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The cardiovascular risks of the weight-loss combination drug naltrexone-bupropion are still uncertain, because the FDA-mandated safety trial, LIGHT, was terminated prematurely due to the sponsoring drug company’s breach of confidentiality. Other irregularities also were discovered, according to a report published online March 8 in JAMA.
Orexigen violated its agreement with FDA not to disclose the findings of an interim analysis performed after only 25% of expected CV events accrued. These findings appeared highly favorable for the drug, prompting the sponsor to publicly, and prematurely, claim naltrexone-bupropion reduced CV risk by 41% independently of its weight-loss effect. This favorable outcome was later found to be “driven almost exclusively by a 12-to-1 imbalance in death favoring naltrexone-bupropion among patients who were no longer taking the study drug,” said Dr. Steven E. Nissen of the Cleveland Clinic Center for Cardiovascular Research and his associates.
They now report the results of a second interim analysis of LIGHT (Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors) performed after 50% of expected CV events accrued, as well as those of a final analysis performed when the trial was halted and 64% of expected CV events accrued. These findings are much less favorable, showing no significant difference between naltrexone-bupropion and placebo in the rate of major adverse cardiovascular events (MACE). In addition, extremely poor adherence to both active treatment and placebo over time, together with the complex statistical issues involved, call into question any interpretation of the results and preclude “any reliable conclusions about the long-term safety of naltrexone-bupropion,” the investigators said.
“The cardiovascular safety of this treatment remains uncertain and will require evaluation in a new, adequately powered outcome trial.” The results of such a study, should it be undertaken, wouldn’t be available for at least 3-4 years, they noted.
In their report, the investigators described in detail why the FDA required a CV safety study even though the agency had already approved naltrexone-bupropion as a weight-loss treatment.
The study was a phase IIIb randomized, double-blind, placebo-controlled trial involving 8,910 overweight/obese patients aged 45 or older (mean age, 61 years) who were at risk of adverse CV outcomes due to preexisting CV disease; exercise-induced angina; an unfavorable ankle/brachial index; stenosis of coronary, carotid, or lower extremity arteries; type 2 diabetes; hypertension; dyslipidemia; or smoking. These participants received daily tablets of either 32 mg naltrexone plus 360 mg bupropion or a matching placebo and were to be followed for 4 years at 266 U.S. medical centers.
The analysis performed after 50% of expected CV events accrued showed that MACE – the primary safety outcome – occurred in 2.0% of the naltrexone-bupropion group and 2.3% of the placebo group, a nonsignificant difference. Differences between the two study groups also were nonsignificant for the individual components of the primary outcome, including cardiovascular death (0.4% vs. 0.8%), nonfatal stroke (0.5% vs. 0.4%), and nonfatal MI (1.2% vs. 1.2%). These results were confirmed in a sensitivity analysis based on the final data collection, when 64% of expected CV events accrued: MACE occurred in 2.7% of the naltrexone-bupropion group and 2.8% of the placebo group, another nonsignificant difference.
The active treatment also was no better than placebo regarding all secondary outcomes, including all-cause mortality, CV hospitalization, and coronary revascularization, Dr. Nissen and his associates said (JAMA. 2016 Mar 8. doi: 10.1001/jama.2016.1558). Treatment adherence was low. At 16 weeks, only 64% of the naltrexone-bupropion group and 72% of the placebo group were still taking the study treatment. By 2 years, only 27% of the naltrexone-bupropion group and 17% of the placebo group were. The mean duration of treatment was only 18.4 weeks for naltrexone-bupropion and 16.3 weeks for placebo. Most treatment discontinuations were due to a failure to lose weight, but a substantial proportion occurred because of treatment-related increases in blood pressure or heart rate.
The active treatment’s ability to reduce body weight was deemed “modest.” When the trial was halted, the mean decrease in weight was 3.9 kg with naltrexone-bupropion, representing a 3.6% reduction in total weight, and was 1.2 kg with placebo, representing a 1.1% reduction.
