Madhukar H Trivedi1, Robrina Walker1, Walter Ling1, Adriane Dela Cruz1, Gaurav Sharma1, Thomas Carmody1, Udi E Ghitza1, Aimee Wahle1, Mora Kim1, Kathy Shores-Wilson1, Steven Sparenborg1, Phillip Coffin1, Joy Schmitz1, Katharina Wiest1, Gavin Bart1, Susan C Sonne1, Sidarth Wakhlu1, A John Rush1, Edward V Nunes1, Steven Shoptaw1. 1. From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).
Abstract
BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).
RCT Entities:
BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).
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