A Prospective Precision Medicine Phase 3 Clinical Trial of Low-dose Ondansetron (a 5-ht3 Antagonist) to Treat Heavy and Very Heavy Drinkers With Alcohol Use Disorder

Abstract This 6-month, double-blind, randomized, Phase-3 clinical trial in Alcohol Use Disorder (AUD; n = 303) tested ondansetron 0.33 mg/twice daily (AD04) vs placebo in reducing the Percentage of Heavy Drinking Days (PHDD) among a genetic subgroup with variations at the serotonin transporter and 5-HT3A/5-HT-3B receptors who consumed < 10 Standard Drinks/Drinking Day (DDD) (heavy drinkers) or ≥ 10 DDD (very heavy drinkers). At Month 6, the least square (LS) mean change in PHDD from baseline was 8.5% greater in the heavy drinkers AD04 group compared with placebo (LS mean (SD): -46.7% (2.7%), 95%CI: -52.1% to -41.2% vs. -38.1% (2.9%), 95%CI: -43.8% to -32.5%; p = 0.03) with lower effect (LS mean difference: 7.0%, p = 0.07) for Months 5 and 6 combined. At Month 6, for the total AD04 group compared with the placebo group, heavy drinkers had a better quality of life (OR = 3.4, 95% CI: 1.03–11.45, p = 0.04), fewer AUD symptoms (Mild: AD04 group 33% vs. placebo group 39%; Severe: AD04 group 10% vs. placebo group 24%) (p = 0.05), and similar adverse event profiles. No treatment-related effects differentiated AD04 and placebo in very heavy drinkers. This study showed AD04’s promise as a precision medicine treatment for heavy drinkers with a specific genetic profile.