S27. EFFICACY, SAFETY, AND PHARMACOKINETICS OF BI 425809 ONCE DAILY IN PATIENTS WITH SCHIZOPHRENIA: METHODOLOGY OF A RANDOMIZED TRIAL

Abstract

Background: Cognitive impairment is a core feature of schizophrenia and a major determinant of poor functional outcome, but no pharmacological treatment is currently approved for this aspect of the disease. N‐methyl‐Daspartate (NMDA) receptor hypofunction is known to be associated with cognitive impairment in schizophrenia. BI 425809 is a novel glycine transporter (GlyT1) inhibitor that increases the concentration of the NMDA receptor co‐activator glycine in the synaptic cleft and may therefore lead to improvement of negative and cognitive symptoms in patients with schizophrenia. This study aims to provide proof of clinical concept and dosefinding data for BI 425809, and to assess the safety and pharmacokinetics of BI 425809. Methods: This double‐blind, parallel‐group, phase II study aims to recruit patients with schizophrenia on stable antipsychotic therapy, across approximately 80 trial centers in 11 countries. It is planned that 504 patients will be randomized 1:1:1:1:2 to oral BI 425809 (2, 5, 10, and 25 mg) once daily or placebo for 12 weeks. The primary endpoint is change from baseline in cognitive function as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite score after 12 weeks of treatment. The change from baseline in the Schizophrenia Cognition Rating Scale (SCoRS) is being used to assess daily functioning at Week 12 as a secondary endpoint. The study also includes a number of novel exploratory endpoints (to be assessed only at US sites; 155 randomized patients planned), including the change from baseline in the Balloon Effort task scores at Week 12. As motivational deficits are considered a negative symptom of schizophrenia, this computerized task will assess the patient's willingness to exert effort and as such, the role of motivation in schizophrenia. The Probabilistic Reversal Learning task, which assesses executive function, is also used to evaluate change from baseline in cognitive function at Week 12. In this task, patients choose between two stimuli (one commonly and one rarely rewarded). Once the patient learns which is the more frequently rewarded stimulus, the reward contingencies reverse, and the patient must modify their value representations through feedback. Scores from the Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS), a new patient‐centric assessment tool to evaluate patients' subjective experience of how bothersome they perceive cognitive impairment in schizophrenia to be, are also assessed. Results: The study is currently recruiting, with study completion expected in Q4 2019. As part of the poster presentation, an overview will be provided of the current study status, including details on screening failures. The completion rates on the novel exploratory endpoints will be discussed, along with the experience of using these tools and collecting these data as part of a large multi‐country, multi‐center study. Discussion: This study will allow analysis of the effects of glutamatergic modulation with BI 425809 on cognitive impairment in schizophrenia, a core feature of the schizophrenia symptomatology. In addition to the traditional endpoints that assess cognition and functioning, we also evaluate novel clinical trial endpoints of motivation and value representation.