An implantable version of buprenorphine (Probuphine) for addiction treatment wasn’t inferior to a sham implant in patients already stable on sublingual buprenorphine, researchers found.
In the final data from a 24-week study that was used to support FDA approval, large majorities of patients remained abstinent for illicit drug use when assigned either to the implant or to remain on sublingual buprenorphine (96.4% and 87.6%, respectively), which met criteria for non-inferiority, Richard Rosenthal, MD, of Mount Sinai Institute of Mental Health in New York City, and colleagues reported online in the Journal of the American Medical Association.
“In this study, buprenorphine implants were non-inferior to sublingual buprenorphine for the primary endpoint of at least 4 of 6 months with no illicit opioid use by drug testing and self-report among opioid-dependent adults maintaining clinical stability with sublingual buprenorphine,” they wrote.
Probuphine, marketed by Titan and Braeburn Pharmaceuticals, was approved in May, after the FDA rejected it in 2013 for insufficient dosing, as many patients had to take rescue doses of buprenorphine or were abusing other opioids.
The company went back to the drawing board and worked with FDA to design a study in a subpopulation of patients who were stable on lower doses of buprenorphine, hence this final publication.
They conducted a double-blind, double-dummy study at 21 sites in the U.S. from June 26, 2014 to May 18, 2015, enrolling 177 patients who had been stable on 8 mg/day or less of sublingual buprenorphine for at least 90 days. They were randomized to either 4 80-mg implants plus sublingual placebo or to 4 sham implants plus sublingual buprenorphine for 24 weeks.
The primary endpoint was the between-group difference in the proportion of responders, defined as at least 4 months without opioid-positive urine tests and self-reported drug use. Secondary endpoints included the cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use.
Overall, 93% of patients completed the trial. The high proportion of responders in both groups was significant for non-inferiority, but these proportions were hotly debated at the FDA advisory committee hearing on Probuphine. FDA’s clinical reviewers found the figures to be closer to 69% and 64%.
In terms of secondary endpoints, they found that 85.7% of those with the real implants and 71.9% of those with sham implants maintained opioid abstinence over 6 months, but the confidence interval was wide (HR 13.8, 95% CI 1.8 to 25.8, P=0.03).
The investigators said there were similar rates of adverse events in both groups (48.3% implant, 52.8% sham), and implant-specific adverse events were numerically higher in the drug group (23% and 13.5%).
The transition from sublingual buprenorphine to an implant wasn’t disruptive clinically, “obviating concerns regarding increases in opioid withdrawal, craving, need, or desire to use,” the researchers wrote.
However, they acknowledged that their results are limited by their very select study population. These patients had to be stable on buprenorphine treatment and had to be abstinent from other opioid use for at least 90 days prior to study entry. Also, they were mostly white, employed, and had at least a high school education, so questions remain as to how the treatment will perform with wider use.
David Juurlink, MD, PhD, of the University of Toronto, agreed that the high response rate likely reflects the inclusion criteria.
“This seems to me like a group preordained to do well,” Juurlink told MedPage Today.
Lewis Nelson, MD, of NYU Langone Medical Center, said the high response rate in both groups highlights the “important beneficial role of buprenorphine in reducing opioid use by whatever route the buprenorphine is administered.”
He added that the non-inferiority trial doesn’t offer the same rigor as a superiority study.
“The cost differential and other logistical differences between [Probuphine and sublingual buprenorphine] raise the bar for proving a practical benefit of the implant, and this study does not directly address this issue,” Nelson told MedPage Today.
“For some the implant may be the right choice, while for most — especially those who need higher doses of buprenorphine than the implant can supply — the sublingual route, with a generic version of the drug, will prove to be the optimal solution,” Nelson said.
In an accompanying editorial, however, leaders of the National Institute on Drug Abuse championed the implant.
“This novel implant system may help buttress patients’ decision-making deficits that are a core component of the addiction by making these life-saving medication adherence decisions far more infrequent,” wrote NIDA deputy director Wilson Compton, MD, and director Nora Volkow, MD.
They cautioned, however, that the implants are only FDA approved for “up to 1 year of treatment for a subgroup of patients who have already achieved and sustained prolonged clinical stability while receiving low to moderate doses of oral transmucosal buprenorphine, a caveat clearly stated in the product label.”
“Even so,” they concluded, “this novel approach to delivering care may open up treatment for new, previously difficult-to-reach populations or for those in the criminal justice system.”
The authors disclosed financial relationships with Braeburn, CVS Caremark, Orexo, PCM Scientific, Pinney Associates, Indivior, and Demerx.
The editorialists disclosed no financial relationships with industry.
Source:: Google – Health]]>