A Study to Evaluate Efficacy and Safety of Bitopertin in Participants With Persistent, Predominant Negative Symptoms of Schizophrenia

Study Overview
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Brief Summary
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This Phase 3, multi-center, randomized, double blind, parallel-group, placebo-controlled study will evaluate the efficacy and safety of RO4917838 (bitopertin) in participants with persistent, predominant negative symptoms of schizophrenia. Participants, on stable treatment with antipsychotics, will be randomized to receive daily oral doses of RO4917838 or matching placebo for 52 weeks, followed by an optional treatment extension for up to 3 years.

Official Title
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A Phase III, Multi-Center, Randomized, 24 Week, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate Efficacy and Safety of RO4917838 in Stable Patients With Persistent, Predominant Negative Symptoms of Schizophrenia Treated With Antipsychotics Followed by a 28 Week, Double-Blind Treatment Period

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Placebo
* Drug: Bitopertin
* Drug: Antipsychotics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Based on the screening Structured Clinical Interview for and Statistical Manual of Mental Disorders, 4th Edition (DSM IV) - Clinical Trial (SCID CT), a DSM-IV- Text Revision (DSM-IV-TR) diagnosis of schizophrenia, paranoid, disorganized, residual, undifferentiated or catatonic subtype A score of 40 or greater on the sum of the 14 PANSS negative and disorganized thought factor items (items scored 1-7 for a maximum possible score of 98) A score of 22 or less on the sum of the 8 PANSS positive symptom factor items. The score of the items of P1 (delusions), P3 (hallucinatory behavior), P6 (suspiciousness) and G9 (unusual thought content) meet the following requirements: no more than 2 of the above items have a score of 4; all of the above items score less than 5 Clinical stability for 6 months prior to randomization as well as antipsychotic treatment stability for the past 8 weeks at the time of randomization Are at least moderately ill, as defined by Clinical Global Impression - Severity (CGI S) of negative symptoms score more than or equal to (>/=) 4 Stable doses of anticholinergic, antidepressive medication for at least 8 weeks prior to randomization is allowed as long as the respective scales cut-off entry criteria are met With the exception of clozapine, participants are on any of the available marketed atypical or typical antipsychotics (treatment with a maximum of 2 antipsychotics) Have a caregiver considered reliable by the investigator Female participants who are not either surgically sterile or post-menopausal must agree to use at least one effective forms of contraception from agree to remain sexually abstinent from screening until 90 days after the completion of the study medication Exclusion Criteria: Evidence that participant has clinically significant, uncontrolled and unstable disorder (for example, cardiovascular, renal, hepatic disorder) Body Mass Index (BMI) of less than (<) 17 or more than (>) 40 kilograms per meter square (kg/m^2) Depressive symptoms, defined as a score of 9 or greater on the Calgary Depression Rating Scale for Schizophrenia (CDSS) A severity score of >/=3 on the Parkinsonism item of the Extrapyramidal Symptoms Rating Scale - Abbreviated (ESRS-A) (Clinical Global Impression, Parkinsonism) Positive result on the serum pregnancy test or are breast feeding at screening, or intend to become pregnant during the course of the trial. History of neuroleptic malignant syndrome (NMS) Based on the DSM-IV-TR criteria and screening SCID-CT have: other current DSM-IV-TR Axis I diagnosis; alcohol or substance dependence within 12 months or abuse within 3 months with the exception of nicotine; dementia, delirium and other amnestic disorder per DSM-IV-TR Treated with electroconvulsive therapy (ECT) within 6 months prior to randomization Ever received RO4917838 or another glycine transporter 1 (GLYT 1) inhibitor Require high doses of benzodiazepines (> 4 mg per day lorazepam or equivalent) Have a positive urine drug screen for amphetamines (including 3,4-Methylenedioxymethamphetamine [MDMA]/ecstasy), cocaine, barbiturate, cannabis and/or opiates

