Extended-Release vs. Oral Naltrexone Alcohol Treatment in Primary Care

Study Overview
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Brief Summary
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The proposed study is a pragmatic, randomized, open-label clinical trial of 24 weeks of XR-NTX vs. O-NTX using a COMBINE-adapted Medical Management primary care treatment model. 237 adults >18yo with alcohol dependence will be recruited from the community into treatment in public sector primary care settings. The primary outcome which powers this study is a dichotomous good clinical outcome defined by abstinence or moderate drinking, and as measured by the Timeline Follow-back and analyzed using an intention-to-treat approach among all randomized participants. Secondary outcomes include the incremental cost effectiveness of the two arms, differences between arms by continuous measures of alcohol intake (drinks/day, % days abstinent, time to first heavy drinking day, bio-markers), and the exploratory analysis of factors possibly associated with effectiveness, including gender, prior treatment abstinence, and mu opioid receptor (OPRM1) genotypes. Specific Aim 1: Treatment Effectiveness. To evaluate the effectiveness of extended-release naltrexone (XR-NTX) vs. oral naltrexone (O-NTX) in producing a primary good clinical outcome, defined as abstinence or moderate drinking (≤2 drinks/day, men; ≤1 drink/day,women; and ≤2 heavy drinking occasions/month), during the final 20 of 24 weeks of primary care-based Medical Management for alcohol dependence. Hypothesis: The rate of this good clinical outcome will be approximately twice as great among participants receiving XR-NTX compared with those receiving O-NTX. Specific Aim 2: Cost Effectiveness. To estimate the incremental cost effectiveness of XR-NTX vs. O-NTX,both in conjunction with primary care-based Medical Management. Hypothesis: XR-NTX treatment will be more cost effective than O-NTX. Specific Aim 3: Patient-Level Predictors of Effectiveness. To identify patient-level characteristics associated with effectiveness in both arms.

Detailed Description
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Rationale: Though integration of alcohol pharmacotherapy into primary care settings is receiving increasing emphasis and support, rigorous data to inform clinicians' treatment choice is lacking. The most recently FDA-approved alcohol treatment medication, an extended-release depot form of naltrexone (XR-NTX, Vivitrol®), could greatly simplify the medical home-centered alcohol treatment emphasized in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Clinician's Guide. Injected once a month, XR-NTX offers a long-acting and thus potentially more effective form of pharmacotherapy than oral naltrexone (O-NTX), which, despite the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) trial and systematic reviews supporting some efficacy, has been characterized by low rates of overall prescribing, poor adherence, suboptimal monthly refill and inadequate treatment retention. Yet while promising as an alternative to O-NTX, XR-NTX is substantially more expensive ( $1100 vs.  $100 per month), and no head-to-head trials have compared the two forms of naltrexone. A comparative effectiveness approach is required to systematically evaluate the following key questions: In primary care settings, what is the relative clinical effectiveness of XR-NTX vs. O-NTX? What are the benefits and costs of XR-NTX relative to O-NTX? And can patient and system characteristics be identified to inform treatment choice to maximize the probability of successful outcome? Implications: Despite several years of experience, the comparative effectiveness of XR-NTX compared to older alcohol medications remains uncertain, particularly in a mainstream, primary care treatment model that is generalizable and broadly accessible. Newer, novel, expensive medications for addiction disorders are historically greatly underutilized by primary care physicians. This study is innovative both as a 'head-to-head' evaluation of XR-NTX vs. O-NTX in primary care, and because expected participants will be primarily Medicaid-covered or uninsured persons who will not be excluded based on medical and psychiatric co-morbidities that often preclude participation in efficacy studies. If health insurance expansion, parity reforms, medical homes and accountable care organizations are to define primary care as a core alcohol treatment setting in the coming decade, exactly this type of study is required to guide treatment protocols and resource allocation. Ultimately, more widespread adoption of cost-effective alcohol pharmacotherapies will result in longer,healthier lives and lower costs.

Official Title
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Randomized, Open-label Clinical Trial of Extended-Release vs. Oral Naltrexone for Alcohol Treatment in Primary Care.

Conditions
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Alcohol Dependence

Intervention / Treatment
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* Drug: XR-NTX (Extended-Release Naltrexone)
* Drug: Oral Naltrexone (O-NTX)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults, age ≥18 y.o. English- or Spanish- speaking and able to understand study procedures and provide full consent. DSM IV diagnosis of alcohol dependence as determined by study physician and DSM IV checklist. Endorses goal of abstinence, and is able to achieve alcohol abstinence without inpatient detoxification, per study physician. Exclusion Criteria: Current opioid dependence and/or positive urine toxicology for extended opioids. Pregnancy or female planning conception. Allergy to naltrexone or the PGL XR-NTX formulation or diluent. Severe liver disease, liver failure, or liver function test levels greater than three times normal. Other severe, untreated or uncontrolled medical illness (e.g., severe heart failure or dementia).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: XR-NTX<br>Xr-NTX 380mg IM injection monthly x 6 months | Drug: XR-NTX (Extended-Release Naltrexone)<br>* 380mg (4cc) XR-NTX administered by IM injection 1x/month for 6 months.<br>* Other names: Vivitrol;|
| Active Comparator: Oral Naltrexone<br>Oral naltrexone 50mg/day x 6 months | Drug: Oral Naltrexone (O-NTX)<br>* 50mg pill form of naltrexone taken 1x/day for 6 months.<br>* Other names: Revia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Alcohol Abstinence or Moderate Drinking | Percentage of participants who had the following number of drinks (≤2 drinks/day, men; ≤1 drink/day, women; and ≤2 heavy drinking occasions/month) during the final 20 of 24 weeks of primary care-based Medical Management for alcohol dependence. | 4-24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Naltrexone, Extended-release naltrexone, Oral naltrexone, Vivitrol, XR-NTX, alcohol dependence, primary care, Medical Management