Adverse effects developed in 28.1% of patients taking naltrexone-bupropion, which was a significantly greater proportion than the 8.7% rate in the placebo group. The most common adverse events leading to discontinuation of the study drug affected the gastrointestinal system (nausea, constipation, vomiting), the CNS (tremor, dizziness, headache), and mental/emotional problems (insomnia, anxiety, hallucinations, depression).
The sponsor of this trial, Orexigen Therapeutics, disregarded the multiple harms caused by breaches of confidentiality, treated the academic investigators unfairly, ignored the trial’s data monitoring committee, and defied the FDA. Their statements about the naltrexone-bupropion’s cardiovascular efficacy were highly misleading, and there were obvious signs that the supporting data were not reliable. For example, nearly all of the CV mortality in the first interim analysis occurred well after participants had stopped taking their medication.
Yet the drug company was not sanctioned, and the naltrexone-bupropion retains FDA approval. At a minimum, the FDA should withhold approval until a viable replacement study is conducted, or it should require Risk Evaluation and Mitigation Strategies to counter the misinformation disseminated by the study sponsor, or it should restrict use of the drug outright.
Clinicians should be aware of these research improprieties and should know that the purported weight-loss benefit of naltrexone-bupropion is only 2.7 kg more than that achieved with placebo. How does this modest benefit balance against an unknown cardiovascular risk? In addition, the drug’s lack of efficacy clearly contributed to the very poor adherence rate in this trial: At 1 year, only 37.5% were still taking naltrexone-bupropion and 26.3% were still taking placebo.
Dr. Joshua M. Sharfstein is in the department of health policy and management at Johns Hopkins Bloomberg School of Public Health, Baltimore. Dr. Bruce M. Psaty is in the Cardiovascular Health Research Unit and the departments of medicine, epidemiology, and health services at the University of Washington, Seattle. They reported that this work was supported by the National Heart, Lung, and Blood Institute. Dr. Sharfstein reported serving as principal deputy commissioner of the FDA in 2009-2011. Dr. Psaty reported serving on the data monitoring committee of a clinical trial funded by Zoll LifeCor, on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson, and on the FDA Science Board. Dr. Sharfstein and Dr. Psaty made these remarks in an editorial accompanying Dr. Nissen’s report (JAMA. 2016;315:984-6).
The sponsor of this trial, Orexigen Therapeutics, disregarded the multiple harms caused by breaches of confidentiality, treated the academic investigators unfairly, ignored the trial’s data monitoring committee, and defied the FDA. Their statements about the naltrexone-bupropion’s cardiovascular efficacy were highly misleading, and there were obvious signs that the supporting data were not reliable. For example, nearly all of the CV mortality in the first interim analysis occurred well after participants had stopped taking their medication.
Yet the drug company was not sanctioned, and the naltrexone-bupropion retains FDA approval. At a minimum, the FDA should withhold approval until a viable replacement study is conducted, or it should require Risk Evaluation and Mitigation Strategies to counter the misinformation disseminated by the study sponsor, or it should restrict use of the drug outright.
Clinicians should be aware of these research improprieties and should know that the purported weight-loss benefit of naltrexone-bupropion is only 2.7 kg more than that achieved with placebo. How does this modest benefit balance against an unknown cardiovascular risk? In addition, the drug’s lack of efficacy clearly contributed to the very poor adherence rate in this trial: At 1 year, only 37.5% were still taking naltrexone-bupropion and 26.3% were still taking placebo.
Dr. Joshua M. Sharfstein is in the department of health policy and management at Johns Hopkins Bloomberg School of Public Health, Baltimore. Dr. Bruce M. Psaty is in the Cardiovascular Health Research Unit and the departments of medicine, epidemiology, and health services at the University of Washington, Seattle. They reported that this work was supported by the National Heart, Lung, and Blood Institute. Dr. Sharfstein reported serving as principal deputy commissioner of the FDA in 2009-2011. Dr. Psaty reported serving on the data monitoring committee of a clinical trial funded by Zoll LifeCor, on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson, and on the FDA Science Board. Dr. Sharfstein and Dr. Psaty made these remarks in an editorial accompanying Dr. Nissen’s report (JAMA. 2016;315:984-6).
