Trial of Naltrexone/Bupropion for the Treatment of Methamphetamine Use Disorder

Randomized, Placebo-Controlled, Multi-Site Trial of Extended-Release Naltrexone Injection/Bupropion XL Tablets in the Treatment of Methamphetamine Use Disorder

The primary objective of this study is to evaluate the efficacy of extended release naltrexone plus bupropion XL (XR-NTX/BUP-XL) compared to matched injectable and oral placebo (iPLB/oPLB) in reducing methamphetamine (MA) use in individuals with moderate or severe methamphetamine use disorder (MUD) seeking to stop or reduce MA use.

Study Overview

• Status: Not yet recruiting
• Conditions: Methamphetamine-dependence; Methamphetamine Abuse
• Intervention / Treatment: Drug: extended-release naltrexone (XR-NTX); Drug: extended release bupropion (BUP-XL) tablets (BUP-XL); Drug: iPLB; Drug: oPLB

Detailed Description

This is a double-blind, placebo-controlled, randomized clinical trial in which 360 individuals with moderate or severe MUD will be randomly assigned at a 1:1 ratio to receive either 1) extended release naltrexone (XR-NTX; as Vivitrol®) plus once daily oral extended release bupropion (BUP-XL) tablets (the XR-NTX/BUP-XL group) or 2) both the matching injection placebo (iPLB) and once daily oral placebo (oPLB) tablets (the iPLB/oPLB group). The study intervention consists of a 12-week treatment phase. It is hypothesized that the XR-NTX/BUP-XL arm will be associated with a greater number of "responders," defined as participants who provide at least 3 MA-negative urine drug screens (UDS) out of 4 samples obtained during the evaluation period (i.e., Weeks 11-12) of the 12-week long treatment phase, relative to the iPLB/oPLB arm. Secondary objectives include evaluating the effect of the extended release naltrexone plus bupropion XL (XR-NTX/BUP-XL) arm compared to the iPLB/oPLB arm on safety, other substance use outcomes, depression scores, quality of life, overall functioning, clinic attendance, and medication adherence.

• Study Type: Interventional
• Enrollment (Estimated): 360
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jennifer Wong, PhD; Phone Number: 301-827-6267; Email: Jennifer.Wong3@nih.gov
• Study Contact Backup: Name: Jana Drgonova, PhD; Phone Number: 301-827-5933; Email: jana.drgonova@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Is 18 to 65 years of age;
2. Meets DSM-5 criteria for moderate or severe MUD (4 or more criteria);
3. Is interested in reducing or stopping MA use;
4. Is able to speak English sufficiently to understand the study procedures and provide written informed consent to participate in the study;
5. Self-reports MA use on 18 or more days in the 30-day period prior to consent using the Timeline Followback (TLFB);
6. Provides at least 2 urine samples positive for MA out of up to 3 tests, which will occur at least 2 days apart within a 10-day period;
7. If assigned as female at birth and/or currently has a uterus, is not pregnant, agrees to use acceptable birth control methods, and have periodic urine pregnancy testing done during participation in the study unless documentation of hysterectomy provided;
8. Is not physically dependent on opioids and meets subjective and objective measures of being opioid-free prior to naltrexone injection per study medical clinician's determination, including, if clinically required, a negative naloxone challenge;
9. Is willing to comply with all study procedures and medication instructions;
10. Agrees to use a smartphone app (downloaded for free to own device or on a study provided smartphone device) to take daily videos of medication dosing.

Exclusion Criteria:

