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

• ClinicalTrials.gov Identifier: NCT03078075
• Recruitment Status: Completed
• First Posted: March 13, 2017
• Results First Posted: March 29, 2021
• Last Update Posted: May 3, 2021
• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Institute on Drug Abuse (NIDA); The Emmes Company, LLC
• Information provided by (Responsible Party): Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Methamphetamine Use Disorder	Drug: Naltrexone: Vivitrol®; Drug: Placebo (PLB) Injectable; Drug: Bupropion: Wellbutrin XL®; Drug: Placebo (PLB) Oral	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 403 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: NIDA (National Institute on Drug Abuse) CTN (Clinical Trials Network) Protocol 0068: Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for Methamphetamine Use Disorder
• Actual Study Start Date: May 5, 2017
• Actual Primary Completion Date: July 3, 2019
• Actual Study Completion Date: July 25, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Response During Medication Phase at Stage 1 [ Time Frame: At weeks 6 ]

   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).

2. Number of Participants With Treatment Response During Medication Phase at Stage 2 [ Time Frame: 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.

Secondary Outcome Measures :

1. Treatment Effectiveness Score of Participants at Stage 1 [ Time Frame: At weeks 6 ]
   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.
2. Treatment Effectiveness Score of Participants at Stage 2 [ Time Frame: At week 12 ]
   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.
3. Percentage of Participants Who Used Methamphetamine in the Pre-evaluation Period [ Time Frame: Weeks 1-4 and Weeks 7-10 ]
   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 )
4. Mean Maximum Number of Consecutive Visits Negative UDS at Stage 1 [ Time Frame: At week 6 ]
   Measured by maximum consecutive negative UDS: Count the number and range 0-12 and report the maximum number.
5. Mean Maximum Number of Consecutive Visits Negative UDS at Stage 2 [ Time Frame: 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.
6. Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 1 [ Time Frame: At week 6 ]
   Measured by the number of study weeks during the treatment period with two methamphetamine-negative UDS.
7. Mean Number of Study Weeks With Two Methamphetamine-negative UDS at Stage 2 [ Time Frame: At week12 ]
   Measured by the number of study weeks during the treatment period with two methamphetamine-negative UDS.
8. Mean Change of Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 1 [ Time Frame: 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.

9. Mean Change Percentage of Methamphetamine Abstinent Days Measured by Self-report at Stage 2 [ Time Frame: week 7, week 12 ]

   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.

10. Mean Change of Methamphetamine Craving at Stage 1 [ Time Frame: Baseline, week 6 ]
    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.
11. Mean Change of Methamphetamine Craving at Stage 2 [ Time Frame: week 7, week 12 ]
    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.
12. Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 1 [ Time Frame: At week 6 ]
    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.
13. Mean Number of Abstinent Days of Participants Who Used Other Substance Measured by UDS at Stage 2 [ Time Frame: at week 12 ]
    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.
14. Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 1 [ Time Frame: 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.
15. Mean Change of Proportion of Other Substance Abstinent Days Measured by Self-report at Stage 2 [ Time Frame: week 7, week 12 ]
    Proportion of abstinent days of other substance including Alcohol, Cigarettes and E- Cigarettes was measured by self-report on TLFB during the treatment period.
16. Mean Change in Number of Other Substance Use by Self-report at Stage 1 [ Time Frame: Baseline, week 6 ]
    Number of other substance (Alcohol and Cigarettes) use was measured by self-report recall on Timeline Followback (TLFB) during the treatment period.
17. Mean Change in Number of Other Substance Use by Self-report at Stage 2 [ Time Frame: week 7, week 12 ]
    Number of other substance (Alcohol and Cigarettes) use was measured by self-report recall on Timeline Followback (TLFB) during the treatment period.
18. Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 1 [ Time Frame: Baseline, week 6 ]
    Proportion of abstinent days of E- Cigarettes was measured by self-report at stage 1.
19. Change in Proportion of E-cigarettes Abstinent Days by Self-report at Stage 2 [ Time Frame: week 7, week 12 ]
    Proportion of abstinent days of E- Cigarettes was measured by self-report at stage 2.
20. Mean Change of Depression Symptom Score by PHQ-9 at Stage 1 [ Time Frame: Baseline, week 6 ]

