21. Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Study

Abstract

Background: Currently approved antipsychotics have not demonstrated efficacy in cognitive impairment associated with schizophrenia (CIAS). This study evaluated the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase 9 (PDE9) inhibitor, in patients with CIAS. Methods: This was a Phase II, multicenter, double-blind, placebo-controlled, parallel-group study. Patients (18–55 years) with a diagnosis of schizophrenia, maintained on stable doses of antipsychotics, were randomized (2:1:1:1:1) to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks (4-week follow-up). A novel, exploratory ‘learn-and-confirm’, 2-stage adaptive design was adopted. In Stage 1 (learn), meaningful cognitive endpoints were identified in an unblinded interim analysis of 8 Cambridge Neuropsychological Test Automated Battery (CANTAB) measurements (n = 120; change from baseline, analysis of covariance). In Stage 2 (confirm) the CANTAB endpoints differentiating between BI 409306 and placebo were to be tested. If no CANTAB endpoints were selected, the primary endpoint was change from baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at Week 12. The primary endpoint(s) and an a priori hypothesis testing order were prespecified before Stage 2 database lock and unblinding. Change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) at Week 12 was a key secondary endpoint. Safety endpoints included adverse events (AEs), AEs of special interest (AESI), disease state worsening (Positive and Negative Syndrome Scale; PANSS), and Columbia Suicidal Severity Rating Scale (C-SSRS) score. Results: A total of 516 patients were randomized and treated; 421 (81.6%) completed. The majority (69.8%) of patients were male, of mean age 42.3 years. No endpoints were identified for CANTAB in Stage 1; thus, MCCB was the prespecified primary endpoint. Adjusted mean change from baseline in MCCB composite score at Week 12 ranged from 1.2 to 2.8. This was not statistically significant for any dose group vs placebo. Adjusted mean change from baseline in SCoRS was also not statistically significant vs placebo. AEs were reported in 204 (39.5%) patients overall and increased with BI 409306 dose (10 mg, 33.3%; 100 mg, 53.5%); the AE rate was 36.4% in the placebo group. Serious AEs occurred in 10 (1.9%) patients. No AESI were reported. No worsening psychopathology symptoms were observed in any group (PANSS). There were no reports of suicidal behavior. Conclusion: A novel methodology was adopted to investigate CIAS efficacy. The primary endpoint of improvement in cognition was not met. BI 409306 was well tolerated and demonstrated an acceptable safety profile. Funding: Boehringer Ingelheim (NCT02281773; BI study 1289.6)