Intermittent Oral Naltrexone Enhanced With an Ecological Momentary Intervention for Methamphetamine-using MSM

Study Overview
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Brief Summary
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This is a double-blind, placebo-controlled phase 2b trial in which 54 MSM who use meth will be randomly assigned (2:1) to receive 12 weeks of as-needed intermittent oral naltrexone 50 mg enhanced with an EMA-informed EMI platform, or receive as-needed placebo with EMA-informed EMI. The 12-week treatment period is consistent with other pharmacotherapy trials for substance use disorders. The proposed sample size is also consistent with other phase 2b trials for substance use treatment. Upon enrollment, participants will complete daily EMA assessments and weekly visits for behavioral surveys and urine testing for meth metabolites, study drug dispensing and computer-based counseling for substance use. Safety laboratory assessments and vital signs will be completed monthly. Efficacy (Specific Aims 1-3) will be assessed upon trial completion as measured by proportion meth-positive urine samples; PrEP and ART adherence by drug levels and viral load testing; and sexual risk behavior data accounting for PrEP use and viral suppression.

Detailed Description
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Methamphetamine (meth) use is very common among men who have sex with men (MSM), particularly MSM living with HIV. Meth use among HIV-negative and HIV-positive MSM is up to 13 and 34 times more prevalent than in the general U.S. adult population, respectively. Meth use is independently associated with HIV-related sexual risk behaviors among MSM and can function as a barrier to antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) adherence. Thus, effective interventions to reduce meth use may also function as an important HIV prevention and care intervention by reducing meth-related HIV risk behavior, and optimizing ART and PrEP adherence. MSM comprise two-thirds of the new infections in the United States. Despite this continued domestic HIV epidemic and the high prevalence of meth use among MSM, few interventions have proven efficacious for MSM who use meth. The investigators seek to address this gap by evaluating the efficacy of intermittent oral naltrexone enhanced with an ecological momentary intervention (ION+EMI) for meth use treatment. Naltrexone, a µ-opioid receptor antagonist, is a promising agent for MSM who use meth. Meth is rapidly metabolized to amphetamine in the bloodstream and daily naltrexone has shown efficacy in reducing amphetamine urine-positivity and relapse. Oral naltrexone is inexpensive and has few toxicities, but the standard daily regimen for naltrexone hampers compliance as patients frequently neglect to take the medication. Alternate regimen schedules have been proposed to increase efficacy and expand the population that may benefit from this pharmacologic agent. One alternative approach is the targeted administration of intermittent oral naltrexone (ION), whereby individuals are instructed to take the medication as needed in anticipation of substance use, after exposure to triggers of substance use, or during periods of craving. Administration of naltrexone prior to exposure to amphetamines significantly attenuated amphetamine craving in 4 trials. Additionally, emerging evidence suggests that ecological momentary interventions (EMI) that respond to in-the-moment contexts can lead to positive health behaviors, such as increasing medication dosing. EMI are particularly well-suited to enhancing as-needed dosing of naltrexone because anticipation of meth use and meth craving in a natural setting changes within a person from moment to moment, and the detection of these momentary fluctuations can support the delivery of just-in-time messages to encourage medication use to prevent participants from proceeding from craving to meth use. A pilot study led by our research team on ION found that meth-using MSM who use at least 1 day per week had significantly greater reductions in meth-using days when treated with as-needed naltrexone, compared to placebo. Moreover, naltrexone participants had greater reductions in serodiscordant receptive anal intercourse and serodiscordant condomless receptive anal intercourse, compared to placebo. In the pilot, participants reported taking study drug 64% of the days that they craved or anticipated meth use. Participants also completed ecological momentary assessments (EMA) with a 74% response rate, indicating that real-time assessments are feasible and acceptable. To build on the results of this study and 4 other naltrexone trials, the investigators propose to evaluate intermittent naltrexone to treat meth in a phase 2b efficacy trial supplemented by an EMA-informed EMI that responds to a participant's real-time craving levels or anticipated meth use to provide in-the-moment medication reminders when participants would most benefit from naltrexone. The investigators hypothesize that pairing ION with EMI will further amplify reductions in meth use by providing just-in-time reminders for naltrexone to optimize adherence, thereby interrupting the progression from craving to meth use.

