Avandia Clinical Trials: Methods and Results

Study of Avandia Patient Blood Pressure Related to Cardiovascular Hospitalization and Death:

Name of Trial: RECORD
Rosiglitazone Evaluated for Cardiovascular Outcomes

Purpose: The RECORD study in an ongoing non-inferiority trial (meant to prove that a new treatment is equivalent to standard treatment). It has been conducted with the intention of determining effect on blood pressure as a factor in the risk and incidence of myocardial infarction (heart attack) and other cardiac problems in patients taking Avandia versus those taking previously prescribed medications, namely metformin and sulfonylurea.

Method:
Patient recruitment for RECORD began in 2001 and the study itself began in 2003. Results were published in 2007, although the study is ongoing at this time. A total of 4,447 patients with type II diabetes are being evaluated for RECORD. Eligible patients were recruited between the ages of 40 and 75, and were already on monotherapy with either metformin or sulfonylurea for glycemic control. Those with a hospitalization for a cardiac event in the 3 months prior to the trial, those having a planned cardiac intervention,  and those with heart failure, hepatic disease, renal impairment or uncontrolled hypertension were ineligible to participate in RECORD. Throughout the course of the trial, patients were given one of the following combinations of medication:

• test group: 1,117 patients received a combination of metformin and Avandia
• test group: 1,103 patients received a combination of sulfonylurea and Avandia
• control group: 2,227 patients received a combination of metformin and sulfonylurea
  Of these patients, 1,105 were previously on monotherapy with metformin, and 1,122 were previously on monotherapy with sulfonylurea.

The primary outcome measure of RECORD is time to hospitalization and/or death related to a cardiac event. The secondary outcome measure is designed to target similar glycemic control in both the Avandia group and the control group, and to assess blood pressure level independent of glycemic control, as a risk factor for cardiovascular events and deaths..

Results:
Primary outcome measure: After 3.75 years, published results concluded that patients on Avandia did show an increase in risk factors for heart failure. However, the number of patients that experienced a cardiovascular hospitalization or cardiovascular related death was not significantly higher in the Avandia group than in the control group.

Secondary outcome measure: According to results published in 2008, blood pressure (BP) levels as measured at 12 months after the study began were significantly lowered in those taking rosiglizatone in addition to either metformin or sulfonylurea.  BP levels at 6 months were reduced, but not significantly.

Conclusions:
Primary outcome measure: Because results were published less than 4 years after the study began, the statistical evidence is not as strong as it should be. As the patients involved in RECORD continue to take their assigned medication, it is predicted that additional cardiac hospitalizations and deaths will occur. At the time of publication, the results were inconclusive and insufficient to prove non-inferiority.

Secondary outcome measure: Avandia therapy, when combined with either metformin or sulfonylurea and administered for 12 months, does reduce blood pressure to a greater extent than the combination of metformin and sulfonylurea.

Diabetes Prevention - Study of Avandia's Effect on Prediabetic Patients:

Name of Trial: DREAM
Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication

Purpose:
The DREAM trial was designed to measure the effects of Avandia and rampiril in prediabetic patients with impaired glucose tolerance (IGC) and/or impaired isolated fasting glucose (IIFG. The goal of DREAM was to determine whether treatment with Avandia an/or rampiril is effective in decreasing the frequency of type II diabetes mellitus.

Method
The DREAM trial measured glucose levels in 5,269 patients over an 18 month period, with continued monitoring for a 3 year period after the trial. This study is ongoing but no longer recruiting participants. Participants in the study were over 30 years old, with an average age of 54.7. Eligible patients had IGC and/or IIFG. Those with a history of diabetes, heart disease, high risk of heart failure, uncontrolled hypertension, renal or hepatic disease, or other major illness were not eligible for participation in the DREAM study. In a double-blind, placebo controlled study, patients were administered one of the following:

• Daily dose of Avandia
• Daily dose of Rampiril
• Daily dose of both Avandia and Rampiril
• Daily dose of two placebos

The primary outcome measure of DREAM is incidence and time of progression into diabetes or death. The secondary outcome measure of DREAM was incidence of cardiovascular health problems and deaths.

