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Proposal 1257

Title of the Proposed Research

An independent evaluation of the cardiovascular risk of rosiglitazone: meta-analysis of GSK’s publicly available clinical trial data

Lead Researcher

Joseph S. Ross, MD, MHS

Affiliation

Yale University School of Medicine
Yale-New Haven Hospital Center for Outcomes Research and Evaluation

Funding Source

None: This research is not supported by any external grants or funds.

Potential Conflicts of Interest

Dr. Ross receives support from Medtronic, Inc., and Johnson and Johnson, Inc. to develop methods of clinical trial data sharing, from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting, from the Pew Charitable Trusts to examine U.S. pharmaceutical regulatory policy, and from the Food and Drug Administration (FDA) to develop methods for post-market surveillance of medical devices. Dr. Ross is supported by the National Institute on Aging (K08 AG032886) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. Dr. Ross reports that he is a member of a scientific advisory board for FAIR Health, Inc.

Dr. Krumholz receives support from Medtronic, Inc., and Johnson and Johnson, Inc. to develop methods of clinical trial data sharing, from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting, and from the Food and Drug Administration (FDA) to develop methods for post-market surveillance of medical devices. Dr. Krumholz is supported by a National Heart Lung Blood Institute Cardiovascular Outcomes Center Award (1U01HL105270-02). Dr. Krumholz reports that he chairs a scientific advisory board for UnitedHealthcare.

Dr. Desai receives support from Johnson and Johnson, Inc. to develop methods of clinical trial data sharing.

Dr. Lin receives support from Johnson and Johnson, Inc. to develop methods of clinical trial data sharing.

Data Sharing Agreement Date

22 September 2015

Lay Summary

Rosiglitazone (Avandia), manufactured by GSK, was approved for use by the U.S. Food and Drug Administration in 1999 for the treatment of type 2 diabetes mellitus. The approval was based on clinical trials that demonstrated the effectiveness of the medication at lowering serum blood glucose concentrations. Use of rosiglitazone grew rapidly in the ensuing years and annual sales peaked at approximately $2.5 billion in 2006.

However, concerns were raised about the medication when, in May 2007, a meta-analysis suggested it increased risk of myocardial infarction. These findings led to widespread public and regulatory scrutiny of the medication, triggering a safety alert by the FDA that same month and Congressional hearings on the topic shortly thereafter in June 2007. In September 2007, a second meta-analysis of this data using a slightly different statistical approach was published, which identified no increased risk. Despite these conflicting findings, in September 2010, the FDA updated rosiglitazone’s product label to include information on cardiovascular risks and in May 2011, the FDA implemented a risk evaluation and mitigation strategy (REMS), which restricts the drug’s availability and applies specified criteria for use.

In 2013, FDA eased the restrictiveness of the rosiglitazone REMS after an updated analysis of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes (RECORD) study that compared heart attack risk of standard diabetes treatments found the medication’s risk to be in line with that of other diabetes drugs. However, even with eased restrictions, the previous boxed warning may instill a lingering apprehension in doctors and patients for prescribing rosiglitazone. While fewer patients today are using rosiglitazone, with eased restrictions and upcoming availability of rosiglitazone in a cheaper, generic formulation, we can expect rosiglitazone utilization to increase in the future.

One key limitation of both prior meta-analyses on this topic has been the use of summary-level data from the identified clinical trials for meta-analysis. However, the recent announcement by GSK to make patient-level clinical trial data available to external investigators in an effort to facilitate further research that can help advance medical science or improve patient care presents a unique opportunity to address the question of rosiglitazone’s cardiovascular risk through the meta-analysis of all of GSK’s clinical trial program data of this medication.

Our research objective is to conduct a meta-analysis of GSK's rosiglitazone clinical trial program data to better understand the cardiovascular risk associated with use of the medication, including risk of heart failure events, acute myocardial infarction, cardiovascular-related deaths, and all-cause deaths. Results from this research will be submitted for publication to a peer-reviewed biomedical journal.

