A Study of the Safety and Exploratory Efficacy of Oral AFA-281 in Patients with Alcohol Use Disorder

This study will determine the safety, tolerability, and exploratory efficacy of AFA-281. This study is a randomized, double-blind, placebo-controlled, human laboratory study of 36 community-based, non-treatment-seeking male and female individuals with current (i.e., past month) moderate-to-severe AUD (DSM-5). This study will be conducted by Dr. Lara Ray at UCLA. The total study duration is approximately 42 days including a 2-week screening period. Eligible participants will be randomized into one of three cohorts: 60 mg AFA-281, 120 mg AFA-281, or Placebo. Participants will start at a lower dose and increase the dose over 2 weeks then continue to maintain the dose for an additional 2 weeks. In week 4, participants will complete 7 daily visits to complete assessments and questionnaires.

Inclusion criteria

• Age between 21 and 65
• Must voluntarily sign and date each informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
• Meet current (i.e., past 12 months) DSM-5 diagnostic criteria for moderate or severe AUD
• Report drinking at least 28 drinks per week if male, 21 drinks per week if female, in the 28 days prior to consent.
• Must be surgically sterile (vasectomy, tubal ligation, or hysterectomy) or agree to be sexually inactive or agree to use a barrier method of birth control (i.e., condom) from the start of screening until study completion, and agree to refrain from donating sperm for 90 days after study drug administration.

Exclusion criteria

• Current treatment for alcohol use or a history of treatment in the 30 days before enrollment or treatment seeking
• Current (last 12 months) DSM-5 diagnosis of dependence on any psychoactive substances other than nicotine
• Current DSM-5 diagnosis of substance use disorder for any substance other than alcohol and nicotine
• Lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder
• Current DSM-5 major depressive disorder with suicidal ideation
• Positive urine screen for narcotics, amphetamines, or sedative hypnotics
• Clinically significant alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
• Pregnancy, nursing, or refusal to use reliable method of birth control if female
• History of significant sensitivity to any drug.
• Has a clinically significant abnormal ECG or an ECG with a QTc interval corrected for heart rate using the Fridericia formula (QTcF) > 430 ms.
• History of epilepsy, any clinically significant cardiac, respiratory (except mild asthma), renal, hepatic, gastrointestinal, hematologic, endocrine, dermatological, metabolic or psychiatric disease or disorder, or any uncontrolled medical illness.
• Has an estimated creatinine clearance (CrCl) outside of normal range.
• History of head trauma with loss of consciousness, seizures or convulsions, including febrile, alcohol or drug withdrawal seizures.
• History of gastric surgery, vagotomy, bowel resection or any surgical procedure that might interfere with gastrointestinal motility, pH, or absorption.
• Positive test result for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or HIV antibodies (HIV Ab). Negative HIV status will be confirmed at Screening and the results will be maintained confidentially by the study site.
• Liver enzymes AST, ALT, or GGT ≥ 3 times upper normal limit.
• Positive urine drug screen for drugs of abuse at Screening or Day -1.
• Receipt of any drug by injection within 30 days prior to study drug administration.
• A clinically notable vital sign abnormality including a history of syncopal or near syncopal events following abrupt change in posture.
• Donation or loss of 550 mL or more blood volume (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to study drug administration.
• Pregnant or nursing women.
• Receipt of any investigational products within 6 weeks prior to study drug administration.
• Current enrollment in another clinical study.
• Previous enrollment in this study.
• Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to participate in the AFA-281 Phase I1a Study.