Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs Daily Sublingual Buprenorphine With Naloxone for Treatment of Opioid Use Disorder: A Randomized Clinical Trial

Abstract

Importance: Buprenorphine treatment for opioid use disorder may be improved by sustained-release formulations.

Objective: 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.

Interventions: 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.

Results: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT02651584.

Conflict of interest statement

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.

Figures

Figure 1.. Enrollment and Study Retention Through Follow-up

The SL-BPN/NX group received a sublingual (SL) combination of buprenorphine and naloxone plus subcutaneous (SC) placebo injections; the SC-BPN group, SC buprenorphine injections plus SL placebo. ITT indicates intention to treat; LFT, liver function test. aThe 3 most common reasons for not meeting inclusion and/or exclusion criteria were abnormal laboratory values (n = 24), factors or medical conditions that could adversely affect participant safety and adequate adherence (n = 21), and not being a good candidate for buprenorphine treatment per the site investigator (n = 9).

Figure 2.. Study Outcomes

Treatment week 0 indicates randomization day. Triangles indicate sublingual (SL) buprenorphine hydrochloride-naloxone, and circles are subcutaneous (SC) buprenorphine. A, Participants receiving study medication over time. B, Mean (SD) SL buprenorphine-naloxone doses were converted to SC buprenorphine dose equivalents based on the following conversions: SL buprenorphine hydrochloride daily doses of 8, 16, and 24 mg were converted to weekly SC buprenorphine hydrochloride doses of 16, 24, and 32 mg, respectively, and monthly SC buprenorphine hydrochloride doses of 64, 96, and 128 mg, respectively. Sublingual buprenorphine hydrochloride at a dosage of 32 mg/d was converted to SC buprenorphine hydrochloride,160 mg/mo. C, Cumulative distribution function of percentage of opioid-negative urine samples affirmed with no illicit opioid use by self-report from weeks 4 to 24. D, For the mean percentage of opioid-negative samples affirmed with self-report of no illicit opioid use by time point, missing values were imputed as positive. Circled values indicate random urine tests. E, Mean (SD) visual analog scale (VAS) score of worst or strongest need to use opioids since the last visit (0 indicates no need to use; 100, maximum need to use) over time, with the first 2 values plotted after day 0 representing days 2 and 4 of week 0 (analysis of covariance [ANCOVA] shows no significant treatment effect). F, Mean (SD) Clinical Opiate Withdrawal Scale total score over time, with the first 2 values plotted after week 0 representing days 2 and 4. Scores of 5 to 12 indicate mild withdrawal (ANCOVA shows no significant treatment effect). aP ≤ .05 per time point (using analysis of variance) between groups; overall P = .02 (Wei Lachin test).

Figure 3.. Clinical Outcomes from Noninferiority and Superiority Analyses

Missing urine samples are counted as positive, and P values are 2 sided for superiority, unless otherwise specified. Dashed gray lines indicate prespecified noninferiority (NI) margins. CDF indicates cumulative distribution function; SC-BPN, group randomized to subcutaneous buprenorphine; and SL-BPN/NX, group randomized to sublingual combined buprenorphine and naloxone. aTreatment difference between SC-BPN and SL-BPN/NX groups for location variables and risk difference for proportions. bMargin of 11% using analysis of variance model. cNegative illicit opioid urine test results affirmed by self-report of no illicit opioid use. dMargin of 10% using the χ2 test for responders defined as participants with opioid-negative urine samples in phase 1 (at week 12 and for at least 2 of 3 weeks from weeks 9 to 11) and in phase 2 (at least 5 of 6 assessments from weeks 12-24, including month 6). eCalculated using the Wilcoxon rank sum test. fMargin of 15% for study retention (χ2 test). gIntravenous (IV) drug use identified at baseline among 114 participants in the SC-BPN group and 110 in the SL-BPN/NX group.