A Study to Investigate the Efficacy, Safety and Tolerability of Four Different Doses of BI 409306 Compared to Placebo Given for 12 Weeks in Patients With Schizophrenia on Stable Antipsychotic Treatment.

Study Overview
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Brief Summary
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The objective of the study is to investigate the efficacy, safety and tolerability of four different doses of BI 409306 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 Study to Evaluate the Efficacy, Safety, and Tolerability of Four Orally Administrated Doses of BI 409306 During a 12-week Treatment Period in Patients With Schizophrenia on Stable Antipsychotic Treatment

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: BI 409306 100 mg QD
* Drug: BI 498306 50 mg QD
* Drug: Placebo
* Drug: BI 498306 25 mg QD
* Drug: BI 409306 10 mg QD


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with established diagnoses of schizophrenia (per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)) with the following clinical features: a) Clinically stable and are in the residual (non-acute) phase of their illness for at least 8 weeks b) Current antipsychotic and concomitant psychotropic medications must meet the criteria below: b)-1 Maintained on current atypical (second generation) antipsychotic medications (in any approved dosage form) other than Clozapine and on current dose for at least 8 weeks prior to randomisation, and/or b)-2 Maintained on current typical (first generation) antipsychotic medications and on current dose for at least 6 months, optionally combined with anticholinergics if treated with a stable dose for at least 6 months prior to randomisation, and/or b)-3 Maintained on current concomitant psychotropic medications other than anticholinergics, antiepileptics and lithium, and on current dose for at least 8 weeks prior to randomisation. Antiepileptics and lithium are allowed if initiated at least 6 months prior to randomisation. b)-4 Anticholinergics, antiepileptics and lithium have been washed out for at least 6 months prior to randomisation if the treatments that patients were using before entering the clinical trial are discontinued. c) Have no more than a moderate severity rating on hallucinations and delusions (Positive and Negative Syndrome Scale (PANSS)-positive syndrome Hallucinatory Behavior item score < =4 and Delusions item score < = 4) d) Have no more than a moderate severity rating on positive formal thought disorder (PANSS-positive syndrome Conceptual Disorganization item score < = 4) e) Have a minimal level of extrapyramidal symptoms (Simpson-Angus Scale total score < 6) and depressive symptoms (PANSS-general psychopathology syndrome Depression item score < = 4) Male or female patients age 18 to 55 years Patients must exhibit reliability, physiologic capability, and an educational level sufficient to comply with all protocol procedures,in the investigator's opinion. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and the local legislation. If the patient needs a legal representative, then this legal representative must give written informed consent as well. Patients must have an identified informant who will be consistent throughout the study. The informant must interact with the subject at least 2 times a week. Note: Informant ratings are needed for SCoRS global ratings at Randomisation Visit (Visit 2) and (early) End of Treatment Visit. In person informant ratings on the study visits are preferred whenever possible. However, if the informant is not available for in person ratings, telephone interview is acceptable. The informant must be available for a telephone interview at Visit 2 and (e)EOT Visit. Exclusion criteria: Patient treated with more than two antipsychotic medications (including more than two dosage forms) Patient's cognitive impairment severity compromises the validity of the cognitive outcome measures, in the clinical judgment of the investigator Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior) 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) In the judgment of the investigator, any clinically significant finding of the medical examination (including BP, PR and ECG) or laboratory value deviating from normal or any evidence of a clinically significant concomitant disease or any other clinical condition that would jeopardize a patient's safety while participating in the clinical trial History or diagnosis of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, hematological or hormonal disorders For female patients: Pre-menopausal women (last menstruation < =1 year prior to informed consent) who: are nursing or pregnant or are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial until 28 days after the last treatment administration, and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, vasectomized partner, transdermal patch, intra uterine devices/systems (IUDs/IUSs), combined estrogen-progestin oral contraceptives as well as implantable or injectable hormonal contraceptives. Complete sexual abstinence (if acceptable by local health authorities) is allowed when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Double barrier methods are permissible (if acceptable by local health authorities, note that this is not an acceptable method in EU countries). For male patients: Men who are able to father a child, unwilling to be abstinent or use adequate contraception for the duration of study participation and for at least 28 days after treatment has ended. Known history of HIV infection Diseases of the central nervous system (including but not limited to any kind of seizures, stroke or any psychiatric disorders other than schizophrenia) Any subject who on the Mini-international neuropsychiatric Interview (M.I.N.I.) has a categorical diagnosis of another current major psychiatric disorder. History of malignancy within the last 5 years, except for basal cell carcinoma Planned elective surgery requiring general anaesthesia, or hospitalisation for more than 1 day during the study period Significant history of drug dependence or abuse (including alcohol, as defined in DSM-5-substance use disorder or in the opinion of the investigator) within the last two years prior to informed consent, or a positive urine drug screen for cocaine, opioid, PCP, amphetamine, heroin, or marijuana at screening Patient needs to take long-acting hypnotics and anxiolytics (i.e. Diazepam) Patients taking medications that are known to be strong or moderate CYP3A4 inhibitors Participation in another trial with an investigational drug or procedure within 30 days or 6 half-lives (whichever is longer) or participation in another trial with any cognitive-enhancing therapy or procedure within 90 days prior to screening Previous participation in any BI 409306 study Not fluent in the language of the batteries/questionnaires which will be used in the country

