Trial Outcomes & Findings for Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for Methamphetamine Use Disorder (NCT NCT03078075)

NCT ID: NCT03078075

Last Updated: 2021-05-03

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 403 participants
• Primary outcome timeframe: At weeks 6
• Results posted on: 2021-05-03

Participant Flow

All participants were randomized to either the AMC arm or the Placebo arm in Week 1; thus all are represented in the two Stage 1 categories (total 403). All participants also are represented in Stage 2. Some participants were re-randomized at Week 7 and some were not; thus the four Stage 2 categories also total 403.

Participant milestones

Measure	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 Placebo 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 re-randomized to AMC at stage 2.	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 non-responders at week 5 and 6 and then not re-randomized at stage 2, remained in the Placebo arm.	Stage 1 Placebo 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.	Stage 1 AMC Remaining on AMC at Stage 2 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).
Overall Study STARTED	111	114	59	10	109
Overall Study COMPLETED	106	103	19	9	78
Overall Study NOT COMPLETED	5	11	40	1	31

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Active Medication Combination (AMC) n=109 Participants 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	Matched Placebo (PLB) n=294 Participants 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	Total n=403 Participants Total of all reporting groups
Age, Continuous	41 years STANDARD_DEVIATION 10.6 • n=93 Participants	41 years STANDARD_DEVIATION 10.0 • n=4 Participants	41 years STANDARD_DEVIATION 10.1 • n=27 Participants
Sex: Female, Male Female	31 Participants n=93 Participants	95 Participants n=4 Participants	126 Participants n=27 Participants
Sex: Female, Male Male	78 Participants n=93 Participants	199 Participants n=4 Participants	277 Participants n=27 Participants
Race/Ethnicity, Customized Not Hispanic/ Latino	96 participants n=93 Participants	249 participants n=4 Participants	345 participants n=27 Participants
Race/Ethnicity, Customized Hispanic/Latino	13 participants n=93 Participants	42 participants n=4 Participants	55 participants n=27 Participants
Race/Ethnicity, Customized Unknown Ethnicity	0 participants n=93 Participants	2 participants n=4 Participants	2 participants n=27 Participants
Race/Ethnicity, Customized Refused to answer Ethnicity	0 participants n=93 Participants	1 participants n=4 Participants	1 participants n=27 Participants
Race/Ethnicity, Customized American Indian/Alaska Native	2 participants n=93 Participants	4 participants n=4 Participants	6 participants n=27 Participants
Race/Ethnicity, Customized Asian	1 participants n=93 Participants	10 participants n=4 Participants	11 participants n=27 Participants
Race/Ethnicity, Customized Black/ African American	10 participants n=93 Participants	38 participants n=4 Participants	48 participants n=27 Participants
Race/Ethnicity, Customized Native Hawaiian/ Pacific Islander	1 participants n=93 Participants	1 participants n=4 Participants	2 participants n=27 Participants
Race/Ethnicity, Customized White	82 participants n=93 Participants	205 participants n=4 Participants	287 participants n=27 Participants
Race/Ethnicity, Customized Other Race	6 participants n=93 Participants	14 participants n=4 Participants	20 participants n=27 Participants
Race/Ethnicity, Customized Multiracial	3 participants n=93 Participants	13 participants n=4 Participants	16 participants n=27 Participants
Race/Ethnicity, Customized Unknown Race	2 participants n=93 Participants	8 participants n=4 Participants	10 participants n=27 Participants
Race/Ethnicity, Customized Refused to answer Race	2 participants n=93 Participants	1 participants n=4 Participants	3 participants n=27 Participants

PRIMARY outcome

Timeframe: At weeks 6

Population: Intention to treat analysis was done including drop-out

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).

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Number of Participants With Treatment Response During Medication Phase at Stage 1 Responders (Methamphetamine negative UDS results)	10 Participants	18 Participants	—	—	—	—
Number of Participants With Treatment Response During Medication Phase at Stage 1 Non-responders (Methamphetamine positive UDS results)	284 Participants	91 Participants	—	—	—	—

PRIMARY outcome

Timeframe: At week 12

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo n=69 Participants 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 AMC n=109 Participants 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 Placebo 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 AMC 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).
Number of Participants With Treatment Response During Medication Phase at Stage 2 Responders (Methamphetamine negative UDS results)	2 Participants	13 Participants	9 Participants	21 Participants	—	—
Number of Participants With Treatment Response During Medication Phase at Stage 2 Non-Responders (Methamphetamine positive UDS results)	109 Participants	101 Participants	60 Participants	88 Participants	—	—

SECONDARY outcome

Timeframe: At weeks 6

Population: Intention to treat analysis was done including drop-out

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.

