Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for Methamphetamine Use Disorder

Study Overview
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Brief Summary
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This is a double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy of extended-release naltrexone plus bupropion as a combination pharmacotherapy for methamphetamine use disorder. Participants will be randomly assigned to the active medication combination (AMC) group or matching placebo group and will receive medications over the course of 12 weeks. Follow-ups will occur in weeks 13 and 16.

Detailed Description
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There will be 400 adults with moderate or severe methamphetamine use disorder randomized into this multi-site study. Eligibility will be determined during a maximum 21 day screening period. After screening is completed and eligibility is confirmed, including successful administration of a naloxone challenge, participants will begin the 12 week medication phase of the trial. Participants will be randomized to either the 1) AMC arm and receive injections of extended release naltrexone (XR-NTX; as Vivitrol®) plus once-daily oral extended-release bupropion tablets (BUP-XL) or the 2) matching placebo (PLB) arm and receive injections of placebo (iPLB) plus once-daily oral placebo (oPLB) tablets. During the course of the study, participants may 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. Injections will be administered every three weeks, in weeks 1, 4, 7, and 10. Take-home oral study medication (BUP-XL or oPLB) will be dispensed weekly for dosing on non-clinic days. Participants will be asked to attend the clinic twice weekly for observed oral medication dosing, assessments, collection of urine samples, and once-weekly medical management. On non-clinic days, participants will participate in smartphone app-based medication adherence activities. Participants will be asked to complete assessments as indicated on the schedule of assessments. Following the 12 week medication phase, participants will complete a follow-up phase, including a medication taper and post-medication phase follow-up visits during weeks 13 and 16.

Official Title
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NIDA (National Institute on Drug Abuse) CTN (Clinical Trials Network) Protocol 0068: Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for Methamphetamine Use Disorder

Conditions
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Methamphetamine Use Disorder

Intervention / Treatment
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* Drug: Naltrexone: Vivitrol®
* Drug: Placebo (PLB) Injectable
* Drug: Bupropion: Wellbutrin XL®
* Drug: Placebo (PLB) Oral


