Development of a Selective ALDH2 Inhibitor to Treat AUD

Study Overview
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Brief Summary
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Alcohol use disorder (AUD) represents a highly prevalent, costly, and often untreated condition in the United States. Pharmacotherapy offers a promising avenue for treating AUD and for improving clinical outcomes for this debilitating disorder. While developing novel medications to treat AUD remains a high priority research area, there are major opportunities to refine the process of screening novel compounds. A promising novel pharmacology for AUD consists of the ANS-6637 compound which provides novel aldehyde dehydrogenase 2 (ALDH2) inhibition. Unlike disulfiram, a non-selective and irreversible ALDH2 and ALDH1 inhibitor, which produces an aversive flushing response, the oral ANS-6637 compound is a selective and reversible inhibitor of ALDH2 that attenuates the surge in dopamine (DA). Specifically, a preclinical study found that ANS-6637 blunted the surge of DA in ventral tegmental neurons without affecting the basal levels of DA in vivo in a rodent model of alcohol seeking behavior. In rodent models, selective and reversible ALDH2 inhibitors decrease alcohol seeking and taking, prevent operant self-administration, and block cue-induced reinstatement. These results suggest that ANS-6637 may be an effective treatment to reduce heavy drinking and suppress relapse in individuals with AUD. This is a randomized, double-blind, placebo-controlled, dose response study of ANS-6637. A total of 75 men and women with current AUD will be randomly assigned to receive (a) ANS-6637 (200 mg), (b) ANS-6637 (600 mg), or (c) matched placebo for 7 days. On Day 4, participants will complete an fMRI task before and 45-minutes after a priming dose of alcohol (target Breath Alcohol Concentration (BrAC) of 0.03 g/dl). On Day 7 participants will return to the laboratory to complete an oral alcohol administration paradigm. The successful completion of this study will advance medications development for AUD by advancing the development of ANS-6637, a novel and promising compound for AUD.

Official Title
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Development of a Selective ALDH2 Inhibitor for the Treatment of Alcohol Use Disorder

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: ANS-6637 Low Dose
* Drug: ANS-6637 High Dose
* Drug: Matched Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 21 years and older (adult, older adult); meeet DSM-5 diagnostic criteria for alcohol use disorder (moderate or severe); report drinking at least 48 standard drinks in a 30-day period, during the 90 days before enrollment. Exclusion Criteria: current treatment for alcohol problems; a history of treatment for alcohol problems in the 30 days before enrollment; currently seeking treatment for alcohol problems; current DSM-5 diagnosis of dependence on any psychoactive substances other than alcohol or nicotine; lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder; positive urine screen for narcotics, amphetamines, or sedative hypnotics; serious alcohol withdrawal symptoms as indicated by a score of ≥10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) pregnant, nursing, or refusal to use reliable birth control method (if female); medical condition that may interfere with safe study participation (e.g. unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes); AST, ALT, or GGT ≥ 3 times upper limit of normal; attempted suicide in the past 3 years and/or serious suicidal intention or plan in the past year; currently on prescription medication that contraindicates use of ANS-6637; other circumstances that, in the opinion of the investigators, compromises participant safety

Ages Eligible for Study
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Minimum Age: 21 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: Randomized, triple-blind, placebo-controlled, parallel-group study of ANS-6637 (200mg, 600mg, 0mg [palcebo])
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ANS-6637 Low Dose<br>200mg ANS-6637 (2 tablets) | Drug: ANS-6637 Low Dose<br>* ANS-6647 is a selective, reversible, and orally bioavailable aldehyde dehydrogenase 2 (ALDH2) inhibitor. It will be tested at a low dose (200mg) and a high dose (600mg) against matched placebo.<br>|
| Active Comparator: ANS-6637 High Dose<br>600mg ANS-6637 (2 tablets) | Drug: ANS-6637 High Dose<br>* ANS-6647 is a selective, reversible, and orally bioavailable aldehyde dehydrogenase 2 (ALDH2) inhibitor. It will be tested at a low dose (200mg) and a high dose (600mg) against matched placebo.<br>|
| Placebo Comparator: Placebo<br>0mg matched placebo (2 tablets) | Drug: Matched Placebo<br>* ANS-6647 is a selective, reversible, and orally bioavailable aldehyde dehydrogenase 2 (ALDH2) inhibitor. It will be tested at a low dose (200mg) and a high dose (600mg) against matched placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Subjective Response to Alcohol | Participants will complete an oral alcohol challenge and will rate their subjective responses to alcohol at baseline (BrAC = 0.00 g/dl) and at 30, 45, 60, 120, and 180 minutes post alcohol. The primary outcome variables will be (a) alcohol craving, (b) stimulant/reward, and (c) sedative/aversive effects of alcohol. | Baseline, 30-, 45-, 60-, 120-, and 180-minutes post alcohol | 
| Change in Neural Alcohol Cue Reactivity | Participants will complete a neuroimaging paradigm in which they view alcoholic and non-alcoholic beverage cues and will rate their subjective craving for alcohol. The primary outcome variable will be BOLD activation to alcohol cues in mesocorticolimbic reward circuitry. | Assessed on Day 4. Scan duration 1 hour. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol Use Disorder, Medications Development