The sponsor of this trial, Orexigen Therapeutics, disregarded the multiple harms caused by breaches of confidentiality, treated the academic investigators unfairly, ignored the trial’s data monitoring committee, and defied the FDA. Their statements about the naltrexone-bupropion’s cardiovascular efficacy were highly misleading, and there were obvious signs that the supporting data were not reliable. For example, nearly all of the CV mortality in the first interim analysis occurred well after participants had stopped taking their medication.
Yet the drug company was not sanctioned, and the naltrexone-bupropion retains FDA approval. At a minimum, the FDA should withhold approval until a viable replacement study is conducted, or it should require Risk Evaluation and Mitigation Strategies to counter the misinformation disseminated by the study sponsor, or it should restrict use of the drug outright.
Clinicians should be aware of these research improprieties and should know that the purported weight-loss benefit of naltrexone-bupropion is only 2.7 kg more than that achieved with placebo. How does this modest benefit balance against an unknown cardiovascular risk? In addition, the drug’s lack of efficacy clearly contributed to the very poor adherence rate in this trial: At 1 year, only 37.5% were still taking naltrexone-bupropion and 26.3% were still taking placebo.
Dr. Joshua M. Sharfstein is in the department of health policy and management at Johns Hopkins Bloomberg School of Public Health, Baltimore. Dr. Bruce M. Psaty is in the Cardiovascular Health Research Unit and the departments of medicine, epidemiology, and health services at the University of Washington, Seattle. They reported that this work was supported by the National Heart, Lung, and Blood Institute. Dr. Sharfstein reported serving as principal deputy commissioner of the FDA in 2009-2011. Dr. Psaty reported serving on the data monitoring committee of a clinical trial funded by Zoll LifeCor, on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson, and on the FDA Science Board. Dr. Sharfstein and Dr. Psaty made these remarks in an editorial accompanying Dr. Nissen’s report (JAMA. 2016;315:984-6).
The cardiovascular risks of the weight-loss combination drug naltrexone-bupropion are still uncertain, because the FDA-mandated safety trial, LIGHT, was terminated prematurely due to the sponsoring drug company’s breach of confidentiality. Other irregularities also were discovered, according to a report published online March 8 in JAMA.
Orexigen violated its agreement with FDA not to disclose the findings of an interim analysis performed after only 25% of expected CV events accrued. These findings appeared highly favorable for the drug, prompting the sponsor to publicly, and prematurely, claim naltrexone-bupropion reduced CV risk by 41% independently of its weight-loss effect. This favorable outcome was later found to be “driven almost exclusively by a 12-to-1 imbalance in death favoring naltrexone-bupropion among patients who were no longer taking the study drug,” said Dr. Steven E. Nissen of the Cleveland Clinic Center for Cardiovascular Research and his associates.
They now report the results of a second interim analysis of LIGHT (Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors) performed after 50% of expected CV events accrued, as well as those of a final analysis performed when the trial was halted and 64% of expected CV events accrued. These findings are much less favorable, showing no significant difference between naltrexone-bupropion and placebo in the rate of major adverse cardiovascular events (MACE). In addition, extremely poor adherence to both active treatment and placebo over time, together with the complex statistical issues involved, call into question any interpretation of the results and preclude “any reliable conclusions about the long-term safety of naltrexone-bupropion,” the investigators said.
“The cardiovascular safety of this treatment remains uncertain and will require evaluation in a new, adequately powered outcome trial.” The results of such a study, should it be undertaken, wouldn’t be available for at least 3-4 years, they noted.