Official Title
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The ION+EMI Study: Intermittent Oral Naltrexone Enhanced With an Ecological Momentary Intervention for Methamphetamine-using MSM

Conditions
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Methamphetamine Use Disorder

Intervention / Treatment
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* Drug: Naltrexone Hydrochloride
* Drug: Placebo
* Behavioral: Ecological Momentary Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: cisgender male (male gender and sex assigned at birth) age 18-70 years* (naltrexone's tolerability and safety has been demonstrated among older adults up to age 70) self-reported condomless anal sex with men or missing Pre-Exposure Prophylaxis or antiretroviral therapy doses due to meth use in the prior three months while under the influence of meth self-reported meth use at least weekly mild, moderate or severe meth use disorder positive meth sample via sweat patch or urine testing during screening interested in reducing meth use no current acute illness requiring prolonged medical care no chronic illness that is likely to progress clinically during trial able and willing to provide informed consent and adhere to visit schedule current CD4 count ≥ 200 cells/mm3; or CD4 count of 100-199 cells/mm3 and HIV viral load < 200 copies/mL (if living with HIV) baseline complete blood count, total protein, albumin, glucose, alkaline phosphatase, creatinine, blood urea nitrogen test, and electrolytes without clinically significant abnormalities as determined by study clinician in conjunction with symptoms, physical exam, and medical history Exclusion Criteria: any psychiatric (e.g., depression with suicidal ideation) or medical condition that would preclude safe participation known allergy or prior adverse reaction to naltrexone current use of any opioids or a known medical condition which currently requires or may likely require opioid analgesics opioid-positive urine test at screen/enrollment visits (naltrexone can induce opioid withdrawal) moderate or severe liver disease (aspartate aminotransferase test, alanine aminotransferase test, or total bilirubin > 3 times upper limit of normal) impaired renal function (creatinine clearance < 60 ml/min) currently participating in another intervention research study with potential overlap severe alcohol use disorder as determined by structured clinical interview for DSM-5 criteria any condition that, in the PI and/or study clinician's judgment interferes with safe participation or adherence to study procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2:1 Naltrexone with EMI vs. Placebo with EMI
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naltrexone with ecological momentary intervention<br>Naltrexone Hydrochloride, 50 mg., intermittent with ecological momentary assessment (EMA) | Drug: Naltrexone Hydrochloride<br>* Intermittent Oral Naltrexone, 50 mg<br>* Other names: ReVia;Behavioral: Ecological Momentary Intervention<br>* Receive ecological momentary intervention if ecological momentary assessment reports meth craving, stress, not taking study drug, or antecedents detected for high risk meth use.<br>* Other names: EMI;|
| Placebo Comparator: Placebo with ecological momentary intervention<br>Placebo, intermittent with ecological momentary assessment (EMA) | Drug: Placebo<br>* Intermittent Oral Placebo<br>Behavioral: Ecological Momentary Intervention<br>* Receive ecological momentary intervention if ecological momentary assessment reports meth craving, stress, not taking study drug, or antecedents detected for high risk meth use.<br>* Other names: EMI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in meth-positive urine tests from baseline to week 12 between Intermittent Oral Naltrexone vs. placebo groups | As measured by the proportion of meth-positive urine tests. | Every week from enrollment to the end of treatment at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in sexual risk behaviors from baseline to week 12 between Intermittent Oral Naltrexone vs placebo groups. | As measured by reducing meth-associated sexual risk behaviors | Every four weeks from enrollment to the end of treatment at 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methamphetamine, meth, naltrexone