Clinical Trial of BI 425809 Effect on Cognition and Functional Capacity in Schizophrenia

Study Overview
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Brief Summary
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The objective of the study is to investigate the efficacy, safety and pharmacokinetics of four different doses of BI 425809 once daily compared to placebo given for 12 weeks in patients with schizophrenia on stable antipsychotic treatment.

Official Title
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A Phase II Randomised, Double-blinded, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of 4 Oral Doses of BI 425809 Once Daily Over 12 Week Treatment Period in Patients With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: BI 425809 dose 1
* Drug: BI 425809 dose 2
* Drug: BI 425809 dose 3
* Drug: BI 425809 dose 4
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Men or women who are 18-50 years (inclusive) of age at time of consent Established schizophrenia with the following clinical features: Outpatient, with no hospitalization for worsening of schizophrenia within 3 months prior to randomisation Medically stable over the prior 4 weeks and psychiatrically stable without symptom exacerbation within 3 months prior to randomisation patients who have no more than a moderate severe rating on the Positive and Negative Symptom Scale (PANSS) positive items P1, P3-P7 and no more than a moderate rating on the PANSS positive item P2 Current antipsychotic and concomitant psychotropic medications as assessed at Visit 1 must meet the criteria below: patients may have up to 2 antipsychotics (typical and/or atypical) patients must be maintained on current typical and/or atypical antipsychotics other than Clozapine and on current dose for at least 4 weeks prior to randomisation and/or maintained on current long acting injectable antipsychotics and current dose for at least 3 months prior to randomization patients must be maintained on current concomitant psychotropic medications, anticholinergics, antiepileptics and/or lithium for at least 3 months prior to randomisation and on current dose for at least 4 weeks prior to randomisation Women of child-bearing potential must be ready and able to use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly. Patients must exhibit reliability, physiologic capability, and an educational level sufficient to comply with all protocol procedures, in the investigator´s opinion Patients must have an identified informant who will be consistent throughout the study. Further inclusion criteria apply Exclusion criteria: Patients who have a categorical diagnosis of another current major psychiatric disorder Diseases of the central nervous system that may impact cognitive test performance Movement disorder not currently controlled Patients receiving another investigational drug or procedure within 30 days or 6 half-lives (whichever is longer) or recent participation in another trial with any cognitive enhancing therapy Recent participation in formal cognitive remediation program Recent electroconvulsive therapy Patients who have been on BI 409306, encenicline or other investigational drug testing effects on cognition in schizophrenia within the last 6 months prior to randomisation or who have previously been on bitopertin Participation in a clinical trial with repeated Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) assessments within the last 6 months Patients who required change in ongoing stable benzodiazepine or sleep medication regimen within the last 4 weeks prior to randomisation Treatment with Clozapine within 6 months prior to randomisation Treatment with medical devices (e.g. Transcranial Magnetic Stimulation (TMS), neurofeedback) for any psychiatric condition within the last 3 months prior to randomisation Patients taking strong or moderate Cytochrome P450 (CYPA4) inhibitors or inducers within the last 30 days prior to randomization Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior) prior to randomisation Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-SSRS) in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent) prior to randomisation Known history of Human Immunodeficiency Virus (HIV) infection and/or a positive result for ongoing Hepatitis B or C infection on the Visit 1 central lab report Hemoglobin less than 120 g/L (12g/dL) in men or 115 g/L (11.5 g/dL) in women History of hemoglobinopathy such as thalassemia major or sickle-cell anemia Women who are pregnant, nursing, or who plan to become pregnant while in the trial or men who are able to father a child, unwilling to be abstinent or use adequate contraception for the duration of the study participation and for at least 28 days after treatment has ended Significant history of drug abuse disorder (including alcohol) within the last 6 months prior to informed consent or a positive urine drug screen at screening (except for Benzodiazepines taken according to prescription and as an ongoing, stable regimen) Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 425809 dose 1<br> | Drug: BI 425809 dose 1<br> <br> Drug: Placebo<br> <br> |
| Experimental: BI 425809 dose 2<br> | Drug: BI 425809 dose 2<br> <br> Drug: Placebo<br> <br> |
| Experimental: BI 425809 dose 3<br> | Drug: BI 425809 dose 3<br> <br> Drug: Placebo<br> <br> |
| Experimental: BI 425809 dose 4<br> | Drug: BI 425809 dose 4<br> <br> Drug: Placebo<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Cognitive Function as Measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Overall Composite T-score After 12 Weeks of Treatment | MCCB overall composite T-score was derived from scores of 7 cognitive domains (Speed of Processing, Verbal Learning, Working Memory, Reasoning and Problem Solving, Visual Learning, Social Cognition, Attention) obtained from a total of 10 tests (Trail Making, Brief Assessment of Cognition in Schizophrenia, Hopkins Verbal Learning, Wechsler Memory Scale, Letter-Number Span, Neuropsychological Assessment Battery, Brief Visuospatial Memory, Category Fluency, Mayer-Salovey-Caruso Emotional Intelligence, Continuous Performance) and ranges typically between -20 and +99, a larger T-score indicates better cognition. Change from baseline in MCCB overall composite T-score after 12 weeks of treatment was modeled using a MMRM with fixed, categorical factors of treatment at each visit, and continuous factors of baseline at each visit, using visit (week 6 and week 12 of treatment) as repeated measures, subject as random effect, adjusted mean (standard error) after 12 weeks of treatment is reported. | Baseline, after 6 and 12 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Total Score After 12 Weeks of Treatment | SCoRS total score was derived as the sum of non-missing responses from 20 interview-based items rated by an interviewer on a 4-point scale. A response of not available to an item was treated as missing. If six or more of the 20 items were missing for a participant at a visit, then the corresponding SCoRS total score was missing for that participant at the visit. If five or less of the 20 items were missing for a participant at a visit, then the item(s) with missing value(s) were imputed first with the average of the non-missing item values, then the SCoRS total score for the participant at the visit was derived as the sum of non-missing item values and the imputed item values. SCoRS total score is between 20 and 80 where higher score values represent greater degree of impairment in day-to-day functions due to cognitive deficits. Analysis of covariance model was fitted to calculate adjusted mean and standard error, model details in the Statistical Analysis section. | Baseline and after 12 weeks of treatment | 
| Percentage of Participants With Any Adverse Event | Percentage of participants with any Adverse Event. | On-treatment period, that is, from first intake of any trial drug until the last intake of any trial drug (planned: 84 days) + residual effect period (11 days), up to 103 days |