Abstract
Abstract
Background
Trials of pharmacotherapies targeting cognition in schizophrenia have produced mainly negative results, and there are no approved cognition-enhancing pharmacological treatments available for patients with schizophrenia. This may be due in part to varying levels of concurrent cognitive stimulation, particularly for pharmacotherapies targeting neuroplasticity, which is activity-dependent (i.e. responds to cognitive demand). Often, the surroundings and environment of patients with schizophrenia provide only a low level of cognitive demand. At-home computerized cognitive training (CCT) can be one way to increase the level of environmental cognitive stimulation for these patients.
BI 425809, a glycine transporter 1 inhibitor, increases glycine in the synaptic cleft and thus should lead to improved glutamatergic neurotransmission, synaptic neuroplasticity, and cognition. We describe a large randomized multicenter trial conducted across several countries that aims to explore whether enhanced cognitive stimulation through at-home CCT combined with BI 425809 pharmacotherapy could significantly improve cognition in patients with schizophrenia.
Methods
This double-blind, parallel group trial plans to recruit patients with schizophrenia on stable antipsychotic therapy, across approximately 40 centers in 7 countries. We plan to randomize 200 patients who are compliant with CCT during a 2-week run-in period in a 1:1 ratio to either BI 425809 or placebo once daily for 12 weeks. The at home CCT should be optimally performed across 3–5 sessions (approximately 2.5 hours in total) per week. The primary endpoint will be change from baseline in neurocognitive function, measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 12 weeks of treatment. The neurocognitive composite score was selected specifically because it excludes the social cognition domain, which is typically targeted by separate training procedures. Novel exploratory endpoints include the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) to assess skills for daily functioning and the Balloon Effort task to assess the role of motivation in cognitive performance and also in patients’ willingness to comply with at-home CCT. Scores from the Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS), which is being developed to assess patients’ subjective experiences of cognitive impairment in schizophrenia, will also be assessed in a subset of patients.
Results
Initiation of the trial is planned for February 2019 and the last patient out is planned for December 2020. Results are expected in early 2021.
Discussion
This trial is critical to the field for several reasons. Firstly, the results will show if there is an enhanced benefit to combining pharmacotherapy with increased cognitive stimulation through at-home CCT in patients with schizophrenia. Second, the trial will evaluate the impact of BI 425809 with adjunctive CCT on outcomes relating to patients’ daily functioning, including the novel virtual reality test, VRFCAT. Third, the role of motivation in cognition, CCT compliance, and CCT performance will be explored. Finally, this trial will demonstrate if at-home CCT can be effectively implemented in a large trial across many centers and several countries. One key strength of this trial is the relatively large sample size which should result in robust data.
Funding: Boehringer Ingelheim International GmbH (1346.38)
