Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of AD04 (Ondansetron) in Adults With Alcohol Use Disorder (AUD) and Selected Polymorphisms in the Serotonin Transporter and Receptor Genes
Overview
- Phase
- Phase 3
- Intervention
- AD04 (ondansetron)
- Conditions
- Alcohol Use Disorder
- Sponsor
- Adial Pharmaceuticals
- Enrollment
- 302
- Locations
- 24
- Primary Endpoint
- Change from baseline in the percentage of monthly heavy drinking days (PHDD)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
Randomized, multi-center, double-blind, parallel-group, placebo-controlled study. Eligible subjects will be randomized to receive either 0.33 mg AD04 or placebo orally twice-daily for 24 weeks in conjunction with brief psychological counseling. Randomization will be stratified by:
- Level of alcohol consumption prior to enrollment in the study (heavy drinkers averaging <10 drinks per day of drinking or very heavy drinkers averaging ≥10 drinks per day of drinking), and
- Gender (male or female).
Detailed Description
Target enrollment of subjects with AUD who regularly engage in risk alcohol consumption (i.e. \>6/day or more heavy alcohol consumption in the 4 weeks preceding the screening visit), and have selected genotypes (LL/TT genotype and/or 1, 2 or 3 of the SNPs on the genes for the 5-HT3 receptor subunits: rs1150226-AG or rs1176713-GG in the gene that encodes the 5-HT3A receptor subunit, and rs17614942-AC in the gene that encodes the 5-HT3B receptor subunit), and who are eligible to participate in the study based on meeting the remaining study inclusion/exclusion criteria. Eligible subjects will be randomized to receive either 0.33 mg AD04 or placebo BID for 24 weeks. The trial will have a 16-week grace period to enable medication effects to be optimal for comparison with placebo. The grace period starts immediately after beginning of study drug treatment, in which consumption of alcohol is not counted as a failure. All primary and secondary efficacy endpoints will be assessed during the last 8 weeks of treatment (i.e. weeks 17-24). The primary measure of efficacy, incidence risk alcohol consumption, will be assessed over the last 8 weeks of treatment. The secondary measure of efficacy evaluating the incidence of risk alcohol consumption over the last 4 weeks of treatment, important because it has been used commonly to validate efficacy for regulatory agencies such as the European Medicines Agency, was also calculated. To enhance study feasibility, subjects will be evaluated every week during the first 8 weeks of treatment and every other week for the remaining 16 weeks of the treatment period.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The subject has signed the Informed Consent Form.
- •The subject has breath alcohol concentration (BAC) of 0.00% at the Screening and \< 0.02 % at the Baseline visit.
- •The subject has moderate to severe diagnosis of AUD as measured by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.
- •Males and females aged 18 and over.
- •Able to provide Timeline Follow-back Method (TLFB) alcohol consumption information for the 28-day period prior to Screening Visit.
- •A subject is eligible for participation in the study if he/she had:
- •≥6 HDDs (HDD is defined as a day with alcohol consumption of 60 g or more for males and 40 g or more for females) in the 4 weeks prior to the Baseline Visit,
- •an average alcohol consumption at the medium risk level (defined by the WHO "International guide for monitoring alcohol consumption and related harm" as \>40 grams of ethanol/day for males and \>20 grams of ethanol/day for females) for the 4 weeks prior to the Screening Visit,
- •≤14 consecutive abstinent days in the 4 weeks preceding the Screening Visit.
- •Willingness to provide a blood sample for DNA analysis at the Screening visit. The blood sample collected for DNA testing contains at least one of the following genotypes as measured by Adial's validated method:
Exclusion Criteria
- •Patients with withdrawal symptoms requiring additional medication for withdrawal. If present at Screening/Baseline Visit, subjects must complete a medically supervised detoxification program prior to being able to enroll in the study.
- •Subjects with diagnosis of any of the following concomitant psychiatric disorders: non-treated, unstable schizophrenia, bipolar disorder, other psychotic disorder during the lifetime of the subject. Recent (within last 12 months) diagnosis of a major depressive disorder, post traumatic stress disorder, panic disorder or eating disorders. Subjects with nicotine use disorder, phobic or other anxiety disorders (other than post-traumatic stress disorder or panic disorder) can be included.
- •The subject reports current or recent (within 8 weeks prior to Baseline Visit) treatment with antipsychotics or antidepressants medications, which can have an effect on serotonin receptor or transporter actions.
- •The subject has been treated with any investigational medicinal product within 30 days or 5 half-lives (whichever is longer) prior to the Baseline Visit.
- •The subject is currently participating or has recently (4 weeks prior to the Baseline Visit) participated in a treatment program for alcohol use disorders.
- •Any subject who has suicidal thoughts as evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS) (i.e., has any suicidal ideation of type 4 or 5 on the C-SSRS in the last month).
- •The subject has a clinically significant untreated and unstable illness, for example, hepatic or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, infectious, neoplastic, or metabolic disturbance.
- •The subject has clinically significant abnormal vital signs.
- •The subject has a clinically abnormal ECG at the Screening/Baseline Visit, clinically significant cardiovascular disease requiring regular or intensive clinical monitoring, a current history of arrhythmias, or a current or past history of clinically significant QT prolongation, including:
- •QTcF \> 450 ms (one ECG at screening and average of 3 12-lead measurements at baseline)
Arms & Interventions
Treatment Arm
AD04 (ondansetron)
Intervention: AD04 (ondansetron)
Treatment Arm
AD04 (ondansetron)
Intervention: Companion Diagnostic for Genetic Testing
Treatment Arm
AD04 (ondansetron)
Intervention: Brief Psychological Counseling
Placebo Arm
Matching Placebo
Intervention: Matching placebo
Placebo Arm
Matching Placebo
Intervention: Companion Diagnostic for Genetic Testing
Placebo Arm
Matching Placebo
Intervention: Brief Psychological Counseling
Outcomes
Primary Outcomes
Change from baseline in the percentage of monthly heavy drinking days (PHDD)
Time Frame: Weeks 16 to 24
Change from baseline in the percentage of monthly HDDs, where (heavy) drinking is defined as the consumption of ≥ 60 g alcohol/day (if male) or ≥ 40 g alcohol/day (if female).
Secondary Outcomes
- Change from baseline in the primary efficacy endpoint at each study month(Weeks 4, 8, 12, 16, 20, and 24)
- Change from baseline in Drinking Risk Levels (DRL), 2-level shift(Week 24)
- Change from baseline in the Patient Health Questionnaire-9 (PHQ-9)(Week 24)
- Change from baseline in percent reduction in monthly total alcohol consumption (TAC)(Weeks 20 to 24)
- Change from baseline in the percent of non-drinking days (PNDD)(Weeks 16 to 24)
- Change from baseline in Drinking Risk Levels (DRL), 1-level shift(Week 24)
- Change from baseline in total alcohol consumption (TAC)(Weeks 16 to 24)
- Change from baseline in AUD symptoms and clinical status(Weeks 12 and 24)
- Change from baseline in risk alcohol consumption responders(Weeks 16 to 24)
- Change from baseline in drinks per drinking day (DDD)(Weeks 16 to 24)