A Study to Evaluate the Effects of Basmisanil in Participants With Cognitive Impairment Associated With Schizophrenia (CIAS) Treated With Antipsychotics

Study Overview
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Brief Summary
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This multicenter study assessed the effects of 24 weeks of basmisanil treatment on cognition and functioning of stable schizophrenia participants treated with antipsychotics.

Official Title
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A Phase IIb, Multicenter, Randomized, Double-Blind, Parallel Group, Placebo Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Basmisanil (RO5186582) as Adjunctive Treatment in Patients With Cognitive Impairment Associated With Schizophrenia Treated With Antipsychotics

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Basmisanil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of schizophrenia of any type utilizing the Mini International Neuropsychiatric Interview and diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) direct clinical assessments, family informants and past medical records Evidence of stability of symptoms for 3 months at screening, that is, without hospitalizations for schizophrenia or increase in level of psychiatric care due to worsening of symptoms of schizophrenia Participants with schizophrenia clinical symptom severity defined by the following: hallucinatory behavior item score less than or equal to (</=) 5 and a delusion item score </= 5 of the PANSS Participants on a stable regimen of antipsychotic therapy for at least 3 months at screening and receiving no more than two antipsychotics Exclusion Criteria: Participants with current DSM-5 diagnosis other than schizophrenia including bipolar disorder, schizoaffective disorder and major depressive disorder Clinically significant neurological illness or significant head trauma that affects cognitive function, in the judgment of the principal investigator Full scale intelligence quotient </=65 on the Wechsler Abbreviated Scale of Intelligence at screening Positive result at screening for hepatitis B, hepatitis C, or human immunodeficiency virus-1 and 2 Moderate to severe substance use disorder (other than nicotine or caffeine), as defined by the DSM-5, within the last 12 months Suicide attempt within 1 year or currently at risk of suicide in the opinion of the Investigator

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received matching Placebo to Basmisanil orally twice daily for 24 weeks. | Drug: Placebo<br>* Participants received matching Placebo to Basmisanil, as per the dosing schedules described above.<br>|
| Experimental: Basmisanil 80mg BID<br>Participants received Basmisanil 80 mg orally twice daily (BID) for 24 weeks. | Drug: Basmisanil<br>* Participants received either 80 milligrams (mg) or 240 mg of Basmisanil, as per the dosing schedules described above.<br>|
| Experimental: Basmisanil 240mg BID<br>Participants received Basmisanil 240 mg orally twice daily (BID) for 24 weeks. | Drug: Basmisanil<br>* Participants received either 80 milligrams (mg) or 240 mg of Basmisanil, as per the dosing schedules described above.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in MATRICS Consensus Cognitive Battery (MCCB) Neurocognitive Composite Score | The MCCB is a cognitive battery to assess 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, reasoning and problem solving). The MCCB neurocognitive composite T-score is a standardized mean of the six domain scores (excluding social cognition). Raw scores are converted to age and sex adjusted t-scores which are standardized to normative data, and have a mean of 50 and standard deviation of 10 in the general healthy population. A higher composite T-score represents lower impairment. | Baseline up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in MCCB Cognitive Domain Scores | The MCCB is a cognitive battery to assess 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, reasoning and problem solving). Raw scores are converted to age and sex adjusted t-scores which are standardized to normative data, and have a mean of 50 and standard deviation of 10 in the general healthy population. A higher T-score represents lower impairment. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Wechsler Memory Scale Fourth Edition, Verbal Paired Associates (WMS IV-PAL) Score | The Paired Associates Learning (PAL I and II) of the WMS-IV (Wechsler Memory Scale Fourth edition) is a test of verbal learning and memory that requires the participant to learn novel word pairs. The participant learns the word pairs across learning trials and is asked to recall them immediately (PAL I) or after a 30-minute delay (PAL II). Data is presented here for 3 Scores: VPA I total raw score, VPA II total raw score and VPA II Recognition total raw score. The total raw score ranges for these 3 Scores are 0 to 56, 0 to 14 and 0 to 40 respectively, with larger total raw scores indicating better performance. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Wechsler Memory Scale Fourth Edition, Logical Memory Test (WMS IV-LM) Score | Logical memory (LM) assesses narrative memory under free-recall conditions. Two short stories are presented orally. The examinee is asked to retell each story from memory immediately after hearing it (LM I). In the delayed condition (LM II), the examinee is asked to retell both stories from the immediate condition (delayed free recall). Data is presented here for 2 Scores: LM I total raw score and LM II total raw score. The total raw score range is from 0 to 50 with larger total raw scores indicating better performance. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Ratio Between Trail Making Test (TMT)- Part B and TMT- Part A Scores | The TMT consists of two parts: Trail Making Part A, which is a part of the standard MCCB and Trail Making Part B additionally included in this study. Circles containing numbers (Part A) or both numbers and letters (Part B) must be sequentially connected. The difference (ratio) in performance between Part A and Part B reflects executive processes and will be used to assess executive functioning including cognitive set shifting abilities and data for this ratio is presented here. Smaller ratio values, hence decreases from baseline (TMT-B/TMT-A ratio values below 1) indicate higher executive functioning capabilities. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Personal and Social Performance (PSP) Total Score | The PSP Total Score is an integer result in the range of 0 to 100. Larger values, hence increases from baseline in the PSP total score, indicate higher social and personal functioning. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Schizophrenia Cognition Rating Scale (SCoRS) Total Score | The main parameter of interest for the Schizophrenia Cognition Rating Scale (SCoRS) is the SCoRS 'Total Score'. The total score range is from 0 to 80 with lower scores indicating better day-to-day functioning. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Clinical Global Impression Severity (CGI-S) Rating | Values for the CGI-S Scale are encoded by the numerical values from 1 to 7 respectively. Higher numerical values represent greater impairment. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Clinical Global Impression Improvement (CGI-I) Rating | Values for the CGI-I Scale are encoded by the numerical values from 1 to 7 respectively. Higher numerical values represent greater impairment. | Baseline up to Week 24 | 
| Change From Baseline to Week 24 in Schizophrenia Quality of Life Scale (SQLS) | The SQLS is a patient reported scale consisting of 33 items: 2 domain scores (Cognition & Vitality Score [SQLS-CV] and Psycho-social Score [SQLS-P]) as well as a Total score (SQLS-T) are derived. The overall score range is from 0 to 100. On all scales, higher scores represent a lower quality of life. | Baseline up to Week 24 | 
| Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events. | Baseline up to 4 weeks after the last dose of study drug (up to 28 weeks) | 
| Apparent Clearance of Basmisanil at Steady State (CL/F,ss) | Population PK model estimated apparent oral clearance of Basmisanil at steady-state. | Pre-dose (hour 0) in Days 7, 14, 42, 84, 168 | 
| Apparent Volume of Distribution of Basmisanil at Steady State (Vz/F,ss) | Population PK model estimated apparent volume of distribution of Basmisanil at steady-state. | Pre-dose (hour 0) in Days 7, 14, 42, 84, 168 | 
| Area Under the Curve of Basmisanil at Steady State (AUC,ss) | Population PK model estimated AUC of Basmisanil at steady-state. | Pre-dose (hour 0) in Days 7, 14, 42, 84, 168 | 
| Maximum Plasma Concentration of Basmisanil at Steady State (Cmax,ss) | Population PK model estimated maximum plasma concentration of Basmisanil at steady-state (ss). | Pre-dose (hour 0) in Days 7, 14, 42, 84, 168 |