Study Data Provided

Study GSK-AVA102675: An open-label extension study of the long-term safety and efficacy of rosiglitazone extended-release (RSG XR) as adjunctive therapy to acetylcholinesterase inhibitors in subjects with mild-to-moderate Alzheimer's disease (REFLECT-4).
Study GSK-AVA102677: An open-label extension study of the long-term safety and efficacy of rosiglitazone extended-release (RSG XR) in subjects with mild-to-moderate Alzheimer's disease (REFLECT-5)
Study GSK-AVA105640: A 24-week, double-blind, double-dummy, randomized, parallel-group study to investigate the effects of rosiglitazone (extended release tablets), donepezil, and placebo as monotherapy on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer’s disease. (REFLECT-1)
Study GSK-AVD111179: A 52 Week Randomized, Double-Blind, Multicenter, Mechanistic Study with a 24 Week Open-Label Follow-Up to Evaluate the Effect of AVANDIA ™ on Bone in Postmenopausal Women with Type 2 Diabetes Mellitus
Study GSK-AVD111960: Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) A Multicenter Randomized Double-Blind Placebo Controlled Trial of a Thiazolidinedione or Placebo and of Vitamin D or Placebo In People With Type 2 Diabetes at Risk For Cardiovascular Disease
Study GSK-49653/048: A Randomized, Double-Blind Study to Compare the Durability of Glucose Lowering and Preservation of Pancreatic Beta-Cell Function of Rosiglitazone Monotherapy Compared to Metformin or Glyburide/Glibenclamide in Patients with Drug-Naive, Recently Diagnosed Type 2 Diabetes Mellitus
Study GSK-49653/137: A Study to Evaluate the Efficacy of Rosiglitazone (BRL-049653) on Reduction of Microalbuminuria in Subjects with Type 2 Diabetes Mellitus
Study GSK-49653/211: A 52-week double-blind study of the effect of rosiglitazone on cardiovascular structure and function in subjects with type 2 diabetes mellitus and congestive heart failure (NYHA class I/II)
Study GSK-49653/231: A long term, open label, randomised study in patients with type 2 diabetes, comparing the combination of rosiglitazone and either metformin or sulfonylurea with metformin plus sulfonylurea on cardiovascular endpoints and glycaemia
Study GSK-49653/325: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Control, Clinical Evaluation of Rosiglitazone in Combination with Glimepiride Compared to Glimepiride Plus Placebo for 24 Weeks in Subjects with Type 2 DiabetesMellitus Who are Inadequately Controlled on Non-TZD Oral Monotherapy
Study GSK-49653/330: A Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Assess the Safety and Efficacy of Three Dose Levels of Rosiglitazone Maleate in the Treatment of Chronic Plaque Psoriasis
Study GSK-49653/331: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety and Efficacy of Rosiglitazone Maleate in the Treatment of Chronic Plaque Psoriasis
Study GSK-49653/334: Effect of rosiglitazone and placebo on carotid intima media thickness in patients with insulin resistance syndrome and/or type 2 diabetes
Study GSK-49653/342: A Randomised study Examining the Effect of Different Diuretics on Fluid Balance in Diabetics Treated with Avandia
Study GSK-49653/347: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Control, Clinical Evaluation of Insulin Plus Rosiglitazone (2mg and 4mg) Compared to Insulin Plus Placebo for 24 Weeks in Subjects with Type 2 Diabetes Mellitus Who are Inadequately Controlled on Insulin
Study 49653/351: A 12 month randomized, double-blind, placebo-controlled, magnetic resonance imaging study to evaulate the effect of rosiglitazone on the structure and composition of carotid atherosclerotic plaques in subjects with type 2 diabetes
Study GSK-49653/352: A 16 Week Randomised, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Effect of Rosiglitazone on Myocardial Glucose Uptake in Subjects with Type 2 Diabetes Mellitus and Stable Coronary Heart Disease
Study GSK-49653/376: A 16-week, randomised, double-blind, placebo-controlled, single-centre study to investigate fluid retention in insulin-treated subjects with type 2 diabetes mellitus and varying degrees of autonomic neuropathy when administered rosiglitazone 4mg twice daily
Study GSK-49653/452: A randomized, double-blind, parallel group, placebo-controlled study to investigate the safety, tolerability and efficacy of six months' administration of AVANDIA (rosiglitazone maleate) in subjects with Relapsing-Remitting Multiple Sclerosis (MS)
Study GSK-49653/461: A double-blind, randomized, placebo-controlled, parallel-group study to investigate the effects of rosiglitazone (extended release tablets) on cerebral glucose utilization and cognition in subjects with mild to moderate Alzheimer's Disease (AD)
Study GSK-ARA102198: A randomised, double-blind, placebo-controlled, parallel group study to investigate the anti-inflammatory and metabolic effects of rosiglitazone XR, 8mg once daily, in subjects with rheumatoid arthritis
