Elsevier

The Lancet

Volume 393, Issue 10173, 23 February–1 March 2019, Pages 778-790
The Lancet

Articles
Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(18)32259-1Get rights and content

Summary

Background

RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder.

Methods

This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18–65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901.

Findings

From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p<0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting.

Interpretation

Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products.

Funding

Indivior.

Introduction

Opioid use disorder is a chronic, relapsing disease1 of worldwide epidemic proportions.2, 3, 4, 5 Standard of care for opioid use disorder in the USA combines medication with behavioural health services,6 which has been associated with a reduction in deaths from overdose, improved retention of individuals in treatment, less opioid use and relapse, and prevention of infectious diseases.7 Several drugs target the μ-opioid receptor (μOR): the full agonist methadone, the partial agonist buprenorphine, and the antagonist naltrexone. The choice of treatment approach can be guided by various factors, including efficacy, safety, and cost-effectiveness.8 The full agonist methadone is likely to be abused, diverted, and misused, and is therefore more highly regulated than other opioid drugs (ie, it is classified as a schedule CII substance in the USA), and it is usually administered to patients via observed dosing in specialised clinics. To avoid precipitated withdrawal, treatment with naltrexone can start only after the patient is completely withdrawn from opioids, whereas treatment with buprenorphine can be titrated to patients' withdrawal symptoms, yielding a better tolerated transition to treatment. Buprenorphine can alleviate opioid withdrawal signs and symptoms, reduce craving, and can block the subjective effects (eg, so-called drug-liking) of other opioids.

Research in context

Evidence before this study

Despite the burgeoning worldwide opioid epidemic and the proven efficacy of medication-assisted therapy, buprenorphine is an under-used medication for the treatment of opioid use disorder. RBP-6000, referred to as BUP-XR (extended-release buprenorphine), was developed by Indivior with the latest understanding of relationships between buprenorphine plasma concentrations, brain μ-opioid receptor (μOR) occupancy, and the pharmacodynamic effects of buprenorphine. Symptoms of opioid withdrawal are suppressed at buprenorphine plasma concentrations of 1 ng/mL or more (≥50% μOR occupancy), whereas at least 2–3 ng/mL (≥70–80% μOR occupancy) is required to achieve blockade of the subjective effects of a μ-opioid full agonist, such as hydromorphone. We hypothesised that this degree of μOR occupancy would facilitate abstinence from illicit opioid use, attenuate craving and decrease withdrawal symptoms throughout the monthly dosing interval. These observations and hypotheses were supported by literature searches using PubMed, MEDLINE, and Ovid, using the search terms “buprenorphine”, “opioid use disorder”, “medication assisted treatment”, “mu-opioid receptor”, “positron emission tomography [PET]”, “[11C]carfentanil”, “withdrawal symptoms”, “craving”, “relapse”, “reinforcing and subjective effects of opioids”, “hydromorphone”, and “opioid blockade”, with no search restrictions.

Added value of this study

In this study, participants' percentage abstinence was significantly higher in both BUP-XR dose groups than in the placebo group. Treatment outcomes were consistent for control of opioid craving and withdrawal symptoms. Both regimens were safe and well tolerated and had higher mean medication satisfaction scores compared with participants who received individual drug counselling and placebo. There was no compensatory non-opioid illicit drug use with BUP-XR treatment. Notably, these results were obtained under a protocol that did not allow supplemental buprenorphine dosing. To our knowledge, this is the first study to translate hypothesised buprenorphine activity, based on the degree of μOR occupancy, into clinical efficacy.

Implications of all the available evidence

BUP-XR was designed to provide sustained target plasma concentrations of buprenorphine over the monthly dosing period; this approach affords a potential advantage over transmucosal buprenorphine, which might provide opioid blockade for only part of the daily dosing interval and can be associated with return of craving or withdrawal symptoms at the end of the day. Furthermore, monthly dosing by a health-care professional should improve adherence to the regimen and the long-acting nature of the formulation will not allow a patient to discontinue treatment for illicit opioid use. Finally, BUP-XR is distributed to and administered by health-care professionals only, which could reduce risks of diversion, misuse, abuse, and accidental paediatric exposure.