Results:
Primary outcome measure: While rampiril was effective in patient regression back to normoglaecmia, but did not ultimately prevent progression into a diabetic state. Avandia was determined to be highly effective in preventing diabetes, showing significantly fewer cases of diabetes than those on placebo treatment over the 3 year monitoring period.

Secondary outcome measure: Actual incidence of heart attacks and other cardiac events did not differ significantly between Avandia patients and those who received placebos. However, patients taking Avandia did see a significant increase in the development of heart failure.

Conclusions:
Primary outcome measures: Avandia, and the use of insulin sensitizers in general, is an effective therapy for the control and prevention of diabetes.

Secondary outcome measures: Although Avandia may be effective in type II diabetes prevention and control, the risk of heart failure associated with its use is of great concern. Additional studies and trials must be completed to determine whether benefits of using Avandia outweigh the risk of heart failure.

Study of Avandia Versus Alternative Monotherapy In Treatment of Type II Diabetes

Name of Trial: ADOPT
A Diabetes Outcome Progression Trial

Purpose:
ADOPT was designed to observe the results and failure rates associated with the use of Avandia in contrast with the use of other monotherapy drugs - specifically metformin and glyburide (a sulfonylurea). ADOPT defined monotherapy failure as confirmed hyperglycemia.

Method:
ADOPT treated 4,360 participants over a median period of 4 years. Results were published in 2006. Patients included in the study were 30-75 years old and had been recently diagnosed with type II diabetes at the time of recruitment. Only patients whose diabetes had been managed by diet and exercise alone were eligible; those already being treated by a drug were not included. Over a period of 4-6 years, patients were treated with one of the following:

• Daily dose of Avandia
• Daily dose of Metformin
• Daily dose of Glyburin
  **Upon evaluation and depending on response, daily doses were increased to the maximum allowable daily dose of each drug, with dose reductions being permitted if adverse side effects were observed.

 Results:
Primary outcome measure: ADOPT found that Avandia presented a 32% reduction in failure compared to metformin, and 63% reduction in failure compared to glyburin.

Secondary outcome measure: In observations, Avandia was associated with a higher rate of heart disease, heart failure, weight gain and adverse effects on cholesterol levels. Metformin patients had more gastrointestinal problems, and those on glyburin had a greater incidence of hypoglycemia.

Conclusions:
Primary outcome measure: Overall, only 60% of the participants in ADOPT actually completed the trial, weakening the results of the study. In terms of those who did complete the trial, Avandia was the most effective in maintaining control of type II diabetes.

Secondary outcome measure: Doctors involved with ADOPT believe that Avandia works well in managing blood sugar levels, but recommend that patients and doctors make an educated decision as to appropriate glycemic therapy based on effectiveness as well as side effects and price (Avandia has no generic, while metformin and glyburin do).

Avandia Meta-Analysis

In 2007, the New England Journal of Medicine published a study completed by researchers at the Cleveland Clinic. Their study was a meta-analysis of 42 previously conducted studies on Avandia including over 27,000 patients. The results of their study concluded that Avandia presents a significantly increased risk of heart failure, heart attack and other cardiac events leading to hospitalization and death. The FDA issued a public safety warning about Avandia in response, and required additional warning information to be printed on the Avandia label. According to GlaxoSmithKline, no study to date has provided enough conclusive evidence of heart-related health risk as a benefit eclipsing side effect. Although many advocacy groups have protested, the FDA has not pulled Avandia from the market; Avandia is still available as a doctor-prescribed drug. Additional studies are being completed to produce more conclusive results on cardiac events and other side effects such as liver damage and osteoporosis.

Other Avandia Studies

For detailed information on all clinical trials conducted by GlaxoSmithKline (GSK) on Avandia/Rosiglitazone, visit the GSK clinical trial register on Avandia. Information is also available at clinicaltrials.gov. Search Avandia for information on these trials.