A randomized, double‐blind, placebo‐controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder

Abstract

Background: In a previous study, ondansetron, a serotonin 5-HT 3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT 3A (HTR3A), and 5-HT 3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. Methods:In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment.Results: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intentto-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no studyrelated serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. Conclusions:We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

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

“…These positive observations replicated our previous ndings (Phase 2a clinical study) wherein low-dose ondansetron was shown to be e cacious at reducing various markers of alcohol consumption in early-onset (but not late-onset) AUD 27 , and among the same speci c genotypes 38 . Other studies have found similar directional results 24,27,34,35,38 except for a recent study 51 , which may have failed because of insu cient statistical power, failure to choose the correct drinking characteristic endophenotype, and the nonstandardized use of the psychosocial intervention (BBCET), with a possible related in ation of the placebo response (Johnson BA, Addolorato G, Lesch O, Liu L, Rodd ZA. A critical scienti c evaluation of a purportedly negative data report -response to…”

“…Combining the strati cation of subjects by level of alcohol consumption and genotype results in speci c essential factors. We have learned that studying for genetic markers within subgroups requires a study of ample sample size, a criterion if not ful lled can lead to equivocal or possibly false-negative results 51 . We feel that this report is a veri cation of the need to have proper statistical power (sample size) to conduct accurate precision medicine clinical research.…”

Medications for treating alcohol use disorder: A narrative review

“…A 16-week RCT (N = 95 individuals with AUD, including 58 of European and 37 of African ancestry) sought to replicate and extend these findings (Seneviratne et al, 2022) by comparing low-dose ondansetron (0.33 mg twice daily) or placebo. To assess pharmacogenetic effects, the sample was stratified into "responsive" and "nonresponsive" genotype groups using population-specific variation at genes encoding the serotonin transporter and the serotonin-3A and serotonin-3B receptors.…”

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

“…Combining the strati cation of subjects by level of alcohol consumption and genotype results in speci c essential factors. We have learned that studying for genetic markers within subgroups requires a study of ample sample size, a criterion that which not ful lled can lead to equivocal or possibly false negative results 57 . We feel that this report is a veri cation of the need to have proper statistical power (sample size) to conduct accurate precision medicine clinical research.…”