Access to and use of buprenorphine in the USA is limited by a scarcity of qualified prescribers, stemming partly from misunderstandings about buprenorphine.9, 10 For example, prescription of inadequate doses that result in relapse might reinforce negative attitudes and doubt among providers and patients regarding the effectiveness of buprenorphine. Patients who take daily transmucosal formulations of buprenorphine can reach target plasma exposures, but concentrations are often not sustained because of large daily fluctuations, poor treatment adherence, or both.11 Taking medication every day is also a constant reminder of the disease. Furthermore, although buprenorphine can be administered in an office setting, physicians have concerns that take-home transmucosal buprenorphine can be diverted,12 misused, abused, and could result in accidental poisoning in children,13 which are at least partly responsible for the underuse and underdosing of buprenorphine for opioid use disorder.14, 15, 16, 17, 18 Although a 6-month subdermal implant of buprenorphine is available, its indication is limited to patients who have achieved and sustained prolonged clinical stability with relatively low daily doses of buprenorphine.

Buprenorphine formulated in the well established ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, MA, USA) is the first subcutaneously injected, extended-release, monthly buprenorphine formulation approved by the US Food and Drug Administration (FDA). BUP-XR was designed to provide sustained exposure of buprenorphine over the entire monthly dosing interval and to deliver average buprenorphine plasma concentrations of 2–3 ng/mL or more, which are necessary to block the subjective effects of exogenous opioids (ie, opioid blockade).19, 20 The novel characteristics of BUP-XR mitigate the requirement for daily medication adherence, the risk of subtherapeutic buprenorphine concentrations over the dosing interval, and the need for supplemental buprenorphine. Additionally, both the closed distribution system (BUP-XR is provided to and administered only by health-care professionals) and the inherent properties of the subcutaneous biodegradable depot formulation are expected to reduce the risks presented by take-home medication.

The primary objective of this study was to assess the efficacy of two dosing regimens of BUP-XR in treatment-seeking individuals with opioid use disorder. Other prespecified objectives of this study were to assess the safety and tolerability of BUP-XR, the effects of BUP-XR on patient-reported outcomes, and to assess the relationship between plasma concentrations of BUP-XR and clinical endpoints (exposure-response relationships).

Section snippets

Study design and participants

This randomised, double-blind, placebo-controlled study was done at 36 treatment centres in the USA. Eligible participants were aged 18–65 years who, by medical history, met the Diagnostic and Statistical Manual of Mental Disorders (fifth edition)1 criteria for moderate or severe opioid use disorder (ie, met at least four of 11 criteria) for the 3 months immediately before signing the informed consent form and seeking treatment. Key exclusion criteria included medication-assisted treatment for

Results

Between Jan 28, 2015, and Nov 12, 2015, 1187 participants were screened for eligibility. 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg plus individual drug counselling (n=201), BUP-XR 300 mg/100 mg plus individual drug counselling (n=203), or placebo plus individual drug counselling (n=50 to 300 mg/300 mg placebo and n=50 to 300 mg/100 mg placebo; figure 1); 33 of 36 centres randomly assigned participants. One participant was incorrectly randomised and did not receive any study

Discussion

This randomised, double-blind, placebo-controlled study showed that both monthly dosing regimens of BUP-XR led to substantial proportions of participants achieving abstinence from opioids, relief of withdrawal symptoms, and control of opioid craving, without the need for daily medication adherence or supplemental buprenorphine. The low mean opioid craving and withdrawal scores across weeks in the placebo group were not surprising because more than 90% of placebo participants were using illicit

Data sharing statement

The authors will not make data collected for the study available to others, including individual participant data and a data dictionary defining each field in the set.

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  • Cited by (0)

    A full list of investigators is included in the appendix

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