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Treatment Effectiveness Score of Participants at Stage 1	5.72 percentage of urine drug screens Standard Deviation 13.41	13.84 percentage of urine drug screens Standard Deviation 22.97	—	—	—	—

SECONDARY outcome

Timeframe: At week 12

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

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Treatment Effectiveness Score of Participants at Stage 2	7.45 percentage of urine drug screens Standard Deviation 16.02	11.55 percentage of urine drug screens Standard Deviation 24.55	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1-4 and Weeks 7-10

Population: Intention to treat analysis was done including drop-out.

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 )

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo n=111 Participants 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 AMC n=114 Participants 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 Placebo n=69 Participants 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 AMC n=109 Participants 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).
Percentage of Participants Who Used Methamphetamine in the Pre-evaluation Period	5.10 percentage of participants	11.93 percentage of participants	7.95 percentage of participants	10.20 percentage of participants	29.46 percentage of participants	22.56 percentage of participants

SECONDARY outcome

Timeframe: At week 6

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

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Maximum Number of Consecutive Visits Negative UDS at Stage 1	0.54 UDS test results Standard Deviation 1.31	1.37 UDS test results Standard Deviation 2.50	—	—	—	—

SECONDARY outcome

Timeframe: Stage 2 evaluation period at Weeks 12

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

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo n=69 Participants 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 AMC n=109 Participants 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 Placebo 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 AMC 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).
Mean Maximum Number of Consecutive Visits Negative UDS at Stage 2	0.61 UDS test results Standard Deviation 1.46	1.18 UDS test results Standard Deviation 2.72	3.10 UDS test results Standard Deviation 4.39	2.63 UDS test results Standard Deviation 4.13	—	—

SECONDARY outcome

Timeframe: At week 6

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

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 1	0.15 weeks Standard Deviation 0.55	0.56 weeks Standard Deviation 1.20	—	—	—	—

SECONDARY outcome

Timeframe: At week12

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

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo n=69 Participants 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 AMC n=109 Participants 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 Placebo 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 AMC 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).
Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 2	0.20 weeks Standard Deviation 0.70	0.50 weeks Standard Deviation 1.35	1.48 weeks Standard Deviation 2.21	1.20 weeks Standard Deviation 2.08	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

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.

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 1	14.0 percentage of abstinent days Standard Error 1.3	27.2 percentage of abstinent days Standard Error 2.88	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

Population: 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

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 2	16 percentage of abstinent days Standard Error 1.5	25.3 percentage of abstinent days Standard Error 2.6	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

Population: Intention to treat analysis was done including drop-out

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.

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Methamphetamine Craving at Stage 1	-22.33 score on a scale Standard Error 1.82	-29.98 score on a scale Standard Error 3.17	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

Population: 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

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Methamphetamine Craving at Stage 2	-20.52 score on a scale Standard Error 1.72	-31.79 score on a scale Standard Error 3.17	—	—	—	—

SECONDARY outcome

Timeframe: At week 6

Population: Intention to treat analysis was done including drop-out

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.

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 Amphetamine	41.89 days Standard Deviation 1.0	41.95 days Standard Deviation 0.3	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 Non-Methamphetamine Drug	28.53 days Standard Deviation 14.7	31.47 days Standard Deviation 13.8	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 Cocaine	41.87 days Standard Deviation 0.6	41.87 days Standard Deviation 0.5	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 Alcohol	36.44 days Standard Deviation 9.5	37.89 days Standard Deviation 7.2	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 Cigarettes	15.29 days Standard Deviation 18.7	16.31 days Standard Deviation 18.2	—	—	—	—

