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.

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

Methamphetamine Use Disorder

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.

Naltrexone: Vivitrol®

Placebo (PLB) Injectable

Bupropion: Wellbutrin XL®

Placebo (PLB) Oral

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

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).

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.

Professor

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 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.

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 )

Measured by maximum consecutive negative UDS: Count the number and range 0-12 and report the maximum number.

Measured by the number of study weeks during the treatment period with two methamphetamine-negative UDS.

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.

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.

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.

Proportion of abstinent days of other substance including Alcohol, Cigarettes and E- Cigarettes was measured by self-report on TLFB during the treatment period.

Number of other substance (Alcohol and Cigarettes) use was measured by self-report recall on Timeline Followback (TLFB) during the treatment period.

Proportion of abstinent days of E- Cigarettes was measured by self-report at stage 1.

Proportion of abstinent days of E- Cigarettes was measured by self-report at stage 2.

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)

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)

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.

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.

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.

The Study satisfaction survey measures participants satisfaction. We do not have a proper score range (varied range with some free text questions also)

injectable extended release naltrexone plus once daily oral extended-release bupropion tablets

injectable matching placebo plus once-daily oral placebo tablets

University of California Los Angeles (UCLA) Center for Behavioral Addiction Medicine (CBAM)

Substance Use Research Unit (SURU) at the San Francisco Dept. of Public Health

Hennepin County Medical Center- Berman Center for Research

New York State Psychiatric Institute (NYSPI)- Substance Use Research Center (SURC)

CODA, Inc.

Behavioral Health Services (BHS) of Pickens County

University of Texas Southwestern Medical Center

University of Texas Health Science Center - Center for Neurobehavioral Research on Addiction (CNRA)

Those participants randomized to the Placebo arm in Stage 1 (Week 1); these participants may or may not be re-randomized in Week 7.

Stage 1 Placebo

Those participants who were randomized to the Active Medication Combination arm in Stage 1 (Study Week 1) remained in the AMC arm throughout the study (Weeks 1-12).

Stage 1 AMC

Those participants who were randomized to the Placebo arm in Stage 1 (Week 1) and were deemed Non-Responders at Study Weeks 5-6 and were re-randomized to the Placebo arm in Stage 2 (Week 7).

Stage 2 Re-Randomized Placebo

Those participants who were randomized to the Placebo arm in Stage 1 (Week 1) and were deemed Non-Responders at Study Weeks 5-6 and were re-randomized to the Active Medication Combination arm in Stage 2 (Week 7)

Stage 2 Re-Randomized AMC

Those participants who were originally randomized to the Placebo arm in Stage 1 (and may or may not have been deemed Non-Responders at Study Weeks 5-6) and were not Re-Randomized, so they remained in the Placebo arm throughout the study (Weeks 1-12).

Stage 2 Not Re-Randomized Placebo

All participants who were randomized to the Active Medication Combination arm in Stage 1 (Week 1) remained in the AMC arm throughout the study (Weeks 1-12).

Stage 2 Not Re-Randomized AMC

injectable extended release naltrexone plus once daily oral extended-release bupropion tablets

Naltrexone: Vivitrol®: Naltrexone: 380 mg vial, 4 intramuscular injections administered every 3 weeks

Bupropion: Wellbutrin XL® (Extended release): Bupropion: 450 mg oral dose daily

Active Medication Combination (AMC)

injectable matching placebo plus once-daily oral placebo tablets

Placebo (PLB) Injectable: Placebo: 4 intramuscular injections administered every 3 weeks

Placebo (PLB) Oral: Placebo: once-daily oral placebo tablets

Matched Placebo (PLB)

