Drugs Xagena
Following premature disclosure of interim study results, the 9,000-patient Light Trial, designed to study the cardiovascular safety of the obesity drug Contrave ( Buproprion and Naltrexone ), has been halted by the trial’s executive steering committee, led by Cleveland Clinic.
The discontinuation of the study was announced by Orexigen Therapeutics. and Takeda Pharmaceuticals, the drug’s developers.
The Light Study was designed to meet the FDA ( Food and Drug Administration )’s requirement for Orexigen to assess the cardiovascular safety of Contrave in overweight and obese patients, who are at a high risk of cardiovascular events due to diabetes and other health factors.
The primary endpoint in the Light Study was the composite of major adverse cardiovascular events ( MACE ) that included death, non-fatal stroke and non-fatal myocardial infarction.
Orexigen was permitted to file for approval of Contrave with a pre-specified interim analysis after approximately 25% of MACE had occurred in the Light Study, if the results ruled out a doubling of cardiovascular risk for patients taking Contrave.
The results of this interim analysis have demonstrated that Contrave met this criterion, and the FDA approved Contrave on September 10, 2014.
At the time of approval of Contrave, the FDA determined that Orexigen had violated the terms of a data access agreement by revealing the 25% interim results to both a wide group of individuals within the company and external business partners.
The FDA also 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% increase in cardiovascular risk could be ruled out.
Subsequently, in March 2015, Orexigen publicly disclosed the confidential 25% 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% interim data inappropriately released in this disclosure by Orexigen.
As a large number of MACE events are necessary to determine effect in a cardiovascular outcome trial, the 25% interim data are not conclusive in establishing either benefit or risk of Contrave on cardiovascular risk.
The data obtained after 50% completion of the trial with a total of 192 events, have demonstrated that 102 primary endpoints ( cardiovascular death, stroke, myocardial infarction ) occurred in the placebo group compared with 90 in the Contrave group ( hazard ratio, HR=0.88, 95% CI 0.66 – 1.17 ).
As previously reported, during the first 25% of the Light Study, 59 cardiovascular events occurred in the placebo treatment group and 35 events in the Contrave group, an estimated hazard ratio of 0.59.
During the second 25% of the Light Study, 43 events occurred in the placebo group and 55 events occurred in the Contrave group.
When non-cardiovascular deaths ( Contrave 26, placebo 17 ) are included in the primary composite endpoint with stroke and myocardial infarction, the results at the 50% time point include 119 events in the placebo group versus 114 in the Contrave group ( HR=0.95, 95% CI 0.74 – 1.23 ).
According to Steven Nissen, chair of the study’s executive steering committee and chair of cardiovascular medicine at Cleveland Clinic, these results do not confirm cardiovascular benefits of Contrave claimed by Orexigen in the patent application based on the data obtained at the 25% time point in the trial.
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. ( Xagena )
Source: Cleveland Clinic, 2015
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