In their report, the investigators described in detail why the FDA required a CV safety study even though the agency had already approved naltrexone-bupropion as a weight-loss treatment.
The study was a phase IIIb randomized, double-blind, placebo-controlled trial involving 8,910 overweight/obese patients aged 45 or older (mean age, 61 years) who were at risk of adverse CV outcomes due to preexisting CV disease; exercise-induced angina; an unfavorable ankle/brachial index; stenosis of coronary, carotid, or lower extremity arteries; type 2 diabetes; hypertension; dyslipidemia; or smoking. These participants received daily tablets of either 32 mg naltrexone plus 360 mg bupropion or a matching placebo and were to be followed for 4 years at 266 U.S. medical centers.
The analysis performed after 50% of expected CV events accrued showed that MACE – the primary safety outcome – occurred in 2.0% of the naltrexone-bupropion group and 2.3% of the placebo group, a nonsignificant difference. Differences between the two study groups also were nonsignificant for the individual components of the primary outcome, including cardiovascular death (0.4% vs. 0.8%), nonfatal stroke (0.5% vs. 0.4%), and nonfatal MI (1.2% vs. 1.2%). These results were confirmed in a sensitivity analysis based on the final data collection, when 64% of expected CV events accrued: MACE occurred in 2.7% of the naltrexone-bupropion group and 2.8% of the placebo group, another nonsignificant difference.
The active treatment also was no better than placebo regarding all secondary outcomes, including all-cause mortality, CV hospitalization, and coronary revascularization, Dr. Nissen and his associates said (JAMA. 2016 Mar 8. doi: 10.1001/jama.2016.1558). Treatment adherence was low. At 16 weeks, only 64% of the naltrexone-bupropion group and 72% of the placebo group were still taking the study treatment. By 2 years, only 27% of the naltrexone-bupropion group and 17% of the placebo group were. The mean duration of treatment was only 18.4 weeks for naltrexone-bupropion and 16.3 weeks for placebo. Most treatment discontinuations were due to a failure to lose weight, but a substantial proportion occurred because of treatment-related increases in blood pressure or heart rate.
The active treatment’s ability to reduce body weight was deemed “modest.” When the trial was halted, the mean decrease in weight was 3.9 kg with naltrexone-bupropion, representing a 3.6% reduction in total weight, and was 1.2 kg with placebo, representing a 1.1% reduction.
Adverse effects developed in 28.1% of patients taking naltrexone-bupropion, which was a significantly greater proportion than the 8.7% rate in the placebo group. The most common adverse events leading to discontinuation of the study drug affected the gastrointestinal system (nausea, constipation, vomiting), the CNS (tremor, dizziness, headache), and mental/emotional problems (insomnia, anxiety, hallucinations, depression).
The cardiovascular risks of the weight-loss combination drug naltrexone-bupropion are still uncertain, because the FDA-mandated safety trial, LIGHT, was terminated prematurely due to the sponsoring drug company’s breach of confidentiality. Other irregularities also were discovered, according to a report published online March 8 in JAMA.
Orexigen violated its agreement with FDA not to disclose the findings of an interim analysis performed after only 25% of expected CV events accrued. These findings appeared highly favorable for the drug, prompting the sponsor to publicly, and prematurely, claim naltrexone-bupropion reduced CV risk by 41% independently of its weight-loss effect. This favorable outcome was later found to be “driven almost exclusively by a 12-to-1 imbalance in death favoring naltrexone-bupropion among patients who were no longer taking the study drug,” said Dr. Steven E. Nissen of the Cleveland Clinic Center for Cardiovascular Research and his associates.
They now report the results of a second interim analysis of LIGHT (Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors) performed after 50% of expected CV events accrued, as well as those of a final analysis performed when the trial was halted and 64% of expected CV events accrued. These findings are much less favorable, showing no significant difference between naltrexone-bupropion and placebo in the rate of major adverse cardiovascular events (MACE). In addition, extremely poor adherence to both active treatment and placebo over time, together with the complex statistical issues involved, call into question any interpretation of the results and preclude “any reliable conclusions about the long-term safety of naltrexone-bupropion,” the investigators said.