Study GSK-AVA100193: A 24 week double-blind, randomised, placebo-controlled, parallel-group dose-ranging study to investigate the effects of rosiglitazone (extended release tablets) on cognition in subjects with mild to moderate Alzheimer's disease
Study GSK-AVA100468: An open-label extension to study AVA100193, to assess the long-term safety and efficacy of rosiglitazone (extended release tablets) in subjects with mild to moderate Alzheimer's disease
Study GSK-AVA102670: A 54-week, study to investigate the effects of rosiglitazone (extended release tablets) as adjunctive therapy to acetylcholinesterase inhibitors on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer’s disease (REFLECT-3)
Study GSK-AVA104617: An open-label extension to study 49653/461, to assess the long-term safety of rosiglitazone (extended release tablets) in subjects with mild to moderate Alzheimer's Disease
Study GSK-AVD100521: A Phase III, 18 Month, Multicenter, Randomized, Double-Blind, Active-Controlled Clinical Trial to Compare Rosiglitazone versus Glipizide on the Progression of Atherosclerosis in Subjects with Type 2 Diabetes Mellitus and Cardiovascular Disease (APPROACH)
Study GSK-49653/292: A Randomized, Double-Blind, Placebo-Controlled Trial to Assess Three Dose Levels of Rosiglitazone Maleate in the Treatment of Moderate to Severe Plaque Psoriasis.
Study GSK-49653/009: A Multicentre, Open-Label Extension Study to Assess the Long-Term Safety, Tolerability and Efficacy of Rosiglitazone When Administered to Patients With Type 2 Diabetes Mellitus.
Study GSK-49653/085: A 26 Week Randomised, Double-Blind, Multicentre Study to Investigate the Effects of Rosiglitazone on Insulin Requirements in Insulin-Treated Type 2 Diabetic Patients
Study GSK-49653/097: A 3-Year Open-Label, Multicenter, Active (Glyburide) Comparison Study, to Evaluate the Effect of BRL49653C 8mg once daily on Cardiovascular Function in Patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM)
Study GSK-49653/112: An Open-Label Extension Study to Assess the Long-Term Safety, Tolerability and Efficacy of Rosiglitazone When Administered Once or Twice Daily in Combination with Glyburide to Patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM)
Study GSK-49653/114: An Open-Label Extension Study to Assess the Long-Term Safety, Tolerability and Efficacy of Rosiglitazone When Administered Once or Twice Daily in Combination with Insulin to Patients with Type 2 Diabetes
Study GSK-BRL-049653/131: A Double-blind, Placebo-controlled, Parallel-group Study to Determine the Effect of BRL- 49653C Rosiglitazone, on Fat Distribution When Administered for 26 Weeks to Subjects With Impaired Glucose Tolerance (IGT)
Study GSK-49653/025: A Multicentre, Double-Blind, Parallel Group Study to Determine the Effects of Rosiglitazone on Insulin Sensitivity, Endothelial Function and Vascular Reactivity in Comparison With Metformin and Placebo When Administered to Patients With Non-insulin Dependent Diabetes Mellitus.
Study GSK-712753/007: A randomized, double-blind trial to evaluate the efficacy and safety of fixed dose rosiglitazone/metformin combination therapy compared to both rosiglitazone and metformin monotherapies in drug naive type 2 diabetes mellitus subjects
Study GSK-712753/002: A phase III, 24 week, multi-centre, randomised, double-blind, parallel group, dose escalation study of Avandamet (rosiglitazone/metformin) and high dose metformin monotherapy in subjects with poorly controlled type 2 diabetes mellitus
Study GSK-712753/003: A Phase III Multi-Centre, Double-Blind, Randomised, Parallel-Group, Dose Escalation Study Comparing the Effects of 32 Weeks Administration of Avandamet and Metformin on Hba1c Targets in Subjects With Mild Type 2 Diabetes Mellitus
Study GSK-712753/009: A 24 week, randomised, double blind, parallel study to compare the change in HbA1c with AVANDAMET® (8.0mg / 2.0g) plus insulin to placebo plus insulin, in subjects with type 2 diabetes starting insulin therapy
Study GSK-AVA102672: A 54-week, double-blind, randomized, placebo-controlled, parallel-group study to investigate the effects of rosiglitazone (extended release tablets) as adjunctive therapy to donepezil on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer’s disease.
Study GSK-49653/183: A 24 Week Randomized, Double-blind, Double-dummy, Multicenter Study to Evaluate the Safety, Efficacy, and Tolerability of Avandia™ XR and AVANDIA™ (4mg BD) in Patients with Type 2 Diabetes
Study GSK-AXR100723: A 24 Week Randomized, Double-blind, Double-dummy, Multicenter Study to Compare the Efficacy of Formulation X and AVANDIA™ (8mg OD) in Subjects with Type 2 Diabetes Mellitus
