Terminated rimonabant trial shows signs of suicide risk.
Those side effects derailed the new drug application of the once-promising endocannabinoid receptor with the Food and Drug Administration in the United States in 2007 and led the European Medicines Agency to withdraw its marketing authorization for the the drug after less than 2 years on the market.
Rimonabant has been shown to reduce appetite and improve metabolic risk factors, including HDL cholesterol, triglycerides, blood glucose, and fasting insulin, wrote Dr. Eric J. Topoi of Scripps Translational Science Institute in La Jolla, Calif., and his colleagues.
To assess the impact of rimonabant on cardiovascular events, researchers designed the Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO) tri al. Between Dec. 22, 2005, and July 29, 2008, this double-blind, placebo-controlled trial enrolled 9,381 adults who were randomized to receive a 20-mg rimonabant tablet daily, and 9,314 adults who were randomized to a placebo. Average age was 64 years; 64% of each group was male. The average waist circumference was 112 cm (about 44 inches) in both groups (Lancet 2010;376:517-23).
When CRESCENDO was discontinued after an average of 14 months" follow-up, significantly more patients in the rimonabant group compared with the placebo group developed gastrointestinal side effects (33% vs. 22%), neuropsychiatric side effects (32% vs. 21%), and serious psychiatric side effects (2.5% vs. 1.3%). In addition, four patients in the rimonabant group and one patient in the placebo group committed suicide during the study period.
"Because of rimonabant's actions on the CNS, screening questions about neurological and psychiatric symptoms were asked at baseline, 1 month, 3 months, and then every 3 months for the duration of the trial, and a neurological examination was to be done at baseline," the researchers said. Patients who showed symptoms were referred to a neurologist or mental health specialist.
The study's primary end point--a composite of cardiovascular death, myocardial infarction, or stroke--occurred in 4% of patients in each group (364 events in the rimonabant group and 375 in the placebo group).
"In this setting, the performance of a long-term trial for an expanded cardiovascular indication was affected by the track record of the drug in clinical practice that was marketed for weight loss," the researchers noted.
In an accompanying editorial, Dr. S. Matthijs Boekholdt and Dr. Ron J.G. Peters of the Academic Medical Center in Amsterdam noted that postmarketing registries of patients using the drug showed an increased risk of suicide, and that the European Medicines Agency's decision to stop marketing authorization was appropriate. Although the study results suggested that endocannabinoid blockers could help manage obesity, concerns about side effects led the European Medicines Agency to stop the marketing authorization for rimonabant in Europe in 2008. The Food and Drug Administration denied approval of the drug in the United States in 2007.
Had the study been completed, a significant improvement in cardiovascular outcomes could have outweighed some side effects. "However, any mortality associated with cardiovascular preventive therapy is generally viewed as unacceptable," Dr. Boekholdt and Dr. Peters wrote (Lancet 2010;376:489-90).
Major Finding: In a trial rimonabant, the primary outcome, a composite of cardiovascular death, MI, or stroke, occurred in 4% of patients in both groups.
Data Source: CRESCENDO, a randomized, multicenter, double-blind, placebo-controlled trial of 18,695 overweight or obese adults with increased risk of vascular disease.
Disclosures: The study was supported by Sanofi-Aventis. The primary study authors disclosed receiving research support, consulting fees, and/or honoraria from Sanofi-Aventis. Neither Dr. Boekholdt nor Dr. Peters had any financial conflicts to report.
BY HEIDI SPLETE FROM THE LANCET
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|Title Annotation:||NEWS FROM THE FDA|
|Publication:||Family Practice News|
|Date:||Sep 1, 2010|
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