Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials

Importance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. Objective: To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. Design, Setting, and Participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. Main Outcomes and Measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). Results: Across the 3 trials (N = 1169; mean SD age, 45 10 years; 824 70.5% men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% 100 of 288; varenicline, 7.3% 7 of 96; topiramate, 11.7% 21 of 179) followed by no heavy drinking days (naltrexone, 51.0% 147 of 288; varenicline, 24.0% 23 of 96; topiramate, 20.7% 37 of 179), WHO 2-level reduction (naltrexone, 75.0% 216 of 288; varenicline, 55.2% 53 of 96; topiramate, 44.7% 80 of 179), and WHO 1-level reduction (naltrexone, 83.3% 240 of 288; varenicline, 69.8 67 of 96; topiramate, 54.7% 98 of 179) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 95% CI, 0.053 -0.375; varenicline, 0.273 95% CI, -0.006 to 0.553; topiramate, 0.230 95% CI, 0.024-0.435) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 95% CI, -0.046 to 0.277; varenicline, 0.338 95% CI, 0.058-0.617; topiramate, 0.014 95% CI, -0.192 to 0.219) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 95% CI, -0.020 to 0.303; varenicline, 0.146 95% CI, -0.133 to 0.426; topiramate, 0.369 95% CI, 0.163-0.574) and no heavy drinking days (naltrexone, Cohen h = 0.140 95% CI, -0.021 to 0.302; varenicline, 0.232 95% CI, -0.048 to 0.511; topiramate, 0.207 95% CI, 0.002-0.413). Conclusions and Relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. Trial Registration: ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.