Dutasteride Treatment for Reducing Heavy Drinking in AUD: Predictors of Efficacy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of dutasteride in reducing drinking and heavy drinking in men and women with alcohol use disorder. The investigators hypothesize that dutasteride 1 mg per day will be well tolerated in this patient population and that, compared to placebo treatment, dutasteride will result in a greater reduction in drinks per week and in the frequency of heavy drinking days.

Detailed Description
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Heavy drinking remains a significant public health problem and is frequently under treated. Although several medications have been shown to help patients stop or reduce drinking, additional medication options are needed as there is considerable variability in effectiveness or tolerability of existing medications for individual patients. Additionally, identification of individual subject level predictors of efficacy are needed to better personalize pharmacotherapy treatment recommendations. This study will seek to replicate and extend our results showing efficacy of a novel medication dutasteride for reducing drinking and will examine potential easily measured predictors of response. Dutasteride is a widely prescribed medication for benign prostatic hypertrophy and androgenic hair loss that also modulates the elimination of cortisol and the production of some neuroactive steroids. Changes in the regulation of cortisol and neuroactive steroids have each been suggested as factors which may contribute to the maintenance of alcohol dependence. Data from a recently completed first randomized placebo controlled trial of dutasteride for AUD in a sample of male drinkers, indicates that dutasteride is well tolerated in alcoholics and has efficacy in helping subjects reduce drinking. Additionally, results indicate that dutasteride may be particularly helpful for patients who drink to cope with anxiety and negative emotions, a group of patients with poor response to other treatments. This 24-week treatment study will use an innovative randomized placebo controlled step therapy design to examine the safety and efficacy of dutasteride to reduce drinking by treatment seeking women and men with hazardous levels of alcohol use. At 12-weeks placebo non-responders will transition to dutasteride and dutasteride non-responders will transition to naltrexone, an FDA approved medication with demonstrated efficacy for reducing heavy drinking. 12-week responders (reduction in drinks/week of 60% or greater compared with screening) will continue for an additional 12-weeks on their initial study medication assignment (dutasteride or placebo). Additionally, the investigators will examine several baseline measures as predictors of dutasteride efficacy, including drinking to cope, anxiety, adverse child events, and perceived life stress as well as stress resilient vs. reactive genotypes of FKBP5 a chaperone protein involved in regulation of glucocorticoid, androgen and progesterone receptor function.

Official Title
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Dutasteride Treatment for Reducing Heavy Drinking in AUD: Predictors of Efficacy

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: Dutasteride Capsules
* Drug: Placebo Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men and women age 35 to 70 yo inclusive have an average weekly ethanol consumption of >24 SD for men and >18 for women and at least 2 HDD/wk over the 8 weeks prior to screening current DSM-5 AUD no evidence of significant cognitive impairment for women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or tubal ligation; or <2 years postmenopausal) must be non-lactating, practicing a reliable method of birth control and agree to continue such throughout the study and for 6 months following participation, and have a negative serum pregnancy test prior to initiation of treatment. Exclusion Criteria: history of serious alcohol withdrawal symptoms (e.g., perceptual distortions, seizures, delirium, or hallucinations) subjects who on clinical examination by a physician are deemed to be too severely alcohol dependent to permit them to participate in a pbo-controlled study (e.g., evidence of serious adverse medical or psychiatric effects that are exacerbated by heavy drinking and would, for safety reasons, lead the physician to urge the patient to be totally abstinent and engage in an empirically supported treatment) current, clinically significant physical disease or abnormality on the basis of medical history, physical examination, or routine laboratory evaluation, including direct bilirubin more than 2.5 times the upper limit of normal or transaminase elevations 5 times the upper limit of normal (the investigators will not exclude patients with hypertension, diabetes, asthma or other common medical conditions, if these are adequately controlled and the patient has an ongoing relationship with a primary care provider) have a serious psychiatric illness on the basis of history or psychiatric examination (i.e., schizophrenia, active clinically significant mood episode of bipolar disorder or major depression, organic mental disorder, current clinically significant eating disorder, or substantial suicide or violence risk) have a current DSM-5 diagnosis of moderate drug use disorder (other than caffeine or nicotine dependence) currently taking finasteride, dutasteride, medication for treatment of AUD, or chronic use of opioid pain medication are considered by the investigators to be an unsuitable candidate for an investigational drug

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 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
Interventional Model Description: The study consists of two 12-week phases, the first being a 12-week parallel-groups comparison of dutasteride and placebo to evaluate the safety and efficacy of dutasteride 1 mg/day in reducing the likelihood of drinking and heavy drinking in treatment-seeking men and women with alcohol use disorder. In the second 12-week phase, responders in phase 1 (defined as a ≥60% reduction in SD/wk for weeks 9-12 compared with screening) will continue on their initial medication assignment, while non-responder subjects treated with placebo in phase 1 will be given dutasteride during phase 2, and non-responder subjects treated with dutasteride in phase 1 will receive naltrexone daily in phase 2. This design maintains double blind conditions in both phases 1 and 2.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: dutasteride<br>two 0.5 mg capsules of dutasteride daily | Drug: Dutasteride Capsules<br>* 1 mg/day oral dutasteride (2 x 0.5 mg capsules)<br>* Other names: Avodart;|
| Placebo Comparator: placebo capsule<br>inactive placebo matched in appearance with dutasteride capsules | Drug: Placebo Capsules<br>* Placebo capsules with matching appearance as Dutasteride Capsules<br>* Other names: inactive placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heavy Drinking Days Per Week by Medication Group | Change in the number of heavy drinking days (i.e., four or more drinks in a day for women and five or more drinks in a day for men) during treatment phase of study. Daily drinking data will be aggregated to the weekly level. | 12 weeks (from initiation to end of treatment phase 1) | 
| Change in Drinks Per Week by Medication Group | Change in the number of drinks per week during treatment phase of study. Daily drinking data will be aggregated to the weekly level. | 12 weeks (from initiation to end of treatment phase 1) |