Olanzapine Plus Samidorphan (ALKS 3831) in Schizophrenia and Comorbid Alcohol Use Disorder: A Phase 2, Randomized Clinical Trial

Objective: Alcohol use disorder (AUD) is a common comorbidity of schizophrenia. No effective pharmacologic treatment is available for both disorders to date.

Methods: In a phase 2, double-blind study, patients with schizophrenia and AUD experiencing ≥ 10 drinking and ≥ 2 heavy-drinking days in the previous month and recent (≤ 6 mo) disease symptom exacerbation were recruited between June 2014 and March 2017. DSM-IV-TR and DSM-5 criteria were used to assign the diagnoses of schizophrenia and AUD, respectively. After a 6-week lead-in period, 234 eligible patients were randomized (1:1) to olanzapine + 10 mg samidorphan tablets (OLZ/SAM) or olanzapine + placebo tablets (olanzapine) for 36-60 weeks of treatment. The primary outcome of time to the first event of exacerbation of disease symptoms (EEDS) was evaluated using the log rank test for treatment comparison, and the Cox proportional-hazards model was used to estimate hazard ratio. Safety was assessed as adverse events and laboratory measures.

Results: No significant difference was observed between groups in the time to first EEDS (hazard ratio = 0.91; 95% CI, 0.53-1.56; P = .746). Patients treated with OLZ/SAM vs olanzapine had numerically lower rates in 6 of 8 criteria to evaluate EEDS. Change from baseline in percentage of heavy-drinking days during the double-blind treatment period was similar in OLZ/SAM- vs olanzapine-treated patients. OLZ/SAM was generally well tolerated with a safety profile similar to olanzapine.

Conclusions: OLZ/SAM was not superior to olanzapine in the time to EEDS and was well tolerated in patients with schizophrenia and AUD. Further research is needed to identify effective treatments for this difficult-to-treat population.

Trial Registrations: ClinicalTrials.gov identifier: NCT02161718; EudraCT number: 2014-001211-39 ‘ ‹