable. These include handling of premature withdrawal and missing data, derivation and transformations of data, as well as definition calculation of assessment windows. See ICT Analysis Plan for details [Cobitz, 2005]. 9. SUMMARY POPULATION The data from the 42 studies from the previous ICT and the 10 additional studies will be pooled together. A summary of the number of randomized patients by study and treatment will be reported. The number of events in the previous ICT data and the number of events in the additional data will be summarized by treatment group and by study. 10. SAFETY ANALYSES ENDPOINTS Myocardial ischaemia and major adverse cardiovascular events (MACE) are the two primary events of interest in these statistical analyses. Details of the analysis are described in Section 4. For studies included in the previous ICT, assignment to myocardial ischaemia will follow what has been defined in the previous ICT [Cobitz, 2005]. For the additional 10 studies listed in Table 1, assignment to myocardial ischaemia is described in Section Assignment to MACE for the 10 additional studies will follow what has been done in a previous analysis and is described in Section Myocardial Ischaemia The review process for identification of myocardial ischaemia will be based on information entered in the AE as well as SAE CRF pages Myocardial Ischaemia Determination Based on Serious AEs Since more information is available for SAEs, event determination for SAEs will be based on a review of the complete narrative for each event, but the reviewer will be blinded to the randomised treatment information. SAE cases for blinded review will be identified as follows: All SAEs coding to a cardiovascular or respiratory body system or organ class Body System of Cardiovascular General, Heart Rate and Rhythm, Myocardial Endocardial Perdicardial Valve or Respiratory System (WHO Dictionary); or System Organ Class of Cardiac Disorders or General Disorders and Administration Site Conditions (MedDRA Dictionary); or 7