Efficacy and Safety of the Glycine Transporter-1 Inhibitor Org 25935 for the Prevention of Relapse in Alcohol-Dependent Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

Background: Org 25935 is a glycine transporter inhibitor that increases extracellular glycine levels and attenuates alcohol-induced dopaminergic activity in the nucleus accumbens. In animal models, Org 25935 has dose-dependent effects on ethanol intake, preference, and relapse-like behavior without tolerance. The current study aimed to translate these animal findings to humans by examining whether Org 25935 prevents relapse in detoxified alcohol-dependent patients. Methods: This was a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult patients diagnosed with alcohol dependence were randomly assigned to receive Org 25935 12 mg twice a day or placebo for 84 days. The primary end point was percentage heavy drinking days (defined as >= 5 standard drinks per day for men and >= 4 for women). Secondary end points included other measures of relapse-related drinking behavior (e. g., drinks per day, time to relapse), as well as measures of global functioning, alcohol-related thoughts and cravings, and motivation. Results: A total of 140 subjects were included in the intent-to-treat analysis. The trial was stopped approximately midway after a futility analysis showing that the likelihood of detecting a signal at study term was <40%. There was no significant difference between Org 25935 and placebo on percentage heavy drinking days or any other measure of relapse-related drinking behavior. Org 25935 showed no safety issues and was fairly well tolerated, with fatigue, dizziness, and transient visual events as the most commonly occurring side effects. Conclusions: Org 25935 demonstrated no benefit over placebo in preventing alcohol relapse. Study limitations and implications are discussed.