26 A Phase 3 Study to Determine the Antipsychotic Efficacy and Safety of ALKS 3831 in Adult Patients with Acute Exacerbation of Schizophrenia

Abstract

Background: ALKS 3831 is composed of a flexible dose of the antipsychotic olanzapine (OLZ) and a fixed dose of samidorphan (a mu‐opioid receptor antagonist) and is under development for the treatment of schizophrenia. ALKS 3831 has been studied in phase 1 (healthy volunteers) and phase 2 (stable schizophrenia) studies. In the phase 2 study, ALKS 3831 mitigated OLZ‐associated weight gain and exhibited an antipsychotic efficacy similar to OLZ. This phase 3 study aimed to assess antipsychotic efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia. Methods: This was a 4‐week, phase 3, randomized, doubleblind, active (OLZ monotherapy) and placebo‐controlled study of ALKS 3831 in patients experiencing acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Following screening, eligible patients (N=403) were randomized 1:1:1 to one of three groups: ALKS 3831, OLZ monotherapy, or placebo. Patients were treated in an inpatient setting for the first 2 weeks of the study period and could be treated as inpatients or outpatients for the remaining 2 weeks. Patients were excluded if they received OLZ within 6 months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression‐ Severity (CGI‐S), and CGI‐Improvement (CGI‐I) scales. The primary endpoint, change from baseline in PANSS total score at Week 4, was analyzed using a mixed model with repeated measurements (MMRM). The key secondary endpoint, change from baseline in CGI‐S at Week 4, was also analyzed by MMRM. PANSS response and CGI‐I response were analyzed by a logistic regression model. Additionally, safety and tolerability were assessed as adverse events (AEs) and were analyzed using descriptive statistics. Results: Of 401 patients randomized and dosed to ALKS 3831 (n =134), OLZ (n =133), and placebo (n =134), 91.0%, 88.7%, and 82.8% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6.0% in the ALKS 3831 group, 6.8% in the OLZ group, and 6.0% in the placebo group). Baseline characteristics were similar between groups: the mean age was 41 years and 61% were male. Baseline mean body mass index was higher in the OLZ group compared with the ALKS 3831 group. Baseline mean +/‐ standard deviation scores were 101.7 +/‐ 11.9 for PANSS total score and 5.1 +/‐ 0.7 for CGI‐S score. The mean OLZ dose was 18.4 mg/day in both active treatment arms. Least squares (LS) mean difference +/‐ standard error (SE) versus placebo from baseline to Week 4 in PANSS total score was ‐ 6.4 +/‐ 1.8 (P<0.001) and ‐ 5.3 +/‐ 1.8 (P= 0.004) for the ALKS 3831 and OLZ groups, respectively. LS mean difference +/‐ SE versus placebo from baseline to Week 4 in CGI‐S score was ‐ 0.38 +/‐ 0.12 (P =0.002) and ‐ 0.44 +/‐ 0.12 (P<0.001) for the ALKS 3831 and OLZ groups, respectively. The percentage of patients with an improvement in PANSS response (defined as >= 30% improvement from baseline) at Week 4 was 59.8%, 53.8%, and 38.3% in the ALKS 3831, OLZ, and placebo groups, respectively. The percentage of patients with an improvement in CGI‐I response (defined as score of =4%) included weight gain, somnolence, dry mouth, anxiety, headache, schizophrenia, and agitation. The number of patients in the two active treatment groups who experienced movement disorders was generally low (