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Clinical Trial
. 2017 Apr;42(5):1012-1023.
doi: 10.1038/npp.2016.214. Epub 2016 Sep 23.

A Phase 2, Double-Blind, Placebo-Controlled Randomized Trial Assessing the Efficacy of ABT-436, a Novel V1b Receptor Antagonist, for Alcohol Dependence

Megan L Ryan  1 , Daniel E Falk  1 , Joanne B Fertig  1 , Beatrice Rendenbach-Mueller  2 , David A Katz  2 , Katherine A Tracy  2 , Eric C Strain  3 , Kelly E Dunn  3 , Kyle Kampman  4 , Elizabeth Mahoney  4 , Domenic A Ciraulo  5 , Laurie Sickles-Colaneri  5 , Nassima Ait-Daoud  6 , Bankole A Johnson  6 , Janet Ransom  7 , Charles Scott  7 , George F Koob  1 , Raye Z Litten  1
Affiliations
Clinical Trial

A Phase 2, Double-Blind, Placebo-Controlled Randomized Trial Assessing the Efficacy of ABT-436, a Novel V1b Receptor Antagonist, for Alcohol Dependence

Megan L Ryan et al. Neuropsychopharmacology. 2017 Apr.

Abstract

Alcohol use disorder has been linked to dysregulation of the brain stress systems, producing a negative emotional state leading to chronic relapsing behavior. Vasopressin receptors appear to have a regulatory role in stress, anxiety, and alcohol. This study evaluated the novel compound, ABT-436, a V1b receptor antagonist, in alcohol-dependent participants in a 12-week clinical trial. Men and women (n=150) who met criteria for DSM-IV alcohol dependence were recruited across four sites. Participants received double-blind ABT-436 or placebo, and a computerized behavioral intervention. ABT-436 was titrated to 800 mg/day during weeks 2-12. Although the primary outcome, percentage of heavy drinking days, was lower in participants receiving ABT-436 compared with placebo, this difference was not statistically significant (31.3 vs 37.6, respectively; p=0.172; d=0.20). However, participants receiving ABT-436 had significantly greater percentage of days abstinent than those receiving placebo (51.2 vs 41.6, respectively; p=0.037; d=0.31). No significant differences were found between treatment groups on any other measures of drinking, alcohol craving, or alcohol-related consequences. Smokers receiving ABT-436 smoked significantly fewer cigarettes per week than those receiving placebo (p=0.046). ABT-436 was well tolerated, with diarrhea (mild-to-moderate severity) being the most common side effect. In subgroup analyses, participants with relatively higher baseline levels of stress responded better to ABT-436 than placebo on select drinking outcomes, suggesting there may be value in testing medications targeting the vasopressin receptor in high stress, alcohol-dependent patients.

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Figures

Figure 1
Figure 1
(a) Percent heavy drinking days and (b) Percent days abstinent. Means are LSMEANS obtained during the maintenance period (weeks 2–12) from a mixed model that includes treatment group, week, site, alcohol treatment goal, trait anxiety score, years drinking regularly, change in drinks per day between the screening and randomization, baseline equivalent of the outcome, and treatment group by week interaction. Error bars are standard errors. *p<0.05; †p<0.07.
Figure 2
Figure 2
(a) POMS tension-anxiety score. Treatment group by tension (POMS) interaction, p=0.152. (b) State trait anxiety inventory (STAI) score. Treatment group by STAI interaction, p=0.309. (c) Peak cortisol level (from ACTH stimulation test). Treatment group by peak cortisol interaction, p=0.676. (d) Drinks per day. Treatment group by drinks per day interaction, p=0.735. (e) Gender. Treatment group by gender interaction, p=0.543.
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