Total

Age, Continuous

Sex: Female, Male

Not Hispanic/ Latino

Hispanic/Latino

Unknown Ethnicity

Refused to answer Ethnicity

American Indian/Alaska Native

Asian

Black/ African American

Native Hawaiian/ Pacific Islander

White

Other Race

Multiracial

Unknown Race

Refused to answer Race

Race/Ethnicity, Customized

The Baseline characteristics are based on stage 1 assignment

Dr. Madhukar Trivedi

Intention to treat analysis was done including drop-out

Number of Participants With Treatment Response During Medication Phase at Stage 1

Number of Participants With Treatment Response During Medication Phase at Stage 2

Treatment Effectiveness Score of Participants at Stage 1

As per study protocol, stage 2 secondary outcomes are reported for only re-randomized groups (Placebo and AMC)

Treatment Effectiveness Score of Participants at Stage 2

Intention to treat analysis was done including drop-out.

Percentage of Participants Who Used Methamphetamine in the Pre-evaluation Period

Those participants randomized to the Placebo arm in Stage 1

Placebo

Those participants who were randomized to the Active Medication Combination arm in Stage 1

AMC (Active Medication Combination Arm)

Mean Maximum Number of Consecutive Visits Negative UDS at Stage 1

Those participants randomized to the Placebo arm in Stage 2

Those participants who were randomized to the Active Medication Combination arm in Stage 2

Stage 2 Re-Randomized AMC (Active Medication Combination Arm)

Mean Maximum Number of Consecutive Visits Negative UDS at Stage 2

AMC (Active Medication Combination)

Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 1

Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 2

Mean Change of Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 1

These numbers come from a model which does not use the Stage 2 Not rerandomized data. As per study protocol, stage 2 secondary outcomes are reported for only re-randomized groups (Placebo and AMC). Data for Not Re-Randomized groups at stage 2 were not included for the main analysis, thus not reported

Mean Change Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 2

Mean Change of Methamphetamine Craving at Stage 1

As per study protocol, stage 2 secondary outcomes are reported for only re-randomized groups (Placebo and AMC). Data for Not Re-Randomized groups at stage 2 were not included for the main analysis, thus not reported

Mean Change of Methamphetamine Craving at Stage 2

Amphetamine

Non-Methamphetamine Drug

Cocaine

Alcohol

Cigarettes

Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1

Non-Methamphetamine drug

Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2

E- Cigarettes

Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 1

Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 2

Mean Change in Number of Other Substance Use by Self-report at Stage 1

As per study protocol, stage 2 secondary outcomes are reported for only re-randomized groups (Placebo and AMC). These numbers come from a model which does not use the Stage 2 Not rerandomized data so we do not have any estimates for the same.

Mean Change in Number of Other Substance Use by Self-report at Stage 2

Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 1

Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 2

Mean Change of Depression Symptom Score by PHQ-9 at Stage 1

Mean Change of Depression Symptom Score by PHQ-9 at Stage 2

Physical Health

Mental Health

General Health

Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 1

Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 2

Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 1

Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 2

Number of Participants Who Completed the Visit in Week 12

We did not collect data about satisfaction.

Participant Satisfaction Rating Measured by Study Satisfaction Survey at the End of the Study

Those participants randomized to the Placebo arm in Stage 1 (Week 1) who were non-responders at week 5 and 6, and then re-randomized to Placebo at stage 2.

Stage 1 Placebo Non-responders Re-randomized to Placebo at Stage 2

Those participants randomized to the Placebo arm in Stage 1 (Week 1) who were non-responders at week 5 and 6, and then re-randomized to AMC at stage 2.

Stage 1 Placebo Non-responders Re-randomized to AMC at Stage 2

Those participants randomized to the Placebo arm in Stage 1 (Week 1) who were non-responders at week 5 and 6 and then not re-randomized at stage 2, remained in the Placebo arm.

Stage 1 Placebo Non-responders Not Re-randomized at Stage 2

Those participants randomized to the Placebo arm in Stage 1 (Week 1) who were responders at week 5 and 6 and then not re-randomized at stage 2, remained in the Placebo arm.

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

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Trial Timing

What is this trial about?

What are the participation requirements?