Evaluation of the Efficacy of BI 425809 Pharmacotherapy in Patients with Schizophrenia Receiving Computerized Cognitive Training: Methodology for a Double-blind, Randomized, Parallel-group Trial

BACKGROUND AND OBJECTIVE: Cognitive impairments associated with schizophrenia (CIAS) predict poor functional outcomes, but there are currently no approved pharmacological treatments for patients with CIAS. Additional cognitive stimulation may be required for pro-cognitive medications to improve efficacy, and computerized cognitive training (CCT) can be used to increase cognitive activity. A trial evaluating the effects of the novel glycine transporter inhibitor BI 425809 compared with placebo, on a background of regularly self-administered CCT in clinically stable patients with schizophrenia has commenced and its methodology is described here. METHODS: This Phase II, multinational, randomized, double-blind, placebo-controlled, parallel-group trial will randomize 200 clinically stable outpatients, aged 18-50 years with established schizophrenia and no other major psychiatric disorder, 1:1 to BI 425809 or placebo once daily for 12 weeks. Following screening, which included a 2-week CCT run-in period, patients sufficiently compliant with CCT (target: ≥ 2 h of CCT per week during CCT run-in) will be randomized. During the 12-week treatment period, all patients should complete a total of approximately 30 h of CCT. The primary endpoint is change from baseline in neurocognitive function as measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), after 12 weeks of treatment. Secondary endpoints include change from baseline in overall MCCB score, Schizophrenia Cognition Rating Scale, Positive and Negative Syndrome Scale, and safety (adverse events [AEs]) and serious AEs. Primary and secondary endpoints will be analyzed using the Restricted Maximum Likelihood-based mixed model for repeated measures. Novel endpoints include the Balloon Effort Task to evaluate patients' motivation and the Virtual Reality Functional Capacity Assessment Tool to assess skills for daily functioning. DISCUSSION: This is one of the largest and longest trials to date to combine pharmacological therapy with CCT in patients with schizophrenia and will determine the benefit of combining BI 425809 pharmacotherapy with cognitive stimulation through self-administered CCT. This trial will further evaluate whether improvements in neurocognition translate into improved everyday functioning, whether self-administered CCT can be effectively implemented in a large multinational trial, and the role of motivation in neurocognitive and functional improvements. TRIAL REGISTRATION: Registered on Clinicaltrials.gov on March 1, 2019 (NCT03859973).