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Are weekly and monthly subcutaneous buprenorphine depot formulations noninferior to a daily sublingual combination of buprenorphine and naloxone when comparing the proportion of urine samples negative for illicit opioids for 24 weeks and the response rate among treatment-seeking adults with moderate-to-severe opioid use disorder?
In this randomized clinical trial of 428 participants, the proportion of opioid-negative urine samples was 1347 of 3834 (35.1%) and response rate was 37 of 213 participants (17.4%) for the subcutaneous depot buprenorphine group compared with 1099 of 3870 (28.4%) and 31 of 215 participants (14.4%), respectively, for the sublingual buprenorphine-naloxone group. Both primary outcomes demonstrated noninferiority.
Long-acting buprenorphine depot formulations appear to be efficacious for treatment of opioid use disorder.
Buprenorphine treatment for opioid use disorder may be improved by sustained-release formulations.
To determine whether treatment involving novel weekly and monthly subcutaneous (SC) buprenorphine depot formulations is noninferior to a daily sublingual (SL) combination of buprenorphine hydrochloride and naloxone hydrochloride in the treatment of opioid use disorder.
Design, Setting, and Participants
This outpatient, double-blind, double-dummy randomized clinical trial was conducted at 35 sites in the United States from December 29, 2015, through October 19, 2016. Participants were treatment-seeking adults with moderate-to-severe opioid use disorder.
Randomization to daily SL placebo and weekly (first 12 weeks; phase 1) and monthly (last 12 weeks; phase 2) SC buprenorphine (SC-BPN group) or to daily SL buprenorphine with naloxone (24 weeks) with matched weekly and monthly SC placebo injections (SL-BPN/NX group).
Main Outcomes and Measures
Primary end points tested for noninferiority were response rate (10% margin) and the mean proportion of opioid-negative urine samples for 24 weeks (11% margin). Responder status was defined as having no evidence of illicit opioid use for at least 8 of 10 prespecified points during weeks 9 to 24, with 2 of these at week 12 and during month 6 (weeks 21-24). The mean proportion of samples with no evidence of illicit opioid use (weeks 4-24) evaluated by a cumulative distribution function (CDF) was an a priori secondary outcome with planned superiority testing if the response rate demonstrated noninferiority.
A total of 428 participants (263 men [61.4%] and 165 women [38.6%]; mean [SD] age, 38.4 [11.0] years) were randomized to the SL-BPN/NX group (n = 215) or the SC-BPN group (n = 213). The response rates were 31 of 215 (14.4%) for the SL-BPN/NX group and 37 of 213 (17.4%) for the SC-BPN group, a 3.0% difference (95% CI, −4.0% to 9.9%; P < .001). The proportion of opioid-negative urine samples was 1099 of 3870 (28.4%) for the SL-BPN/NX group and 1347 of 3834 (35.1%) for the SC-BPN group, a 6.7% difference (95% CI, −0.1% to 13.6%; P < .001). The CDF for the SC-BPN group (26.7%) was statistically superior to the CDF for the SL-BPN/NX group (0; P = .004). Injection site adverse events (none severe) occurred in 48 participants (22.3%) in the SL-BPN/NX group and 40 (18.8%) in the SC-BPN group.
Conclusions and Relevance
Compared with SL buprenorphine, depot buprenorphine did not result in an inferior likelihood of being a responder or having urine test results negative for opioids and produced superior results on the CDF of no illicit opioid use. These data suggest that depot buprenorphine is efficacious and may have advantages.
ClinicalTrials.gov Identifier: NCT02651584
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Accepted for Publication: February 16, 2018.
Corresponding Author: Michelle R. Lofwall, MD, Center on Drug and Alcohol Research, University of Kentucky, 845 Angliana Ave, Lexington, KY 40508 (firstname.lastname@example.org).
Published Online: May 14, 2018. doi:10.1001/jamainternmed.2018.1052
Author Contributions: Drs Chen and Kim had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lofwall, Walsh, Bailey, Frost, Tiberg, Linden, Sheldon, Oosman, Peterson, Chen, Kim.
Acquisition, analysis, or interpretation of data: Lofwall, Walsh, Nunes, Bailey, Sigmon, Kampman, Tiberg, Linden, Peterson, Chen, Kim.
Drafting of the manuscript: Lofwall, Walsh, Bailey, Sigmon, Kampman, Frost, Tiberg, Linden, Kim.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Lofwall, Walsh, Nunes, Tiberg, Peterson, Chen, Kim.
Obtained funding: Sheldon, Kim.
Administrative, technical, or material support: Walsh, Nunes, Bailey, Sigmon, Kampman, Linden, Oosman, Kim.
Study supervision: Tiberg, Sheldon, Oosman, Kim.
Conflict of Interest Disclosures: Dr Lofwall reported receiving research funding from Braeburn Pharmaceuticals, Inc, and consulting fees from Braeburn Pharmaceuticals, Inc, and Indivior. Dr Walsh reported receiving contract research funding and consulting fees from Braeburn Pharmaceuticals, Inc, consulting fees from Camurus AB, and travel support from Indivior. Dr Nunes reported receiving contract research funding from Braeburn Pharmaceuticals, Inc, Alkermes, Inc, and Brainsway, Inc, and unpaid consulting for Alkermes, Inc. Dr Bailey reported receiving research funding, advisory board, and traveling support from Braeburn Pharmaceuticals, Inc; advisory board, speaker bureau fees, and travel support from BioDelivery Science International, Inc, and Alkermes, Inc; and research funding and speaker fees from Indivior. Dr Kampman reported receiving research funding from Braeburn Pharmaceuticals, Inc, Indivior, and Opiant Pharmaceuticals, Inc. Dr Frost reported receiving research funding and consulting fees from Braeburn Pharmaceuticals, Inc; honorarium for talks from Indivior; and consulting fees and speaking honorarium from BioDelivery Sciences International, Inc. Drs Tiberg and Linden reported being employees of Camurus AB. Mss Sheldon and Oosman and Dr Kim reported being employees of Braeburn Pharmaceuticals, Inc. Dr Chen reported receiving consulting fees from Braeburn Pharmaceuticals, Inc. Dr Peterson reported receiving consulting fees from Camurus AB and AstraZeneca Ltd. No other disclosures were reported.
Funding/Support: The study was supported by Braeburn Pharmaceuticals, Inc, and by grant UL1TR001998 from the University of Kentucky Center for Clinical and Translational Science for research services and facilities for the study at this site.
Role of the Funder/Sponsor: Braeburn Pharmaceuticals, Inc, had a role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. They had no role in collection of the data.
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