“The cardiovascular safety of this treatment remains uncertain and will require evaluation in a new, adequately powered outcome trial.” The results of such a study, should it be undertaken, wouldn’t be available for at least 3-4 years, they noted.
In their report, the investigators described in detail why the FDA required a CV safety study even though the agency had already approved naltrexone-bupropion as a weight-loss treatment.
The study was a phase IIIb randomized, double-blind, placebo-controlled trial involving 8,910 overweight/obese patients aged 45 or older (mean age, 61 years) who were at risk of adverse CV outcomes due to preexisting CV disease; exercise-induced angina; an unfavorable ankle/brachial index; stenosis of coronary, carotid, or lower extremity arteries; type 2 diabetes; hypertension; dyslipidemia; or smoking. These participants received daily tablets of either 32 mg naltrexone plus 360 mg bupropion or a matching placebo and were to be followed for 4 years at 266 U.S. medical centers.
The analysis performed after 50% of expected CV events accrued showed that MACE – the primary safety outcome – occurred in 2.0% of the naltrexone-bupropion group and 2.3% of the placebo group, a nonsignificant difference. Differences between the two study groups also were nonsignificant for the individual components of the primary outcome, including cardiovascular death (0.4% vs. 0.8%), nonfatal stroke (0.5% vs. 0.4%), and nonfatal MI (1.2% vs. 1.2%). These results were confirmed in a sensitivity analysis based on the final data collection, when 64% of expected CV events accrued: MACE occurred in 2.7% of the naltrexone-bupropion group and 2.8% of the placebo group, another nonsignificant difference.
The active treatment also was no better than placebo regarding all secondary outcomes, including all-cause mortality, CV hospitalization, and coronary revascularization, Dr. Nissen and his associates said (JAMA. 2016 Mar 8. doi: 10.1001/jama.2016.1558). Treatment adherence was low. At 16 weeks, only 64% of the naltrexone-bupropion group and 72% of the placebo group were still taking the study treatment. By 2 years, only 27% of the naltrexone-bupropion group and 17% of the placebo group were. The mean duration of treatment was only 18.4 weeks for naltrexone-bupropion and 16.3 weeks for placebo. Most treatment discontinuations were due to a failure to lose weight, but a substantial proportion occurred because of treatment-related increases in blood pressure or heart rate.
The active treatment’s ability to reduce body weight was deemed “modest.” When the trial was halted, the mean decrease in weight was 3.9 kg with naltrexone-bupropion, representing a 3.6% reduction in total weight, and was 1.2 kg with placebo, representing a 1.1% reduction.
Adverse effects developed in 28.1% of patients taking naltrexone-bupropion, which was a significantly greater proportion than the 8.7% rate in the placebo group. The most common adverse events leading to discontinuation of the study drug affected the gastrointestinal system (nausea, constipation, vomiting), the CNS (tremor, dizziness, headache), and mental/emotional problems (insomnia, anxiety, hallucinations, depression).
FROM JAMA
Key clinical point: The cardiovascular risks of the weight-loss combination drug naltrexone-bupropion are still uncertain.
Major finding: The primary safety outcome, major adverse cardiovascular events, occurred in 2.0% of the naltrexone-bupropion group and 2.3% of the placebo group, a nonsignificant difference.
Data source: LIGHT, a multicenter randomized placebo-controlled double-blind noninferiority trial involving 8,910 overweight/obese patients.
Disclosures: This trial was sponsored by Orexigen Therapeutics and Takeda Pharmaceuticals. Dr. Nissen reported receiving grants from The Medicines Company, Amgen, Pfizer, AstraZeneca, Esperion Therapeutics, Eli Lilly, and Cerenis, and consulting for numerous drug companies that pay his fees directly to charities. His associates reported ties to numerous industry sources.