SECONDARY outcome

Timeframe: at week 12

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

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 Amphetamine	44.96 days Standard Deviation 0.3	44.95 days Standard Deviation 0.3	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 Non-Methamphetamine drug	30.99 days Standard Deviation 15.2	31.05 days Standard Deviation 16.1	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 Cocaine	44.9 days Standard Deviation 0.4	44.88 days Standard Deviation 0.5	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 Alcohol	38.41 days Standard Deviation 11.9	39.91 days Standard Deviation 9.1	—	—	—	—
Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 Cigarettes	17.11 days Standard Deviation 20.0	19.31 days Standard Deviation 20.1	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

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

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 1 Alcohol	-0.054 proportion of abstinent days Standard Error 0.011	-0.016 proportion of abstinent days Standard Error 0.017	—	—	—	—
Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 1 Cigarettes	0.054 proportion of abstinent days Standard Error 0.010	0.103 proportion of abstinent days Standard Error 0.021	—	—	—	—
Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 1 E- Cigarettes	-0.064 proportion of abstinent days Standard Error 0.009	-0.072 proportion of abstinent days Standard Error 0.016	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

Population: 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

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

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 2 Alcohol	-0.035 proportion of abstinent days Standard Error 0.012	-0.035 proportion of abstinent days Standard Error 0.016	—	—	—	—
Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 2 Cigarettes	0.038 proportion of abstinent days Standard Error 0.012	0.119 proportion of abstinent days Standard Error 0.022	—	—	—	—
Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 2 E- Cigarettes	-0.057 proportion of abstinent days Standard Error 0.011	-0.079 proportion of abstinent days Standard Error 0.014	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

Population: Intention to treat analysis was done including drop-out

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

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change in Number of Other Substance Use by Self-report at Stage 1 Alcohol	0.358 substances Standard Error 1.503	-1.604 substances Standard Error 3.290	—	—	—	—
Mean Change in Number of Other Substance Use by Self-report at Stage 1 Cigarettes	-12.642 substances Standard Error 7.221	-55.873 substances Standard Error 14.154	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

Population: 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.

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

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change in Number of Other Substance Use by Self-report at Stage 2 Alcohol	1.695 substances Standard Error 1.779	-2.942 substances Standard Error 3.121	—	—	—	—
Mean Change in Number of Other Substance Use by Self-report at Stage 2 Cigarettes	-9.925 substances Standard Error 7.801	-58.591 substances Standard Error 14.594	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

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

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 1	-0.064 Proportion of abstinent days Standard Error 0.009	-0.072 Proportion of abstinent days Standard Error 0.016	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

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

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

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 2	-0.057 Proportion of abstinent days Standard Error 0.011	-0.079 Proportion of abstinent days Standard Error 0.014	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

Population: Intention to treat analysis was done including drop-out

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)

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Depression Symptom Score by PHQ-9 at Stage 1	-3.26 score on a scale Standard Error 0.34	-4.78 score on a scale Standard Error 0.70	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

Population: 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

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)

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Depression Symptom Score by PHQ-9 at Stage 2	-3.66 score on a scale Standard Deviation 0.37	-4.39 score on a scale Standard Deviation 0.64	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 6

Population: Intention to treat analysis was done including drop-out

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.

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 1 Physical Health	1.013 score on a scale Standard Error 0.805	1.425 score on a scale Standard Error 1.225	—	—	—	—
Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 1 Mental Health	1.071 score on a scale Standard Error 0.842	3.785 score on a scale Standard Error 1.380	—	—	—	—
Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 1 General Health	-1.168 score on a scale Standard Error 0.957	1.582 score on a scale Standard Error 1.442	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

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

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 2 Physical Health	0.877 score on a scale Standard Error 0.870	1.561 score on a scale Standard Error 1.147	—	—	—	—
Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 2 Mental Health	2.035 score on a scale Standard Error 0.917	2.821 score on a scale Standard Error 1.345	—	—	—	—
Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 2 General Health	0.262 score on a scale Standard Error 1.038	0.152 score on a scale Standard Error 1.365	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, week 6

Population: Intention to treat analysis was done including drop-out

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.

Outcome measures

Measure	Stage 1 Placebo n=294 Participants 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 AMC n=109 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 1	2.2 score on a scale Standard Error 1.0	6.5 score on a scale Standard Error 1.5	—	—	—	—

SECONDARY outcome

Timeframe: week 7, week 12

Population: 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

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.

