PerspectiveIn the Journals

CV safety of obesity drug still unknown after early trial termination

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March 8, 2016

The cardiovascular safety of Contrave remains unknown after early termination of a trial to determine its safety, according to recent study findings.

“Both the sponsor and the FDA agreed to not disclose the 25% interim analysis until completion of the study,” the researchers wrote. “While the trial was ongoing, the sponsor publicly released the confidential 25% interim results via patent publication. The study’s academic leadership recommended termination of the trial due to the breach of confidentiality and the sponsor agreed.”

Steven E. Nissen, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic, and colleagues conducted a randomized, multicenter, placebo-controlled, double blind, noninferiority trial on 8,910 adults (mean age, 61 years) with overweight or obesity at increased risk for CV events from June 13, 2012, to Jan. 21, 2013. Participants were randomly assigned to daily combination Contrave 32 mg/360 mg (naltrexone HCI/bupropion HCI, Takeda; n = 4,456) or placebo (n = 4,454) to determine noninferiority for major CV events compared with placebo.

Steven E. Nissen, MD

Steven E. Nissen

Median BMI among participants was 36.6 kg/m2; 85.2% had type 2 diabetes, 32.1% had established CVD and 17.4% had both conditions.

Major CV events occurred in more of the placebo group (1.3%) compared with the treatment group (0.8%) during the 25% interim analysis (HR = 0.59; 95% CI, 0.39-0.9). Major CV events occurred in 2.3% of the placebo group and 2% of the treatment group after 50% of planned events (HR = 0.88; adjusted 99.7%, 0.57-1.34).

Adverse events occurred in more of the treatment group compared with the placebo group for gastrointestinal adverse effects and central nervous system symptoms (P < .001 for both). Discontinuation due to psychiatric symptoms occurred in 3.1% of the treatment group and 0.9% of the placebo group (P < .001).

“The events leading to the termination of the study serve as a valuable reminder of the importance of maintaining confidentiality during ongoing trials,” the researchers wrote. “Premature release of interim data can result in inappropriate prejudgment about the benefits or risks of the studied therapy and make completion of the trial highly problematic. An FDA guidance for industry explicitly states that interim data from an ongoing clinical trial should remain confidential and warns that ‘such knowledge can bias the outcome of the study by inappropriately influencing its continuing conduct of the plan of analyses.’”

In an accompanying editorial, Joshua M. Sharfstein, MD, associate dean for public health practice and training at Johns Hopkins Bloomberg School of Public Health, and Bruce M. Psaty, MD, PhD, professor in the department of medicine at the University of Washington in Seattle, wrote that “the FDA should review its policy of permitting approval based on interim analyses of ongoing safety studies.”

“The FDA should pursue additional safeguards to prevent breakdowns in sponsor-investigator relationships and avoid the dissolution of future trials,” they wrote. “For example, the agency should consider having data monitoring committees report interim results directly to the FDA, not the sponsor.” – by Amber Cox

Disclosure: The study was sponsored by Orexigen and Takeda. Nissen reports receiving grants from Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion Therapeutics, Pfizer and The Medicines Company. Psaty reports serving on the data monitoring committee of a clinical trial funded by the manufacturer (Zoll LifeCor), on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson and on the FDA Science Board. Sharfstein reports having served as principal deputy commissioner of the FDA from 2009 to 2011. Please see the full study for a list of all other authors’ relevant financial disclosures.

itj+ Perspective

Caroline Apovian

Caroline Apovian

The LIGHT trial was designed to evaluate the risk of major cardiovascular events of the administration of naltrexone/bupropion combination for weight loss on an older population with documented CV risk factors. The study was halted due to public announcement of an interim analysis after 25% of expected events had accrued, which had the potential of affecting future complete results of the study.

The LIGHT trial results were highly anticipated because of the widespread prevalence of obesity in the United States and elsewhere, with few drugs to treat it effectively. The unfortunate leakage of early results caused the sponsor quite a bit in terms of financial remuneration but it teaches us how desperately this country needs an effective and safe drug to treat obesity that companies are willing to take such unlawful risks.

For a clinical lesson, we need to step back a bit and look at the trial study design. In order to capture CV events and the risk of a drug in a finite period of time, the trial had to be designed to be conducted in persons who already had CV risk and therefore, were older. In addition, by the end of year 1, 63% of the intervention group and 74% of the placebo group were not taking the drug or placebo. These two facts tell us: 1. This is a trial looking at what this drug does in an older group with CVD. 2. People did not like taking the drug and therefore did the trial really test the effects of the drug?

What I want in a drug to manage obesity is a drug that can be used in early adulthood before CV risk is evident. In this respect a similar analogy is using hormone replacement therapy in women who are in their 60s and already have CV risk. What about in perimenopause when the likelihood of benefit of the drug is the greatest?

There are many patients I treat with bupropion/naltrexone who have done well and have lost a significant amount of weight, far greater than 5% to 10% in fact. They happen to be younger, female, and have a hint of carbohydrate craving. I have little concern of CV risk in this population. Their lives have changed dramatically because bupropion/naltrexone has facilitated their lifestyle change.

In the future, we need more drugs for chronic weight management, and we need to develop strategies for choosing the right drug for the right type of patient with obesity.

We need to use these drugs early in the disease, and we need to make sure patients will want to stay on the drug. In order to make sure of that, side effects need to be minimal in a particular type of patient, and the drug needs to work in that particular type of patient. In the far, far future, we may realize that the disease obesity is really the diseases of obesity, and we may find many drugs to treat these diseases.

Caroline Apovian, MD
Director of Weight Management,
Boston Medical Center

Disclosure: Apovian reports no relevant financial disclosures.