Investigator: Madhukar Trivedi
Release Date: TBA
Study Objective: The primary objective of this study is to evaluate the efficacy of extended-release naltrexone plus bupropion as a combination pharmacotherapy for methamphetamine use disorder. Secondary objectives include assessing the safety of naltrexone plus bupropion and determining the efficacy of the combination pharmacotherapy on other substance use outcomes, on depression symptom scores, and on quality of life ratings.
Study Design: This is a double-blind, placebo-controlled, adaptive randomized clinical trial in which 370 individuals with moderate or severe methamphetamine use disorder will be randomly assigned to the 1) active medication combination (AMC) arm in which injections of extended-release naltrexone (XR-NTX; as Vivitrol®) plus once daily oral extended-release bupropion (BUP-XL) tablets will be provided or the 2) matching placebo (PLB) arm in which injections of placebo (iPLB) and once daily oral placebo (oPLB) tablets will be provided. During the course of the study, participants may or may not be switched to another arm, as determined by the a priori adaptive aspect of the study design. Participants appearing to respond well to their original treatment assignment will not be switched. Overall, approximately 50% of the participants will receive the AMC. After establishing eligibility during a maximum 21 day screening period, participants will begin the 12 week medication phase. Randomization will be stratified by site. At the end of the 12 week medication phase, participants will complete a follow-up phase, including an oral medication taper. Post-medication phase follow-up visits will occur during Weeks 13 and 16.
Study Participants: The study sample consists of 370 males and non-pregnant, non-lactating females, ages 18 to 65 years old, who have met all eligibility criteria, including DSM-5 criteria for moderate or severe stimulant use disorder (methamphetamine type), who report using methamphetamine 18 or more days during the 30 days prior to signing consent, and who provide at least 2 methamphetamine-positive urine specimens during screening. Potential participants have up to 3 weeks to meet eligibility criteria after signing consent.
Intervention: The study intervention consists of a 12 week medication phase. Participants randomized to the AMC arm will receive injections of extended-release naltrexone (Vivitrol®) plus 450 mg of once-daily oral extended-release bupropion tablets while participants randomized to the PLB arm will receive placebo injections plus once-daily oral placebo tablets. Injectable study medication will be administered every three weeks (weeks 1, 4, 7, and 10). Take-home oral study medication will be dispensed once weekly for dosing on non-clinic days. Once weekly medical management sessions with the study medical clinician will be provided. Medication adherence procedures will include smartphone app-based videos of daily dosing. Participants will be asked to attend clinic twice weekly for observed oral study medication dosing, collection of urine drug screening samples, and self-report assessments. Compensation will be provided for visit attendance and dosing adherence.
Assessments: Screening/baseline assessments include safety and medical measures including a medical and psychiatric history, a physical examination, clinical lab tests (blood chemistry, hematology, and urinalysis), 12-lead electrocardiogram, vital signs, and pregnancy tests (for females). Screening/baseline assessments also include psychological and drug use measures. Methamphetamine use outcome assessments include Urine Drug Screens (UDS), self-reported use via the Timeline Followback (TLFB), and Visual Analog Scale (VAS) craving scores. Other outcome assessments include UDS and TLFB (i.e., alcohol, tobacco, and/or illicit drugs), depression (Patient Health Questionnaire-9), quality of life (QOL), functioning (Treatment Effectiveness Assessment), and clinic attendance. Safety measures include monitoring vital signs, adverse events (AEs), concomitant medications, clinical lab results, and assessments of suicidality. Oral study medication adherence will be assessed by self-report, quantitative blood levels of bupropion and its primary metabolite, and smartphone app-based dosing confirmation procedures.
A blood sample for genetic analysis will be collected from participants who consent to this procedure and the de-identified sample will be sent to a cell and DNA repository.
Analyses: The primary analysis will evaluate the impact of the AMC arm, relative to PLB, on methamphetamine use. The primary efficacy outcome is a measurement of treatment response based on MA-negative urine drug screen results during the medication phase. Outcome variables will be analyzed using appropriate statistical methods for the intention-to-treat (ITT) population and for the evaluable population.
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