Abstract
Background: Attenuated psychosis syndrome (APS) represents a patient subgroup (often adolescents), who exhibit motor, emotional, cognitive, and behavioral alterations between those of healthy individuals and those with psychotic disorders. There is no approved pharmacologic treatment for prevention of first episode psychosis (FEP) in this population. BI 409306, a potent and selective phosphodiesterase-9 inhibitor that may improve N-methyl-D-aspartic acid (NMDA) signaling, is in development for early intervention in APS. Methods: We describe the design of a 52-week proof-of-concept study to investigate the efficacy, safety, and tolerability of BI 409306 vs placebo in patients with APS (BI study 1289.32). Results: This will be a multinational, multicenter, double-blind, parallel-group study. Eligible patients with APS (determined by the Structured Interview for Prodromal Syndromes [SIPS]) will be 16–30 years of age, with a screening risk profile based on the North American Prodrome Longitudinal Study (NAPLS) algorithm [1] indicative of >35% risk of conversion to psychosis within the next 52 weeks. In total, 300 patients are planned for randomization (1:1) to oral BI 409306 or placebo for 52 weeks, with a 4-week follow-up. The primary endpoint will be time to FEP, assessed by positive symptoms (Scale of Prodromal Symptoms [SOPS] criteria) in the psychotic range. Secondary endpoints include change from baseline on the Schizophrenia Cognition Rating Scale (SCoRS) total and the composite score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 24 and 52 weeks of treatment. Change from baseline in Positive and Negative Syndrome Scale (PANSS) scores (positive and negative item scores and total score), Clinical Global Impressions-Severity (CGI-S) scale score, and Patient Global Impressions-Improvements (PGI-I) score will also be assessed after 52 weeks of treatment. Functional measures of brain plasticity (electroencephalography, event-related potentials, and visual-evoked potentials) will be assessed as potential biomarkers to predict treatment response and conversion to psychosis. A novel methodology using speech analyses will also be performed, exploring prediction of psychosis risk. Safety will be assessed based on physical examination, vital signs, laboratory tests, electrocardiogram, suicidality, extrapyramidal symptoms, and adverse events. Conclusion: This will be one of the first studies to test a novel drug mechanism, with the statistical power to detect a significant treatment effect vs placebo, for prevention of FEP in APS. Recruitment is planned to start in Q2 2017. The results will determine whether early intervention with BI 409306 provides clinical benefits in patients with APS. Funding: Boehringer Ingelheim (BI study 1289.32). 1. Cannon T, et al. Arch Gen Psychiatry 2008;65:28–37