Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial

Abstract

Importance: Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation.

Objective: To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment-seeking individuals with OUD.

Design, setting, and participants: This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to-severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit).

Interventions: A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13).

Main outcomes and measures: The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes.

Results: A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P < .001, and CAM2038, 32 mg: effect size, 0.753; P < .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P < .001, and CAM2038, 32 mg: effect size, 0.751; P < .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg).

Conclusions and relevance: CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits.

Trial registration: Clinicaltrials.gov Identifier: NCT02611752.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kim and Ms Sheldon are employees of the sponsor, Braeburn Pharmaceuticals. Dr Tiberg is an employee of Camurus, a partner to the sponsor. Drs Walsh, Comer, Lofwall, and Vince received research contract support from Braeburn Pharmaceuticals to complete the study. Drs Walsh, Lofwall, and Levy-Cooperman and Mr Nuzzo received consultant fees from Braeburn Pharmaceuticals, and Drs Walsh and Comer received consulting fees from Camurus. Dr Comer has received compensation (in the form of partial salary support) from investigator-initiated studies supported by Endo Pharmaceuticals and Indivior PLC/Reckitt-Benckiser Pharmaceuticals. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram Illustrates the Disposition of Patients From Screening Through Study Completion

There had been 114 qualification phase failures. I/E indicates inclusion/exclusion. aOther includes those leaving against medical advice or clinical laboratory and vital sign abnormalities.

Figure 2.. Mean (±1 SEM) Maximum Effect Visual Analog Scale Scores for the Primary Outcome Measure of Drug Liking by Challenge Session for CAM2038 at 24 and 32 mg

The dotted line denotes that this was a bipolar scale. Each hydromorphone dose response challenge (0, 6, and 18 mg; intramuscular) was conducted over a 3-day period, with the randomized dose order fixed within patient. Significant interaction effects for dose by session were found for drug liking (F8,308 = 74; P < .001 and F8,338 = 56.5; P < .001 for CAM2038, 24 mg and 32 mg, respectively). The filled symbols indicate a significant difference between that specific active hydromorphone dose (either 6 or 18 mg) during the qualification phase vs postrandomization challenges (Tukey t test; P < .05). CAM2038, 24 mg: n = 22; 32 mg: n = 24.

Figure 3.. Mean (±1 SEM) Maximum Effect for All but Alertness/Drowsiness (Minimum Effect) Visual Analog Scale Scores by Intramuscluar Hydromorphone Challenge Dose and Challenge Session for CAM2038 at 24 and 32 mg

Significant dose by session interactions were found (see the Results section). The filled symbols indicate a significant difference between that specific active hydromorphone dose (either 6 or 18 mg) during the qualification phase vs postrandomization challenges (Tukey t test; P < .05 in all cases). The dotted line designates the bipolar scale. All other graphs are unipolar scales. CAM2038, 24 mg: n = 22; 32 mg: n = 24.

Figure 4.. Clinical Opiate Withdrawal Scale and Buprenorphine Concentrations

A, Mean (±1 SEM) Peak Ratings for the Clinical Opiate Withdrawal Scale for CAM2038, 24 mg and 32 mg are shown at baseline (ie, before CAM2038 injection) and each study day thereafter. CAM2038 injections were administered on day 0 and day 7. The repeated-measures model revealed a significant main effect of day (all P < .001) for the Clinical Opiate Withdrawal Scale (F14,294 = 39 for 24 mg and F14,322 = 78.4 for 32 mg). B, Graph shows the arithmetic mean (±1 SD) buprenorphine plasma concentrations for the cohorts over the course of the study. CAM2038, 24 mg: n = 22; 32 mg: n = 24. aThe filled symbols indicate a significant difference from the baseline score (Tukey t test; P < .05).