1. Has an acute medical or psychiatric disorder that would, in the judgment of the study medical clinician, make participation difficult or unsafe;
2. Has suicidal or homicidal ideation that requires immediate attention;
3. Has a history of epilepsy, seizure disorder, or head trauma with neurological sequelae (e.g., loss of consciousness that required hospitalization); current anorexia nervosa or bulimia; or any other conditions that increase seizure risk in the opinion of the study medical clinician;
4. Has evidence of second or third degree heart block, atrial fibrillation, atrial flutter, prolongation of the QTc, or any other finding on the screening ECG that, in the opinion of the study medical clinician, would preclude safe participation in the study;
5. Has Stage 2 hypertension as determined by the study medical clinician (e.g., greater than or equal to 160/100 in 2 out of 3 readings during screening);
6. Has any elevated bilirubin test value per laboratory criteria OR any other liver function test (LFT) value > 5 times the upper limit of normal per laboratory criteria;
7. Has a platelet count <100 x 10exp3/microliter;
8. Has a body habitus that precludes gluteal intramuscular injection of XR-NTX in accordance with the administration equipment (needle) and procedures;
9. Has a known allergy or sensitivity to bupropion, naloxone, naltrexone, PLG (polyactideco-glycolide), carboxymethylcellulose or any other component of the XR-NTX diluents;
10. Has been in a prior study of pharmacological or behavioral treatment for MUD within 6 months of study consent;
11. Has taken an investigational drug in another study within 30 days of study consent;
12. Has been prescribed and taken naltrexone or bupropion within 30 days of study consent;
13. Is concurrently enrolled in formal behavioral or pharmacological Substance Use Disorder (SUD) treatment services;
14. Is receiving ongoing treatment with tricyclic antidepressants, xanthines (i.e., theophylline and aminophylline), systemic corticosteroids, nelfinavir, efavirenz, chlorpromazine, MAOIs, central nervous system stimulants (e.g., Adderall, Ritalin, etc.), or any medication that, in the judgment of the study medical clinician, could interact adversely with study medications;
15. Has a current pattern of alcohol, benzodiazepine, or other sedative hypnotic use which would preclude safe participation in the study as determined by the study medical clinician;
16. Requires treatment with opioid-containing medications (e.g., opioid analgesics) during the study period;
17. Has a surgery planned or scheduled during the study period;
18. Is currently in jail, prison or any inpatient overnight facility as required by court of law or have pending legal action or other situation (e.g., unstable living arrangements) that could prevent participation in the study or in any study activities;
19. If assigned as female at birth and/or currently has a uterus, is currently pregnant, breastfeeding, or planning on conception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: XR-NTX/BUP-XL; Participants randomized to the (XR-NTX/BUP-XL) arm will receive 450 mg of once-daily oral extended-release bupropion tablets and once every three weeks (Weeks 1, 4, 7, and 10) injections of extended-release naltrexone (Vivitrol®)	Drug: extended-release naltrexone (XR-NTX); Once per three weeks injections of extended-release naltrexone; Other Names: Vivitrol; Drug: extended release bupropion (BUP-XL) tablets (BUP-XL); Daily oral extended release bupropion tablets; Other Names: Wellbutrin
Placebo Comparator: PLB/PLB; Participants randomized to the PLB arm will receive once-daily placebo tablets and once every three weeks (Weeks 1, 4, 7, and 10) placebo injections.	Drug: iPLB; Once per three weeks injections of placebo; Other Names: Placebo injections; Drug: oPLB; Daily oral placebo tablets; Other Names: Placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with at least 75% methamphetamine-negative urine drug screen tests during the evaluation period (i. e., Weeks 11-12)	Participants will be administered four urine drug screen tests (two tests/week) during the evaluation period. (i.e., Weeks 11-12).	2 weeks (i. e., Weeks 11-12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety measured as frequency and severity of adverse events (AEs)	adverse events (AEs), clinical lab tests, suicidality	16 weeks (12 week treatment plus followup)
Severity of Craving as measured by Visual Analog Scale	Craving score as assessed by Visual Analog Scale that ranges from 0 (no craving) to 100 (most intense craving possible). The Visual Analog Scale will be completed at each screening visit, twice weekly throughout the treatment phase, and at the Week 14 and 16 follow-up visits.	16 weeks (12 week treatment plus followup)
Severity of Depression as assessed by the Patient Health Questionnaire-9	Diagnostic criteria for major depression, severity and frequency of depressive symptoms, presence of suicidal ideation, and functional impairment related to depression will be assessed by the Patient Health Questionnaire-9 (Kroenke et al., 2001)	16 weeks (12 week treatment plus followup)
Treatment Effectiveness as measured by the Treatment Effectiveness Assessment	The Treatment Effectiveness Assessment (TEA; Ling et al., 2012) is a 4-item self-administered assessment to document changes in four life domains: substance use, personal responsibilities, health, and community. The TEA will be collected at screening, mid-treatment (Week 6 visit 2), end-of-treatment (Week 12 visit 2), and follow-up (Weeks 14 and 16).	16 weeks (12 week treatment plus followup)
Quality of Life as measured by PROMIS® Profile 29 for adults	The instrument includes 29 self-administered questions from the PROMIS® Profile 29 for adults. The quality of life questions include physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, and pain intensity over the past 30 days. Each question, except for the pain intensity question, is measured on a 5-point scale. Quality of Life will be assessed at screening, mid-treatment (Week 6 visit 2), end-of-treatment (Week 12 visit 2), and follow-up (Weeks 14 and 16).	16 weeks (12 week treatment plus followup)

Collaborators and Investigators

• Sponsor: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Shwe Gyaw, MD, NIDA/NIH

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: January 22, 2024
• First Posted (Actual): January 31, 2024

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Narcotic Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Alcohol Deterrents; Dopamine Uptake Inhibitors; Naltrexone; Bupropion
• Other Study ID Numbers: NIDA/VA CS #1036

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: we don't plan to make individual participant data (IPD) available to other researchers.

Drug and device information, study documents

• 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.: Yes