Ages Eligible for Study
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Minimum Age: 18 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: Bitopertin 10 mg + Antipsychotics<br>Treatment Period 1: Participants will receive bitopertin 10 milligrams (mg) tablet orally once daily for 24 weeks. Treatment Period 2: Participants will receive bitopertin 10 mg tablet orally once daily for 28 weeks (up to Study Week 52). After Week 52 there will be a 4-week washout period for at least 50 percent (%) of participants (up to Week 56). Long-Term Extension: After Week 56, participants will enter the long term extension period and continue to receive bitopertin 10 mg tablet orally once daily up to 3 years. In addition, throughout the study, participants will continue their same stable antipsychotic treatment as they were receiving prior to entry in the study. | Drug: Bitopertin<br>* Participants will receive 10 mg or 20 mg of bitopertin.<br>* Other names: RO4917838;Drug: Antipsychotics<br>* Participants will continue to receive their stable antipsychotic regiment throughout the study. Study protocol does not specify any particular antipsychotic drug and regimen.<br>|
| Experimental: Bitopertin 20 mg + Antipsychotics<br>Treatment Period 1: Participants will receive bitopertin 20 mg tablet orally once daily for 24 weeks. Treatment Period 2: Participants will receive bitopertin 20 mg tablet orally once daily for 28 weeks (up to Study Week 52). After Week 52 there will be a 4-week washout period for at least 50% of participants (up to Week 56). Long-Term Extension: After Week 56, participants will enter the long term extension period and continue to receive bitopertin 20 mg tablet orally once daily up to 3 years. In addition, throughout the study, participants will continue their same stable antipsychotic treatment as they were receiving prior to entry in the study. | Drug: Bitopertin<br>* Participants will receive 10 mg or 20 mg of bitopertin.<br>* Other names: RO4917838;Drug: Antipsychotics<br>* Participants will continue to receive their stable antipsychotic regiment throughout the study. Study protocol does not specify any particular antipsychotic drug and regimen.<br>|
| Placebo Comparator: Placebo<br>Treatment Period 1: Participants will receive bitopertin matching placebo tablet orally once daily for 24 weeks. Treatment Period 2: Participants will receive bitopertin matching placebo tablet orally once daily for 32 weeks (up to Study Week 56). Long-Term Extension: After Week 56, participants will enter the long term extension period and will be switched to (in blinded manner) bitopertin 10 mg tablet orally once daily up to 3 years. In addition, throughout the study, participants will continue their same stable antipsychotic treatment as they were receiving prior to entry in the study. | Drug: Placebo<br>* Participants will receive bitopertin matching placebo once daily for 56 weeks.<br>Drug: Antipsychotics<br>* Participants will continue to receive their stable antipsychotic regiment throughout the study. Study protocol does not specify any particular antipsychotic drug and regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score at Week 24 |  | Baseline, Week 24 | 
| Percentage of Participants with Adverse Events |  | From baseline up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change from Baseline in the Personal and Social Performance (PSP) Total Score at Week 24 |  | Baseline, Week 24 | 
| Mean Change from Baseline in the PANSS Total Score at Week 24 |  | Baseline, Week 24 | 
| Mean Change from Baseline in the PANSS Factor Scores at Week 24 |  | Baseline, Week 24 | 
| Mean Change from Baseline in the PANSS Subscale Scores at Week 24 |  | Baseline, Week 24 | 
| Percentage of Participants With Response, as Assessed by PANSS Negative Symptom Factor Score |  | Week 24 | 
| Percentage of Participants with Response, as Assessed by CGI-I Overall and Negative Symptoms Rating Score |  | Week 24 | 
| Percentage of Participants with Both At Least 20% Improvement from Baseline in the PANSS Negative Symptom Factor Score and with a CGI-I Negative Symptoms Rating of Either Much or Very Much Improvement |  | Week 24 | 
| Mean Change from Baseline in the CGI-S Overall and Negative Symptoms Rating Score |  | Baseline, Week 24 |