Michelle R Lofwall1, Sharon L Walsh1, Edward V Nunes2, Genie L Bailey3, Stacey C Sigmon4, Kyle M Kampman5, Michael Frost6, Fredrik Tiberg7, Margareta Linden7, Behshad Sheldon8,9, Sonia Oosman8, Stefan Peterson10, Michael Chen11, Sonnie Kim8. 1. Center on Drug and Alcohol Research, University of Kentucky, Lexington. 2. Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Department of Psychiatry, New York. 3. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island. 4. Department of Psychiatry, University of Vermont, Burlington. 5. Department of Psychiatry, Hospital of the University of Pennsylvania, Philadelphia. 6. The Frost Medical Group, LLC, Conshocken, Pennsylvania. 7. Camurus AB, Lund, Sweden. 8. Braeburn Pharmaceuticals, Inc, Princeton, New Jersey. 9. Now affiliated with FORCE Alliance, Princeton, New Jersey. 10. StatMind AB, Lund, Sweden. 11. TDM Group, Inc, Berkeley Heights, New Jersey.
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.
RCT Entities:
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.
Authors: Richard N Rosenthal; Michelle R Lofwall; Sonnie Kim; Michael Chen; Katherine L Beebe; Frank J Vocci Journal: JAMA Date: 2016-07-19 Impact factor: 56.272
Authors: Anil G Suryaprasad; Jianglan Z White; Fujie Xu; Beth-Ann Eichler; Janet Hamilton; Ami Patel; Shadia Bel Hamdounia; Daniel R Church; Kerri Barton; Chardé Fisher; Kathryn Macomber; Marisa Stanley; Sheila M Guilfoyle; Kristin Sweet; Stephen Liu; Kashif Iqbal; Rania Tohme; Umid Sharapov; Benjamin A Kupronis; John W Ward; Scott D Holmberg Journal: Clin Infect Dis Date: 2014-08-11 Impact factor: 9.079
Authors: Evgeny Krupitsky; Edward V Nunes; Walter Ling; Ari Illeperuma; David R Gastfriend; Bernard L Silverman Journal: Lancet Date: 2011-04-30 Impact factor: 79.321
Authors: Gail D'Onofrio; Patrick G O'Connor; Michael V Pantalon; Marek C Chawarski; Susan H Busch; Patricia H Owens; Steven L Bernstein; David A Fiellin Journal: JAMA Date: 2015-04-28 Impact factor: 56.272
Authors: Marc Fishman; Kevin Wenzel; Jennifer Scodes; Martina Pavlicova; Joshua D Lee; John Rotrosen; Edward Nunes Journal: J Adolesc Health Date: 2020-08-29 Impact factor: 5.012
Authors: John Strang; Nora D Volkow; Louisa Degenhardt; Matthew Hickman; Kimberly Johnson; George F Koob; Brandon D L Marshall; Mark Tyndall; Sharon L Walsh Journal: Nat Rev Dis Primers Date: 2020-01-09 Impact factor: 52.329