Cardiovascular safety of naltrexone-bupropion combination remains uncertain after termination of trial
Researchers were forced to stop phase III trial after sponsors released confidential interim data.
Researchers have highlighted the importance of data confidentiality during clinical trials after they were forced to abandon their study when interim findings were made public.
The phase III trial was looking at the cardiovascular safety of the combined obesity treatment naltrexone-bupropion (US brand name Contrave) in 8,910 obese or overweight patients. The researchers, led by Steven Nissen, chair of the cardiovascular medicine department at the Cleveland Clinic in Ohio, set out to discover whether the combination therapy increased major adverse cardiovascular events (MACE).
Interim results that should have remained confidential and that were “highly favourable” to the naltrexone-bupropion combination were made public in a patent filing by drug company Orexigen Therapeutics in March 2015, which sponsored the trial.
The release of the data, which goes against US Food and Drug Administration (FDA) guidance, led to the academics abandoning the trial early, meaning they were unable to determine the cardiovascular safety of the combined therapy.
Reporting their findings in JAMA on 8 March 2016, the researchers say: “The events leading to the termination of the study serve as a valuable reminder of the importance of maintaining confidentiality during ongoing trials.
“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,” they add.
The authors quote the FDA guidance, which warns that the sharing of interim data “can bias the outcome of the study by inappropriately influencing its continuing conduct or the plan of analyses”. They also point out that the FDA, even before public release of the interim data, concluded that the “knowledge of the results by business interests within the sponsor constituted an unacceptable breach of confidentiality that precluded use of the trial to meet the post approval regulatory requirement”.
The trial involved two groups of patients with a mean age of 61 years — 4,456 were given naltrexone-bupropion and 4,454 were given placebo. All participants were given access to an internet-based weight management programme. Some 32.1% of patients had a history of cardiovascular disease and 85.2% had diabetes, with a median body mass index of 36.6.
Results at the interim analysis stage (after 25% of planned events had happened) revealed that MACE occurred in 59 of the placebo-treated patients (1.3%) and 35 of the patients treated with naltrexone-bupropion (0.8%; hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.39–0.90). The same pattern was not evident after 50% of planned events, with “less favourable” results for patients taking the combined therapy. At this stage of the analysis, MACE had occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR 0.88; adjusted 99.7% CI 0.57-1.34).
Adverse effects were more common in the combination therapy patients compared with the placebo patients, and included gastrointestinal events in 14.2% vs 1.9% (P<0.001) and central nervous system symptoms in 5.1% vs 1.2% (P<0.001) of patients.
In a statement issued in May 2015, following the early termination of the trial, the FDA said: “The results from the 50% interim analysis, which do not show a reduction in cardiovascular risk according to the sponsor, indicate that it was premature to draw conclusions [after] 25% [of planned events].”
“This supports the need to definitively evaluate the cardiovascular safety of Contrave with the required postmarketing trial,” the statement said.
The researchers agree that a new cardiovascular outcome trial is required but they warn that findings “will not be available for a minimum of three to four years”.
In the European Union naltrexone/bupropion (brand name Mysimba) has been authorised by the European Medicines Agency for the treatment of people who are overweight or obese since March 2015. It is marketed in the EU by Orexigen Therapeutics Ireland Limited.
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2016.20200850
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