    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)

21. Mean Change of Depression Symptom Score by PHQ-9 at Stage 2 [ Time Frame: week 7, week 12 ]

    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)

22. Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 1 [ Time Frame: Baseline, Week 6 ]
    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.
23. Mean Change of Quality of Life (QOL) by PhenX Core Tier 1 Instrument at Stage 2 [ Time Frame: week 7, week 12 ]
    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.
24. Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 1 [ Time Frame: Baseline, week 6 ]

    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.

25. Mean Change of Overall Functioning as Measured by Treatment Effectiveness Assessment (TEA) at Stage 2 [ Time Frame: week 7, week 12 ]

    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.

26. Number of Participants Who Completed the Visit in Week 12 [ Time Frame: At week 12 ]
27. Participant Satisfaction Rating Measured by Study Satisfaction Survey at the End of the Study [ Time Frame: At week 12 ]
    The Study satisfaction survey measures participants satisfaction. We do not have a proper score range (varied range with some free text questions also)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

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

Los Angeles, California, United States, 90038

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

San Francisco, California, United States, 94102

United States, Minnesota

Hennepin County Medical Center- Berman Center for Research

Minneapolis, Minnesota, United States, 55415

United States, New York

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

New York, New York, United States, 10032

United States, Oregon

CODA, Inc.

Portland, Oregon, United States, 97214

United States, South Carolina

Behavioral Health Services (BHS) of Pickens County

Pickens, South Carolina, United States, 29671

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75235

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

Houston, Texas, United States, 77054

Sponsors and Collaborators

University of Texas Southwestern Medical Center

National Institute on Drug Abuse (NIDA)

The Emmes Company, LLC

Investigators

• Principal Investigator: Madhukar Trivedi, MD; University of Texas Southwestern Medical Center

  Study Documents (Full-Text)

Documents provided by Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center:

Study Protocol  [PDF] January 31, 2019

Statistical Analysis Plan  [PDF] September 13, 2019

Informed Consent Form  [PDF] December 19, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Trivedi MH, Walker R, Ling W, Dela Cruz A, Sharma G, Carmody T, Ghitza UE, Wahle A, Kim M, Shores-Wilson K, Sparenborg S, Coffin P, Schmitz J, Wiest K, Bart G, Sonne SC, Wakhlu S, Rush AJ, Nunes EV, Shoptaw S. Bupropion and Naltrexone in Methamphetamine Use Disorder. N Engl J Med. 2021 Jan 14;384(2):140-153. doi: 10.1056/NEJMoa2020214.

• Responsible Party: Madhukar H. Trivedi, MD, Professor, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03078075
• Other Study ID Numbers: CTN-0068; UG1DA020024 ( U.S. NIH Grant/Contract )
• First Posted: March 13, 2017
• Results First Posted: March 29, 2021
• Last Update Posted: May 3, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data from this study will be available to researchers on the website https://datashare.nida.nih.gov/ after the study is complete and the data is analyzed. This website will not include information that can identify individual study participants.The following information will be posted: Study protocol, reference to study publication of primary outcome, data sets (SAS and ASCII ), annotated case report forms, define file (also known as Data Dictionary), study-specific de-identification notes. Prior to downloading any study data, the user will be prompted to complete a registration agreement for data use. Users will have to register a name and valid e-mail address in order to download data and to accept their responsibility for using data in accordance with the NIDA Data Share Agreement.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center:

Methamphetamine; Methamphetamine Use Disorder; Naltrexone; Bupropion; Vivitrol®

Additional relevant MeSH terms:

Disease; Pathologic Processes; Naltrexone; Bupropion; Alcohol Deterrents; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs; Dopamine Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Dopamine Agents; Neurotransmitter Agents; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors