A Phase 3 Randomized Precision Medicine Clinical Trial Using Low-Dose Ondansetron (a 5-HT3 Antagonist) to Treat Alcohol Use Disorder

Abstract Genetic predisposition may determine treatment response in alcohol use disorder (AUD). This 6-month, double-blind, randomized trial assessed ondansetron (0.33 mg twice daily; AD04) in genotype-specific AUD subjects stratified by drinking endophenotype (<10 (‘heavy’) or ≥10 (‘severe’) drinks per drinking day). In heavy drinkers, at study end (Month 6), the least-squares (LS) mean change in percentage of heavy drinking days from baseline was 8.5% greater with AD04 vs. placebo treatment (LS mean (standard deviation): -46.7% (2.7%) vs. -38.1% (2.9%); p<0.03), with a non-significant effect (LS mean difference: 7.0%, p=0.07) for Months 5 and 6 combined. AD04 vs. placebo treatment increased quality of life (odds ratio=3.4, 95% Confidence Interval: 1.03-11.45; p=0.04) and reduced AUD symptoms (mild symptoms: 33% vs. 39%; severe symptoms: 10% vs. 24%; p=0.05). AD04 had a similar adverse events profile to placebo. ADO4 showed promise as a precision medicine treatment for genotype-specific heavy drinkers.