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 65 years old; Interested in reducing/stopping methamphetamine use; Speak English; Agree to use acceptable birth control (if applicable); Be opioid-free at randomization; Willing to comply with all study procedures and medication instructions; Agree to use a cell phone (or similar study device) to take videos of medication dosing. Exclusion Criteria: Medical or psychiatric condition which would make participation unsafe; Recently participated in a study of pharmacological or behavioral treatment for methamphetamine use disorder; Recently taken an investigational drug; Prescribed and taken naltrexone or bupropion ≤ 30 days from consent; Current or planned extended absence during study period (e.g., jail, surgery, pending legal action); Currently pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: During the study, participants may or may not be switched to another group due to the adaptive aspect of the study design. Participants appearing to respond well to their original treatment assignment will not be switched.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Medication Combination (AMC)<br>injectable extended release naltrexone plus once daily oral extended-release bupropion tablets | Drug: Naltrexone: Vivitrol®<br>* Naltrexone: 380 mg vial, 4 intramuscular injections administered every 3 weeks<br>* Other names: Arm: Experimental - Active Medication Combination (AMC);Drug: Bupropion: Wellbutrin XL®<br>* Bupropion: 450 mg oral dose daily<br>* Other names: Arm: Experimental - Active Medication Combination (AMC);|
| Placebo Comparator: Matched Placebo (PLB)<br>injectable matching placebo plus once-daily oral placebo tablets | Drug: Placebo (PLB) Injectable<br>* Placebo: 4 intramuscular injections administered every 3 weeks<br>* Other names: Arm: Placebo Comparator - matched Placebo (PLB);Drug: Placebo (PLB) Oral<br>* Placebo: once-daily oral placebo tablets<br>* Other names: Arm: Placebo Comparator - matched Placebo (PLB);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Response During Medication Phase at Stage 1 | Treatment response is defined as 'Responder' and 'Non-Responder'. Responder : Participant who meet responder criterion by providing at least 3 out of a possible 4 methamphetamine-negative urine tests at the end of stage 1 (weeks 5-6). Non-Responder: All other participants without 3 or 4 methamphetamine-negative UDS (Urine Drug Screen). | At weeks 6 | 
| Number of Participants With Treatment Response During Medication Phase at Stage 2 | Treatment response is defined as 'Responder' and 'Non-Responder'. Responder : Participant who meet responder criterion by providing at least 3 out of a possible 4 methamphetamine-negative urine tests at the end of stage 1 (weeks 5-6). Non-Responder: All other participants without 3 or 4 methamphetamine-negative UDS. | At week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Effectiveness Score of Participants at Stage 1 | The Treatment Effectiveness Score (TES) as measured by UDS results, during the treatment period. The TES is the percentage of the expected urine drug screens that were negative for each drug. Twelve urine drug screens are expected within each stage. | At weeks 6 | 
| Treatment Effectiveness Score of Participants at Stage 2 | The Treatment Effectiveness Score (TES) as measured by UDS results, during the treatment period. The TES is the percentage of the expected urine drug screens that were negative for each drug. Twelve urine drug screens are expected within each stage. The range of possible scores are 0-100 and higher score indicates better outcomes. | At week 12 | 
| Percentage of Participants Who Used Methamphetamine in the Pre-evaluation Period | Methamphetamine use, as measured by UDS (urine drug screen) in the pre-evaluation period (Weeks 1-4 for Stage 1 and Weeks 7-10 for Stage 2 ) | Weeks 1-4 and Weeks 7-10 | 
| Mean Maximum Number of Consecutive Visits Negative UDS at Stage 1 | Measured by maximum consecutive negative UDS: Count the number and range 0-12 and report the maximum number. | At week 6 | 
| Mean Maximum Number of Consecutive Visits Negative UDS at Stage 2 | Measured by maximum consecutive negative UDS: Count the number and range 0-12 and report the maximum number. | Stage 2 evaluation period at Weeks 12 | 
| Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 1 | Measured by the number of study weeks during the treatment period with two methamphetamine-negative UDS. | At week 6 | 
| Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 2 | Measured by the number of study weeks during the treatment period with two methamphetamine-negative UDS. | At week12 | 
| Mean Change of Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 1 | Methamphetamine use selfreported on TLFB ( Timeline Followback) during the follow-up period. The baseline measure is the percentage of abstinent days in the 30 days prior to randomization. The outcome is the change in percentage of abstinent days. | Baseline, week 6 | 
| Mean Change Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 2 | Methamphetamine use selfreported on TLFB ( Timeline Followback) during the follow-up period. The baseline measure is the percentage of abstinent days in the 30 days prior to randomization. The outcome is the change in percentage of abstinent days. | week 7, week 12 | 
| Mean Change of Methamphetamine Craving at Stage 1 | Severity of methamphetamine craving, as measured by Visual Analog Craving Scales (VAS), during the treatment period. VAS scores range from 0 (no craving) to 100 (most intense craving possible). The VAS is completed at screening, once a week during the treatment period, and at the follow-up visits. | Baseline, week 6 | 