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo 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 AMC 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 Placebo 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 AMC 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).
Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 2	2.5 score on a scale Standard Deviation 1.1	6.2 score on a scale Standard Deviation 1.5	—	—	—	—

SECONDARY outcome

Timeframe: At week 12

Outcome measures

Measure	Stage 1 Placebo n=111 Participants 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 AMC n=114 Participants 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 2 Not Re-Randomized Placebo n=69 Participants 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 AMC n=109 Participants 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 Placebo 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 AMC 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).
Number of Participants Who Completed the Visit in Week 12	106 Participants	103 Participants	28 Participants	78 Participants	—	—

SECONDARY outcome

Timeframe: At week 12

Population: We did not collect data about satisfaction.

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

Outcome measures

Outcome data not reported

Adverse Events

Stage 1 Placebo

Serious events: 4 serious events

Other events: 45 other events

Deaths: 0 deaths

Stage 1 AMC

Serious events: 1 serious events

Other events: 41 other events

Deaths: 0 deaths

Stage 2 Re-Randomized Placebo

Serious events: 4 serious events

Other events: 8 other events

Deaths: 0 deaths

Stage 2 Re-Randomized AMC

Serious events: 3 serious events

Other events: 32 other events

Deaths: 0 deaths

Stage 2 Not Re-Randomized Placebo

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Stage 2 Not Re-Randomized AMC

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Stage 1 Placebo n=294 participants at risk 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 AMC n=109 participants at risk 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 2 Re-Randomized Placebo n=111 participants at risk 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 AMC n=114 participants at risk 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 Not Re-Randomized Placebo n=69 participants at risk 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 AMC n=109 participants at risk 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).
Nervous system disorders Seizure	0.34% 1/294 • Number of events 1 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Psychiatric disorders Substance-induced psychotic disorder	0.34% 1/294 • Number of events 1 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Psychiatric disorders Paranoia	0.34% 1/294 • Number of events 1 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Infections and infestations Gastroenteritis	0.00% 0/294 • Baseline to 12 weeks	0.92% 1/109 • Number of events 1 • Baseline to 12 weeks	0.90% 1/111 • Number of events 1 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Gastrointestinal disorders Pancreatitis	0.34% 1/294 • Number of events 1 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Infections and infestations Pneumonia	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.90% 1/111 • Number of events 1 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.92% 1/109 • Number of events 1 • Baseline to 12 weeks
Infections and infestations Urosepsis	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.90% 1/111 • Number of events 1 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Infections and infestations Cellulitis	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.88% 1/114 • Number of events 1 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Infections and infestations Appendicitis	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	1.4% 1/69 • Number of events 1 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Social circumstances Victim of crime	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.90% 1/111 • Number of events 1 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.88% 1/114 • Number of events 1 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.88% 1/114 • Number of events 1 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks
Cardiac disorders Cardiac failure acute	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.92% 1/109 • Number of events 1 • Baseline to 12 weeks
Psychiatric disorders Depression	0.00% 0/294 • Baseline to 12 weeks	0.00% 0/109 • Baseline to 12 weeks	0.00% 0/111 • Baseline to 12 weeks	0.00% 0/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	0.92% 1/109 • Number of events 1 • Baseline to 12 weeks

Other adverse events

Measure	Stage 1 Placebo n=294 participants at risk 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 AMC n=109 participants at risk 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 2 Re-Randomized Placebo n=111 participants at risk 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 AMC n=114 participants at risk 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 Not Re-Randomized Placebo n=69 participants at risk 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 AMC n=109 participants at risk 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).
Gastrointestinal disorders Nausea	15.3% 45/294 • Baseline to 12 weeks	37.6% 41/109 • Baseline to 12 weeks	7.2% 8/111 • Baseline to 12 weeks	28.1% 32/114 • Baseline to 12 weeks	0.00% 0/69 • Baseline to 12 weeks	5.5% 6/109 • Baseline to 12 weeks

Additional Information

Dr. Madhukar Trivedi

UT Southwestern Medical Center

Phone: 214/648-0188

Email: Madhukar.Trivedi@UTSouthwestern.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place