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

Abstract

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).

Cognitive dysfunction in schizophrenia: An expert group paper on the current state of the art

“…However, a comprehensive meta-analysis ( Sinkeviciute et al, 2018 ) assessing the efficacy of pharmacological cognitive enhancers in schizophrenia, showed only limited positive effects and lack of evidence on the longer term. Many of these studies were poorly designed ( Harvey and Sand, 2017 ) and better studies, including combining cognitive training and cognitive enhancement therapies, are in process ( Harvey et al, 2020 ).…”

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

“…Regarding bitopertin, preclinical studies showed its ability to modulate both glutamatergic and dopaminergic signaling, enhance hippocampal LTP [ 377 ], and improve performance in PFC-dependent tasks [ 384 ], thus mitigating schizophrenia-like behaviors. Early clinical studies pointed to the efficacy of adjunctive bitopertin in treating negative symptoms [ 355 , 384 ], although an inverted U-shaped dose–response profile emerged, leading to inconsistent results when bitopertin was administered at high doses (=60 mg).…”

“…Regarding bitopertin, preclinical studies showed its ability to modulate both glutamatergic and dopaminergic signaling, enhance hippocampal LTP [ 377 ], and improve performance in PFC-dependent tasks [ 384 ], thus mitigating schizophrenia-like behaviors. Early clinical studies pointed to the efficacy of adjunctive bitopertin in treating negative symptoms [ 355 , 384 ], although an inverted U-shaped dose–response profile emerged, leading to inconsistent results when bitopertin was administered at high doses (=60 mg). These results were paralleled, at the preclinical level, by the observations that, at higher concentrations, bitopertin did not affect LTP induction processes, probably as a result of internalization of the NMDAR following an excessive release of glycine [ 327 ].…”

“…BI 425809 was well tolerated in healthy volunteers as well as in patients [ 358 , 385 ]. A randomized trial combining BI 425809 with computerized cognitive training has been recently planned in order to consolidate the results obtained on cognitive functions [ 384 ].…”

Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

“…A recent randomized doubleblind, placebo-controlled phase II study revealed that BI 425809 improved cognitive functions after 12 weeks in patients with schizophrenia (215), suggesting that BI 425809 can provide an effective treatment for cognitive impairment associated with schizophrenia. Currently, another phase II trial of BI 425809 combined with computerized cognitive training for schizophrenic patients is in progress (214,227). Further largescale phase III clinical trials will be necessary to replicate these encouraging findings and to confirm the therapeutic potential of BI 425809 for the treatment of cognitive deficits in schizophrenia.…”