Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials: A Secondary Analysis of 3 Randomized Clinical Trials

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr O’Malley has been a consultant or advisory board member for Alkermes, Amygdala, Cerecor, Hazelden Betty Ford Foundation, Indivior, Mitsubishi Tanabe, and Opiant, including nonfinancial support (eg, travel to advisory meetings); is a DSMB member for NIDA (Emmes Corporation); and has received study medications from Pfizer, Novartis, and AstraZeneca and grant funds from Lilly. Dr Anton previously was a consultant for Lundbeck, Indivior, Laboratorio Farmaceutico CT, and Alkermes; served on Advisory Boards for Alkermes, Indivior, and Lundbeck; and received grant funds from Lilly and Laboratorio Farmaceutico CT. Dr Kranzler has been a consultant, advisory board member, or continuing medical education lecturer for Alkermes, Lundbeck, and Indivior. Dr Mann received honoraria for consultancies with Pfizer, Novartis, and AbbVie, and speaker fees from Lundbeck. Dr Hasin is principal investigator for a study funded by inVentiv Health Consulting, which includes support from Actavis Inc, Endo Pharmaceuticals, Janssen Pharmaceuticals Inc, Mallinckrodt LLC, Pfizer Inc, Purdue Pharma LP, Rhodes Pharmaceuticals LP, Roxane Laboratories Inc, and Zogenix Inc. Drs O’Malley, Witkiewitz, Anton, Litten, Kranzler, Mann, Hasin, and Meulien are members of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE) Workgroup, which, while this article was being developed, was supported by AbbVie, Alkermes, Arbor, Amygdala, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. No other conflicts were reported.

Figures

Figure.. Treatment Effects (Cohen h) for Responder Outcomes by Treatment Month

Treatment effects in the naltrexone (A), varenicline (B), and topiramate (C) trials. In the varenicline trial, Cohen h = −0.401 for the month 1 abstinent outcome was truncated to −0.072 for graphic purposes. The negative Cohen h value was the result of a somewhat higher percentage of participants reporting abstinence in the placebo group than the varenicline group (4% vs 0%, respectively). In the varenicline and topiramate trials, estimates of Cohen h in month 3 do not match those in the last 4 weeks of treatment because they are using overlapping but somewhat different 28-day periods. In both trials, month 3 is study weeks 9 to 12; however, the last 4 weeks of treatment are study weeks 11 to 13 in the varenicline trial and study weeks 11 to 14 in the topiramate trial. WHO indicates World Health Organization.