Efficacy and Safety of a Monthly Buprenorphine Depot Injection for Opioid Use Disorder: A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial

Abstract

Background: RBP-6000 is a subcutaneously injected, extendedrelease, monthly treatment for opioid use disorder (OUD). RBP 6000 addresses potential limitations of other OUD treatments by delivering sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period while controlling withdrawal and craving symptoms. Depot administration exclusively in a healthcare setting mitigates abuse, misuse, diversion, and unintentional paediatric exposure. Method: Treatment-seeking adults in the US with moderate or severe OUD entered a ≤2-week open-label phase with buprenorphine/naloxone sublingual film. Eligible participants were randomised to RBP 6000 300/300 mg (6×300 mg), RBP 6000 300/100 mg (2×300 mg 4×100 mg) or placebo for 24 weeks and received weekly counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was percentage abstinence from opioid use based on negative urine samples and self-reports (Weeks 5-24). The key secondary efficacy endpoint was treatment success (participants with ≥80% abstinence from Weeks 5-24). Secondary efficacy endpoints included opioid craving and withdrawal signs/symptoms. Finding: From January to November 2015, 1187 participants were screened, 665 entered run-in, and 201, 203, and 100 were randomised to RBP 6000 300/300 mg, RBP 6000 300/100 mg, or placebo. Mean (SD) percentage abstinence was 41·3% (39·7%) and 42·7% (38·5%) for RBP 6000 300/300 mg and 300/100 mg compared with 5·0% (17·0%) placebo; treatment success was achieved for 57/196 (29·1%), 55/194 (28·4%), and 2/99 (2·0%) participants, (p<0·0001 both endpoints, each RBP 6000 regimen versus placebo). The RBP 6000 safety profile was consistent with other buprenorphine products for OUD treatment except for injection-site reactions, which were mostly mild and not treatment-limiting. Interpretation: Treatment with RBP 6000 significantly reduced illicit opioid use compared to placebo and was well tolerated. Availability of this monthly formulation delivered by healthcare providers represents an advance in OUD treatment that enhances benefits of buprenorphine by delivering sustained, optimal exposure while limiting risks of current buprenorphine products. Clincial Trial Number: study registered with ClinicalTrials.gov; NCT02357901 Funding Statement: Indivior staff designed the study, collected and analysed the data, and participated in the writing of the manuscript. All authors had full access to all data and agreed to submit the manuscript for publication. Declaration of Interests: BRH was an employee of Indivior Inc at the time the study was conducted. SML is an employee of Indivior Inc and declares no competing interests. CML is an employee of Indivior Inc and declares no competing interests. PJF is an employee of Indivior Inc and declares no competing interests. YZ is an employee of Indivior Inc and declares no competing interests. ASG declares no competing interests. MKG has received consulting fees from Indivior Inc unrelated to preparation of this manuscript. VRN is an employee of Indivior Inc and declares no competing interests. WL is a consultant to Indivior Inc, Braeburn Inc, and Alkermes Inc. He has no other competing interests. CH is an employee of Indivior Inc and declares no competing interests. Ethics Approval Statement: A centralised institutional review board reviewed and approved the protocol in accordance with principles and requirements of the International Council for Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained from participants prior to starting any study-related procedure. An unblinded independent data monitoring committee provided oversight of safety