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: dose 1<br> | Drug: BI 409306 10 mg QD<br> <br> |
| Experimental: dose 2<br> | Drug: BI 498306 25 mg QD<br> <br> |
| Experimental: dose 3<br> | Drug: BI 498306 50 mg QD<br> <br> |
| Experimental: dose 4<br> | Drug: BI 409306 100 mg QD<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 the Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) After 12 Weeks of Treatment | MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning problem solving, and social cognition. The composite score was calculated by summing over the standardised score of each domain for analysis and it varies from -20 to 99 with higher score indicating better outcome. The trial was set up as learn and confirm model including 2 stages. Stage 1 analysis was conducted to identify the meaningful cognition endpoint(s) (CANTAB domain(s)) and the selected endpoint(s) were to be pre-specified as the primary endpoint(s) for Stage 2 analysis. Since none of the CANTAB outcome measures was selected in the Stage 1 analysis at planned time based on the pre-specified criteria, the MCCB composite score was chosen as the primary endpoint in the Stage 2 analysis, as pre-defined. | Baseline and Week 12 | 
| Occurrence of Serious Adverse Events (SAEs) (Including the Abnormalities of Physical Examination, Vital Signs, Electrocardiogram (ECG) Test and Laboratory Tests) | Occurrence of serious adverse events (SAEs) (including the abnormalities of physical examination, vital signs, electrocardiogram (ECG) test and laboratory tests). | Up to 20 weeks | 
| Occurrence of Protocol-specified Adverse Events of Special Interest (AESI) | Occurrence of Protocol-specified adverse events of special interest (AESI). | Up to 20 weeks | 
| Dramatic Worsening of Disease State as Assessed by Positive and Negative Syndrome Scale (PANSS) | Dramatic worsening of disease state as assessed by Positive and Negative Syndrome Scale (PANSS). It contains 30-items including seven positive symptom items, seven negative symptom items and 16 general psychopathology symptom items. Each item was scored on the same seven point severity scale. Fourteen of the PANSS items required input from an informant. Total score ranges from 30 to 210 (minimum is better). The descriptive statistics of change from baseline (CFB) in PANSS score at week 6 (W6) and week 12 (W12) are presented. | Baseline, Week 6 and Week 12 | 
| Suicidality as Assessed by Columbia Suicidal Severity Rating Scale (C-SSRS) | C-SSRS: Number (%) of subjects with an event of Suicidal Ideation (Wish to be dead, Non-specific active suicidal thoughts, Active suicidal ideation with any methods (not plan) without intent to act, Active suicidal ideation with some intent to act without specific plan, Active suicidal ideation with specific plan and intent) or Suicidal Behavior (Preparatory acts or behavior, Aborted attempt, Interrupted attempt, Non-fatal suicide attempt, Completed suicide) or Self-injurious behavior without suicidal intent is presented. C-SSRS used only to evaluate whether the patient developed suicidal ideation or behavior and no composite score will be used. Questions in the 1st section of suicidal ideation and suicidal behavior assessments in C-SSRS are yes and no type questions. If patient had suicidal ideation or behavior, 2nd section will be performed to evaluate the details with the scale from 0 to 5 or 0 to 2 and the larger number means the more severe condition. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Global Ratings After 12 Weeks of Treatment | Change from baseline in everyday functional capacity as measured by Schizophrenia Cognition Rating Scale (SCoRS) global ratings after 12 weeks of treatment. SCoRS is a 20-item interview-based assessment of cognitive deficits and the degree to which they affect day-to-day functions. Each item was rated on a 4-point scale. Higher ratings reflected a greater degree of impairment. The SCoRS global total scores is the sum of the 20 items and it varies from 20 to 80 with 20 being the best outcome and 80 being the worst. If any individual item was missing, it was imputed with the average of that patient's non missing responses. If >5 items were missing, the total score was missing. | Baseline and Week 12 | 
| Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Scale Score After 12 Weeks of Treatment | Change from baseline in Clinical Global Impressions-Severity (CGI-S) scale score after 12 weeks of treatment. The CGI-S is a one-item evaluation completed by the clinician on the patient's severity of psychopathology. The CGI-S was rated ordinally from one to 7. Higher scores indicate more severe symptoms. | Baseline and Week 12 | 
| Patient Global Impressions-Improvement (PGI-I) Scale Score Measured After 12 Weeks of Treatment | Patient Global Impressions-Improvement (PGI-I) scale score measured after 12 weeks of treatment. The PGI of improvement is a simple evaluation completed by the patient to assess the patient's overall evaluation of his/her status. The PGI of improvement was rated ordinally from one to 7. Higher scores indicate more severe symptoms. | Up to 12 weeks | 
| Change From Baseline in PANSS Negative Symptom Factor Score After 12 Weeks of Treatment (for Subset of Patients Diagnosed With Negative Symptom) | Change from baseline in PANSS negative symptom factor score after 12 weeks of treatment (for subset of patients diagnosed with negative symptom). This outcome measure was not analysed due to low number of patients in the PANSS negative symptom subgroup. The PANSS negative symptom scale has 7 items. Each was rated from one to 7 points. The total factor score was the summation of the 7 points for each item, leading the total score ranging from 7 to 49. | Baseline and Week 12 | 
| Change in Psychopathology Symptoms as Assessed by Positive and Negative Syndrome Scale (PANSS) | Change in psychopathology symptoms as assessed by Positive and Negative Syndrome Scale (PANSS). It contains 30-items including seven positive symptom items, seven negative symptom items and 16 general psychopathology symptom items. Each item was scored on the same seven point severity scale. Fourteen of the PANSS items required input from an informant. Total score ranges from 30 to 210 (minimum is better). The descriptive statistics of change from baseline (CFB) in PANSS score at week 6 (W6) and week 12 (W12) are presented. | Baseline, Week 6 and Week 12 |