Study GSK-49653/135: 2-year, Randomized, Double-blind, Parallel Group Study to Compare the Efficacy, Safety and Tolerability of Rosiglitazone Versus Placebo in Combination with Glipizide in Elderly Patients with Type 2 Diabetes Mellitus who are Inadequately Controlled on Glipizide Therapy
Study GSK-49653/136: A 26-week Randomised, Double-Blind, Multicentre, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Rosiglitazone with Concurrent Insulin Therapy and/or a Sulphonylurea in Type 2 Diabetic Patients with Chronic Renal Failure (Not on Dialysis).
Study GSK-49653/140: A Randomised, Double-Blind, Placebo-Controlled Study to Investigate the Effects of Rosiglitazone on Post Prandial Glycaemia in Type 2 Diabetic Patients.
Study GSK-49653/143: A 24-Week Randomized, Double-blind Study to Evaluate the Efficacy, Safety and Tolerability of AVANDIA (8mg once daily) in Combination with Glyburide in African American and Hispanic Patients with Type 2 Diabetes Mellitus who are Inadequately Controlled on Glyburide Monotherapy
Study GSK-49653/284: A 24-Week Randomized, Double-blind, Double-Dummy, Multicenter Study to Compare the Efficacy of AVANDIA when added to Submaximal Doses of Metformin and to Compare the Tolerability of the Combination to Metformin Monotherapy when Administered to Subjects with Type 2 Diabetes Mellitus
Study GSK-49653/326: A 24-week Randomized, Double-Blind, Parallel-Group, Multicenter Study to Demonstrate the Efficacy and Safety of Two Different Rosiglitazone Dosing Regimens, 4mg OD and 8mg OD, in Poorly-Controlled Drug Naive Patients with Type 2 Diabetes Mellitus
Study GSK-BRL-049653/282: A Double-Blind Feasibility Study to Estimate and Compare the Effect of Rosiglitazone in Parallel with Glyburide on Cognition in Patients with Type 2 Diabetes Mellitus
Study GSK-BRL-049653/375: A single-centre, randomised, double-blind, placebo controlled, two 12 week period, cross-over phase III study to investigate the effect of rosiglitazone 4mg bd on the vasodilator response to hyperinsulinaemia in obese insulin resistant subjects.
Study GSK-797620/004: A multi-center, randomized, double-blind, parallel group trial to compare the efficacy and safety of fixed-dose rosiglitazone/glimepiride combination therapy to glimepiride monotherapy and rosiglitazone monotherapy in drug naïve subjects with type 2 diabetes mellitus
Study GSK-049653/109: An Open-label, Positive-controlled, Parallel-group Study to Determine the Effect of BRL 49653C, Rosiglitazone, on Body Fat Distribution When Administered for 26 Weeks to Patients with Type 2 Diabetes
Study GSK-49653/207: A 24-week Randomized, Double-blind, Active-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Rosiglitazone When Administered to Pediatric Patients with Type 2 Diabetes Mellitus
Study GSK-BRL-049653/369: A six-month double-blind, randomised, parallel-group study to compare the effect of oral rosiglitazone (less than or equal to 4mg bd) versus oral glibenclamide therapy (less than or equal to 15mg daily) on body fat distribution when administered to subjects with type 2 diabetes mellitus
Study GSK-49653/015: A Multicentre, Double-Blind, Placebo Controlled, Parallel Group Comparative Study to Evaluate the Efficacy, Safety and Tolerability of Rosiglitazone with Concurrent Sulphonylurea therapy, When Administered to Patients with Type 2 Diabetes Mellitus.
Study GSK-49653/020: A Multicentre, Double-Blind, Parallel Group Comparative Study to Evaluate the Efficacy, Safety and Tolerability of Rosiglitazone vs. Glibenclamide Therapy, When Administered to Patients with Type 2 Diabetes Mellitus.
Study GSK-49653/079: A 26-week Randomized, Double-Blind, Double-Dummy, Multicentered Study to Evaluate the Efficacy, Safety and Tolerability of Rosiglitazone when Administered to Patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM) who are Inadequately Controlled on a Maximal Dose (20 mg/day) of Glyburide.
Study GSK-49653/096: A 26-week Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Rosiglitazone when Administered Once Daily to Patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM) who are Inadequately Controlled on At Least Half-Maximal Dose (≥ 10 mg/day) of Glyburide
Study GSK-49653/082: A 26-Week Randomized, Double-Blind, Multicenter Study to Evaluate the Safety, Efficacy, and Tolerability of BRL49653C when Administered Twice Daily to Patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM) who are Inadequately Controlled on Insulin Monotherapy
Study GSK-49653/095: A 26-week Randomised, Double-Blind, Multicenter Study to Evaluate the Safety, Efficacy, and Tolerability of Rosiglitazone when Administered Once Daily to Patients with Type 2 Diabetes who are Inadequately Controlled on Insulin Monotherapy

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

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