Early termination of the LIGHT trial has left questions about the cardiovascular safety of the obesity treatment naltrexone plus bupropion (Contrave, Takeda Pharmaceuticals) unanswered.

The trial was terminated in May 2015 after Orexigen Therapeutics released favorable 25% interim data to the public through a patent and securities filing. Because of that release, done without the knowledge of the research team, the researchers noted that these findings do not establish the prespecified margin of noninferiority, defined as a hazard ratio (HR) of 1.4, for major adverse cardiovascular (CV) events (MACE).

“Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial,” wrote Steven E. Nissen, MD, of the Cleveland Center for Cardiovascular Research in Ohio, and colleagues.

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Researchers published the results online March 8 in the Journal of the American Medical Association.

LIGHT Trial Results

From June 2012 to January 2013, researchers at 226 US medical centers randomly assigned overweight or obese patients at increased CV risk to placebo (n=4454) or naltrexone-bupropion (n=4456). All patients had access to an Internet-based weight management program.

Time to first MACE was the primary outcome.

At the 25% interim analysis, after approximately 87 events, 59 patients (1.3%) in the placebo group and 35 patients (0.8%) in the naltrexone-bupropion group (HR: 0.59; 95% CI, 0.39- 0.90) experienced MACE.

Researchers noted, however, that 95% CIs vs 99.7% CIs were reported, as the interim analysis evaluated only whether the trial ruled out a noninferiority margin of 2.0 and did not test for the margin of 1.4. The HRs, they explained, were less favorable than the intention-to-treat (ITT) analyses and had wider CIs.

After 50% of planned events, 102 patients in the placebo group (2.3%) and 90 patients (2.0%) in the naltrexone-bupropion group experienced MACE (HR: 0.88; adjusted 99.7% CI: 0.57-1.34).

There were 34 CV deaths (0.8%) in the placebo group compared with 17 (0.4%) in the treatment group (HR=0.50; 99.7% CI: 0.21-1.19). Nineteen patients in the placebo group (0.4%) had nonfatal stroke vs 21 (0.5%) in the naltrexone-bupropion group (HR: 1.10; 99.7% CI, 0.44- 2.78). Fifty-four patients in both groups experienced nonfatal myocardial infarction (MI).

Results from the sensitivity analysis based on the final end-of-study assessment for the primary and secondary CV outcomes in the ITT population showed that 124 patients (2.8%) in the placebo group and 119 (2.7%) in the naltrexone-bupropion group (HR: 0.95; 99.7% CI: 0.65-1.38) experienced MACE.

CV death occurred in 42 patients (0.9%) in the placebo group and 26 (0.6%) in the treatment group (HR: 0.61; 99.7% CI: 0.30-1.27). Twenty-one patients (0.5%) in the placebo group and 28 (0.6%) in the treatment group had nonfatal stroke (HR: 1.32; 99.7% CI, 0.57-3.08), and nonfatal MI occurred in 1.5% of each study group (HR:1.01; 99.7% CI, 0.61-1.66).

This article originally appeared on Endocrinology Advisor