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Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet 2019; 393(10173):778-790Lct

Abstract

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.

Authors+Show Affiliations

Indivior Inc, North Chesterfield, VA, USA.Indivior Inc, North Chesterfield, VA, USA.Indivior Inc, North Chesterfield, VA, USA.Indivior Inc, North Chesterfield, VA, USA.Indivior Inc, North Chesterfield, VA, USA.Indivior Inc, North Chesterfield, VA, USA.Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: mgreen@med.wayne.edu.Indivior Inc, North Chesterfield, VA, USA.UCLA David Geffen School of Medicine, Department of Family Medicine, Center for Behavioral & Addiction Medicine, Los Angeles, CA, USA.Indivior Inc, North Chesterfield, VA, USA.No affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

30792007

Citation

Haight, Barbara R., et al. "Efficacy and Safety of a Monthly Buprenorphine Depot Injection for Opioid Use Disorder: a Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Trial." Lancet (London, England), vol. 393, no. 10173, 2019, pp. 778-790.
Haight BR, Learned SM, Laffont CM, et al. Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2019;393(10173):778-790.
Haight, B. R., Learned, S. M., Laffont, C. M., Fudala, P. J., Zhao, Y., Garofalo, A. S., ... Heidbreder, C. (2019). Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England), 393(10173), pp. 778-790. doi:10.1016/S0140-6736(18)32259-1.
Haight BR, et al. Efficacy and Safety of a Monthly Buprenorphine Depot Injection for Opioid Use Disorder: a Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Trial. Lancet. 2019 02 23;393(10173):778-790. PubMed PMID: 30792007.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. AU - Haight,Barbara R, AU - Learned,Susan M, AU - Laffont,Celine M, AU - Fudala,Paul J, AU - Zhao,Yue, AU - Garofalo,Amanda S, AU - Greenwald,Mark K, AU - Nadipelli,Vijay R, AU - Ling,Walter, AU - Heidbreder,Christian, AU - ,, Y1 - 2019/02/18/ PY - 2018/08/07/received PY - 2018/08/28/revised PY - 2018/09/07/accepted PY - 2019/2/23/pubmed PY - 2019/4/19/medline PY - 2019/2/23/entrez SP - 778 EP - 790 JF - Lancet (London, England) JO - Lancet VL - 393 IS - 10173 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/30792007/Efficacy_and_safety_of_a_monthly_buprenorphine_depot_injection_for_opioid_use_disorder:_a_multicentre_randomised_double_blind_placebo_controlled_phase_3_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(18)32259-1 DB - PRIME DP - Unbound Medicine ER -