| Mean Change of Methamphetamine Craving at Stage 2 | Severity of methamphetamine craving, as measured by Visual Analog Craving Scales (VAS), during the treatment period. VAS scores range from 0 (no craving) to 100 (most intense craving possible). The VAS is completed at screening, once a week during the treatment period, and at the follow-up visits. | week 7, week 12 | 
| Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 | Other substance use including Amphetamine, Non-Methamphetamine Drug, Cocaine, Alcohol, Cigarettes, as measured by UDS, during the treatment period. Opioid use will also be assessed using the Opioid 2000 ng tests on the UDS. | At week 6 | 
| Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 | Other substance use including Amphetamine, Non-Methamphetamine Drug, Cocaine, Alcohol, Cigarettes, as measured by UDS, during the treatment period. Opioid use will also be assessed using the Opioid 2000 ng tests on the UDS. | at week 12 | 
| Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 1 | Proportion of abstinent days of other substance including Alcohol, Cigarettes and E- Cigarettes was measured by self-report on TLFB during the treatment period. | Baseline, week 6 | 
| Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 2 | Proportion of abstinent days of other substance including Alcohol, Cigarettes and E- Cigarettes was measured by self-report on TLFB during the treatment period. | week 7, week 12 | 
| Mean Change in Number of Other Substance Use by Self-report at Stage 1 | Number of other substance (Alcohol and Cigarettes) use was measured by self-report recall on Timeline Followback (TLFB) during the treatment period. | Baseline, week 6 | 
| Mean Change in Number of Other Substance Use by Self-report at Stage 2 | Number of other substance (Alcohol and Cigarettes) use was measured by self-report recall on Timeline Followback (TLFB) during the treatment period. | week 7, week 12 | 
| Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 1 | Proportion of abstinent days of E- Cigarettes was measured by self-report at stage 1. | Baseline, week 6 | 
| Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 2 | Proportion of abstinent days of E- Cigarettes was measured by self-report at stage 2. | week 7, week 12 | 
| Mean Change of Depression Symptom Score by PHQ-9 at Stage 1 | Patient Health Questionnaire-9 (PHQ-9) measures participants depression symptoms. Possible scores range from 0-27, with higher scores indicating a more severe depression symptoms. PHQ-9 scores reflect depression severity, ranges from 0-27 (0 no depressive symptoms, 1-4 minimal depression, 5-9 mild depression, 10-14 moderate depression, 15-19 moderately severe depression, 20-27 severe depression) | Baseline, week 6 | 
| Mean Change of Depression Symptom Score by PHQ-9 at Stage 2 | Patient Health Questionnaire-9 measures participants depression symptoms. Possible scores range from 0-27, with higher scores indicating a more severe depression symptoms. PHQ-9 scores reflect depression severity, ranges from 0-27 (0 no depressive symptoms, 1-4 minimal depression, 5-9 mild depression, 10-14 moderate depression, 15-19 moderately severe depression, 20-27 severe depression) | week 7, week 12 | 
| Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 1 | Mean change score of QOL (General health, Physical health, and Mental health) from baseline will be assessed by PhenX (Phenotypes and eXposures) Core Tier 1 instrument: Quality of Life (QOL), which measures participants' quality of life during the past 30 days. Possible scores range from 0 to 30 (number of days in the past 30 in which health was good), with higher scores indicating a better quality of life. | Baseline, Week 6 | 
| Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 2 | Mean change score of QOL (General health, Physical health, and Mental health) from baseline will be assessed by PhenX Core Tier 1 instrument: Quality of Life (QOL), which measures participants' quality of life during the past 30 days. Possible scores range from 0 to 30 (number of days in the past 30 in which health was good), with higher scores indicating a better quality of life. | week 7, week 12 | 
| Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 1 | The Treatment Effectiveness Assessment is a 4-item self-administered assessment that uses a Likert scale (1-10) to document changes in four life domains: substance use, health, lifestyle, and community and is collected at screening, mid-treatment (Week 6 Visit 2) and end-of-treatment (Week 12 Visit 2). Possible scores range from 4-40, with higher scores indicating a higher overall functioning. | Baseline, week 6 | 
| Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 2 | The Treatment Effectiveness Assessment is a 4-item self-administered assessment that uses a Likert scale (1-10) to document changes in four life domains: substance use, health, lifestyle, and community and is collected at screening, mid-treatment (Week 6 Visit 2) and end-of-treatment (Week 12 Visit 2). Possible scores range from 4-40, with higher scores indicating a higher overall functioning. | week 7, week 12 | 
| Number of Participants Who Completed the Visit in Week 12 |  | At week 12 | 
| Participant Satisfaction Rating Measured by Study Satisfaction Survey at the End of the Study | The Study satisfaction survey measures participants satisfaction. We do not have a proper score range (varied range with some free text questions also) | At week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methamphetamine, Methamphetamine Use Disorder, Naltrexone, Bupropion, Vivitrol®