Le Trac, Mercer University College of Pharmacy
In September 2014, the United States Food and Drug Administration (FDA) approved Contrave® (naltrexone hydrochloride and bupropion hydrochloride extended-release tablets) for the treatment of chronic weight management. 
At the time of approval, the FDA learned that Orexigen, the manufacture of Contrave®, had disclosed data from the LIGHT trial without the authorization of the study’s academic leadership. Thus, the FDA requested numerous post-marketing follow-up studies, including a cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave® use. 
|Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial |
|Design||Phase 3b, multicenter, randomized, double-blind, noninferiority, placebo-controlled; N= 8,910|
|Objective||To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients|
|Study Groups||Naltrexone 32 mg/day and bupropion 360 mg/day (n= 4,456); placebo (n= 4,454)|
|Methods||Patients at 266 centers in the United States who were overweight or obese and at increased cardiovascular risk were enrolled in the trial. Patients in each group received a dose escalation during the first four weeks of treatment, beginning with one tablet daily (each tablet contained an extended-release formulation of 8 mg of naltrexone and 90 mg of bupropion or placebo) during the first week, increasing to two tablets during week two, three tablets during week three, and four tablets daily during week 4 and thereafter. An internet-based weight management program was provided to all participants.|
|Duration||June 13, 2012 to January 21, 2013|
|Primary Outcome Measure||Time from randomization to first confirmed occurrence of a MACE (cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction)|
|Baseline Characteristics||Mean age was 61 years, 54.5% were female, 83.5% were white, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes. The median body mass index was 36.6. Concomitant medications included statins in 79.2% of patients, antihypertensive medications in 92.0%, and glucose-lowering agents in 75.1%.|
|Results||Primary outcome||Placebo (%)||Naltrexone-bupropion (%)||Hazard ratio (95% confidence interval)|
|25% interim analysis|
|Composite primary outcome||1.3||0.8||0.59 (0.39-0.90)
|Cardiovascular death||0.4||0.1||0.26 (0.10-0.70)
|Nonfatal stroke||0.2||0.2||0.70 (0.27-1.83)|
|Nonfatal myocardial infarction||0.7||0.5||0.70 (0.41-1.18)
|50% interim analysis|
|Composite primary outcome||2.3||2.0||0.88 (0.57-1.34)
|Cardiovascular death||0.8||0.4||0.50 (0.21-1.19)
|Nonfatal stroke||0.4||0.5||1.10 (0.44-2.78)|
|Nonfatal stroke||1.2||1.2||1.00 (0.57-1.75)|
|Adverse Events||Common Adverse Events: gastrointestinal events (14.2%), central nervous system symptoms (5.1%)|
|Serious Adverse Events: N/A|
|Percentage that Discontinued due to Adverse Events: 3.1%|
|Study Author Conclusions||Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4.|
The FDA requested the study to be terminated early at week 16 due to safety concerns related to small increases in blood pressure and heart rate. The sponsor of this trial, Orexigen, publically released the 25% interim results of the trial, which are more favorable than the results at study completion; therefore, the cardiovascular risks still remain uncertain. Additional trials are needed to further investigate the safety profile of naltrexone-bupropion treatment.
- FDA approves weight-management drug Contrave. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm413896.htm. Accessed March 8, 2016.
- Clinical Trial Testing Safety Of Obesity Drug Contrave Halted; 50 Percent Interim Data Released By The Study’s Executive Committee. Available at: http://my.clevelandclinic.org/about-cleveland-clinic/newsroom/releases-videos-newsletters/2015-5-12-clinical-trial-testing-safety-of-obesity-drug-contrave-halted. Accessed March 8, 2016.
- Nissen SE, Wolski KE, Prcela L, et al. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. JAMA. 2016;315(10):990-1004.