Early termination of Light Study evaluating CV safety of obesity drug
Following premature disclosure of interim study results, the 9,000-patient Light Trial – designed to study the cardiovascular safety of the obesity drug buproprion-naltrexone – has been halted by the trial’s executive steering committee. The drug containing naltrexone HCI and bupropion HCl extended-release tablets was being developed by Orexigen Therapeutics Inc and Takeda Pharmaceuticals.
The Light Study was set up to meet the U.S. Food and Drug Administration’s requirement for Orexigen to assess the cardiovascular safety of buproprion-naltrexons in overweight and obese patients, who are at a high risk of cardiovascular events due to diabetes and other health factors. In the Light Study, buproprion-naltrexone was evaluated against placebo, in addition to diet and exercise counselling, in 8909 overweight and obese patients with certain CV risk factors.
The press release of the drug companies note that ‘The Light Study is not being terminated due to a finding of superiority or harm.’
A press release of the Cleveland Clinic (Cleveland, Ohio, USA), where dr. Steven Nissen, chair of the study’s executive steering committee is based, gives more information. The primary endpoint in the Light Study is the composite of major adverse cardiovascular events (MACE) that included death, non-fatal stroke and non-fatal myocardial infarction (MI). Orexigen was permitted to file for approval of the drug with a pre-specified interim analysis after approximately 25 percent of MACE had occurred in the Light Study, if the results ruled out a doubling of cardiovascular risk for patients taking buproprion-naltrexone. The results of this interim analysis, which were intended to remain confidential, demonstrated that buproprion-naltrexone met this criterion, and the FDA approved the agent on September 10, 2014.
The Cleveland Clinic press release reports that, contrary to intentions, the 25 percent interim results had been revealed within the company and to external business partners. They write that the FDA stated that this breach of confidentiality had sufficiently undermined its confidence in the ongoing trial; a new trial would be required to determine whether a 40 percent increase in cardiovascular risk could be ruled out.
More recently, Orexigen publicly disclosed the confidential 25 percent interim analysis of the Light Study as part of a patent and securities filing, without the authorization of the study’s academic leadership. At the time of this disclosure, the study’s executive steering committee strongly cautioned against any potential misinterpretation of the preliminary 25 percent interim data inappropriately released in this disclosure by Orexigen, since a large number of MACE events are necessary to determine effect in a cardiovascular outcome trial.
The Cleveland Clinic press release provides more outcome data. The data obtained after 50 percent completion of the trial with a total of 192 events, demonstrate that 102 primary endpoints (cardiovascular death, stroke, myocardial infarction) occurred in the placebo group compared with 90 in the buproprion-naltrexone group (HR=0.88, 95%CI: 0.66 – 1.17). As previously reported, during the first 25 percent of the Light Study, 59 cardiovascular events occurred in the placebo treatment group and 35 events in the buproprion-naltrexone group, an estimated hazard ratio (HR) of 0.59. During the second 25 percent of the Light Study, 43 events occurred in the placebo group and 55 events occurred in the buproprion-naltrexone group. When non-cardiovascular deaths (buproprion-naltrexone 26, placebo 17) are included in the primary composite endpoint with stroke and MI, the results at the 50 percent time point include 114 events in the placebo group vs. 119 in the buproprion-naltrexone group (HR=0.95, 95%CI: 0.74 – 1.23).
“These results do not confirm cardiovascular benefits of buproprion-naltrexone claimed by Orexigen in the patent application based on the data obtained at the 25 percent time point in the trial,” said dr. Nissen. “These results show neither benefit nor harm for patients taking the drug, but are consistent with the requirement by the FDA that the Light Trial demonstrate an absence of a doubling of cardiovascular risk for patients taking the drug,” Dr. Nissen added. “The inconsistency of effects on cardiovascular outcomes between the first 25 percent and the second 25 percent of the Light Study clearly illustrates the risks inherent in pre-judgment of clinical trial results based upon an interim analysis and demonstrate why interim results should remain confidential during any ongoing trial.”
The executive steering committee expects to report the final Light Study data in a scientific forum after all of the cardiovascular events in the Light Study have been collected and properly adjudicated.