CLEVELAND, OH — A large-scale clinical trial designed to study the cardiovascular safety of the weight-loss drug Contrave (Orexigen/Takeda Pharmaceuticals; marketed as Mysimba in Europe), a naltrexone/bupropion combination, has been halted following the early disclosure of trial results.
The trial in question—known as the LIGHT study—was officially stopped by the executive steering committee in March 2015 after Orexigen Therapeutics publicly released data through a patent and securities filing without knowledge from the study's clinical-trial leaders.
Following an interim analysis, which was intended to be strictly confidential and part of an approval pathway designated by the US Food and Drug Administration (FDA), Orexigen released the results in a filing to the Securities and Exchange Commission (SEC) and in a patent application for Contrave. The filings included the number of clinical events in the treatment and placebo arms and suggested the weight-loss drug reduced the risk of major cardiovascular events by more than 40%.
That analysis, however, was far from complete and inconclusive for determining either harm or benefit. In fact, the 41% reduction in MI, stroke, and cardiovascular mortality was based on an analysis of just 25% of the enrolled patients. The interim analysis was agreed on by the FDA but was intended only to show Contrave did not double the risk of cardiovascular events, given earlier reports that the drug increased blood pressure.
After the public release of the data, "it was concluded that completing the trial would be essentially impossible," lead investigator Dr Steven Nissen (Cleveland Clinic, OH) told heartwire from Medscape. "Why would anybody take a drug, one that's available on the market, in a blinded, placebo-controlled trial if they think the drug produces a 41% benefit? So we considered the trial to be no longer scientifically viable."
When the trial was stopped, the data safety and monitoring board (DSMB) performed an analysis of data that included 50% of the enrolled patients. When this analysis was performed, investigators found the 41% reduction in cardiovascular events all but disappeared. With the trial halfway completed, with 192 clinical events (MI, stroke, or cardiovascular death), there were 102 events in the placebo arm vs 90 among those who received Contrave, a 12% difference that was no longer statistically significant.
In fact, there were early signals that the suggestion of benefit was likely just statistical noise. There was even a suggestion of more noncardiovascular deaths in the Contrave arm in the 50% interim analysis.
"Essentially, when they filed the patent the company chose what they were going to put in there and what they were going to leave out," said Nissen. "Frankly, the executives in the company never should have had access to the data. We felt it was in the public interest to take an unprecedented step and release the 50% data because we couldn't allow unreliable data to be used in clinical decision making. We had a duty to the public and also to the investment community, to tell the truth."
At the time of publication, Orexigen has not responded to calls requesting comment from heartwire .
What to Do Next?
With the trial now stopped, and with data from 50% of the enrolled patients available, Nissen said they have been going back and forth with Orexigen for the past 6 weeks trying to draft a press release, but the company continued to delay. He stressed that all interested parties, including the DSMB, the Cleveland Clinic researchers, and Takeda Pharmaceuticals, the company licensed to market Contrave, were all able to agree on the wording of the press release, but Orexigen couldn't come to terms on the language.
Earlier this morning, Orexigen and Takeda issued a press release stating the LIGHT trial had been stopped but provided no data except to say the trial was stopped for neither superiority nor harm. Nissen told heartwire they had an obligation to issue their own press release, one that specifically highlighted the 50% interim analysis and stated the interim "results do not confirm the cardiovascular benefits of Contrave claimed by Orexigen in the patent application based on the data obtained at the 25% time point in the trial."
Contrave was approved by the FDA in September 2014 as a weight-loss drug in patients who are overweight and obese and are at a high risk of cardiovascular events (it was approved in Europe this past March). The approval was based on weight loss and also on absence of cardiovascular harm at the 25% time point of the LIGHT trial. This pathway, where approval is based on the interim analysis of an ongoing trial, is intended to expedite medications to market so that patients can have access to the drugs while the FDA continues to assess cardiovascular safety.
Nissen told heartwire that four Orexigen executives signed a detailed contract to ensure the strict confidentiality of the data, one that stipulated the interim results would be adequately firewalled until the LIGHT study was completed. This did not happen. Instead, as Forbes reported today, more than 100 people saw the results, including Orexigen employees, outside consultants, and lawyers. As a result of the leak, the FDA said LIGHT would no longer be good enough and that Orexigen would need to conduct another study showing cardiovascular safety to satisfy the agency's postmarketing requirements.
"This is a very sad situation," said Nissen. "This trial could have been completed in 2017 and with additional patients enrolled could have answered the clinical question in a robust way. Now it'll be 2022 until we get an answer, and patients will be left in the lurch in the meantime."
Nissen said the consequences from LIGHT have the potential to affect more than Contrave and Orexigen (Forbes pegs the cost of another cardiovascular safety trial at more than $100 million).
"If the FDA comes to believe that industry can't be trusted to handle the confidential data, we will lose this approach that leads to the accelerated development of drugs," he said. "Everybody will be harmed. Patients won't be able to get drugs sooner, and industry will spend a lot more time and money developing the drugs. Orexigen not only threw patients under the bus, but they threw the entire industry under the bus. That's a very bad thing to do."
Cite this: LIGHT Stopped: Contrave CVD Safety Study Halted Following Premature Release of Data - Medscape - May 12, 2015.