Heart risk of obesity treatment unknown after trial stopped early

The study was stopped because preliminary data was leaked, which researchers said can introduce bias into trials and the analysis of their results.
By Stephen Feller  |  March 8, 2016 at 11:16 AM
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CLEVELAND, March 8 (UPI) -- Researchers said they remain unsure of the risk for cardiovascular events associated with an obesity treatment after preliminary results from a clinical trial were leaked, causing them to halt the study.

Although the early data showed giving patients naltrexone and bupropion has potential for treating obesity, researchers said the release of early results by the trial's sponsor compromised its results and directly led to their termination of the study.

The treatment had been showing fewer major adverse cardiovascular events -- cardiovascular death, nonfatal stroke, or nonfatal heart attack -- than those given a placebo in the double-blind study. The early release of data at the 25 percent and 50 percent points could have introduced additional bias to analysis, the researchers said.

As part of a patent application and a report to the Securities and Exchange Commission, the trials' sponsor, Orexigen Therapeutics, publicly released the results. While intended to show their two-drug treatment reduced cardiovascular events significantly, the company and researchers agreed that releasing that information could taint the results of the rest of the study.

Two obesity drugs, fenfluramine and sibutramine, were both taken off the market after cardiovascular harm and events were reported by patients using them. The medical community, as well as the U.S. Food and Drug Administration, have been hesitant with newer obesity drugs because of concern for cardiovascular events.

The naltrexone, an opioid antagonist, and bupropion, used to treat depression, used together showed potential for reducing weight during previous clinical trials, but researchers said the FDA still had concerns about increases in blood pressure and heart rate.

"Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial," researchers wrote in the study, published in the Journal of the American Medical Association.

For the study, researchers at 266 medical centers in the United States recruited 8,910 participants with a mean age of 61 and median BMI of 36.6, 54.5 percent of whom were women, 32.1 percent had a history of cardiovascular disease, and 85.2 percent had diabetes.

At the 25 percent interim analysis, 1.3 percent of patients given a placebo had a cardiovascular event, while 0.8 percent on the drug combination had one. By the 50 percent interim analysis, 2.3 percent of the placebo group had an event, while 2 percent of the treatment group had one. Adverse effects were seen more often in the treatment group, however, as 14.2 percent had gastrointestinal events and 5.1 percent had central nervous system symptoms, compared to 1.9 percent and 1.2 percent of the placebo group.

While the researchers consider the trial to have been useful, they also say another must be mounted with more care dedicated to keeping preliminary information confidential.

In an editorial published in the Journal of the American Medical Association with the incomplete study, researchers at Johns Hopkins University suggest the FDA amend its policy on approving drugs after overwhelming evidence is reported in the middle of a study.

While it would prevent early approval of drugs, requiring the completion of full safety studies could keep data private and prevent future studies from being halted, even when showing promise to help patients, the researchers wrote.

"The FDA should pursue additional safeguards to prevent breakdowns in sponsor-investigator relationships and avoid the dissolution of future trials," the Johns Hopkins researchers, who were not involved in the study, wrote. "For example, the agency should consider having data monitoring committees report interim results directly to the FDA, not to the sponsor."

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