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

Phase 3

Completed

Conditions: Schizophrenia

Interventions: Drug: Placebo
Drug: Bitopertin
Drug: Antipsychotics

Registration Number: NCT01192880

Lead Sponsor: Hoffmann-La Roche

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 625

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bitopertin 10 mg + Antipsychotics	Antipsychotics	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.
Placebo	Antipsychotics	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.
Bitopertin 20 mg + Antipsychotics	Antipsychotics	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.
Placebo	Placebo	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.
Bitopertin 10 mg + Antipsychotics	Bitopertin	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.
Bitopertin 20 mg + Antipsychotics	Bitopertin	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Mean Change from Baseline in the PANSS Total Score at Week 24	Baseline, Week 24
Mean Change from Baseline in the PANSS Subscale Scores at Week 24	Baseline, Week 24
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 Factor Scores at Week 24	Baseline, Week 24
Percentage of Participants with Response, as Assessed by CGI-I Overall and Negative Symptoms Rating Score	Week 24
Percentage of Participants With Response, as Assessed by PANSS Negative Symptom Factor 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

Trial Locations

Locations (103): Clinical Innovtions Inc
🇺🇸
Costa Mesa, California, United States
Synergy Clinical Research of Escondido
🇺🇸
Escondido, California, United States
San Fernando Mental Health Center
🇺🇸
Granada Hills, California, United States
University of California San Diego
🇺🇸
La Jolla, California, United States
Excell Research
🇺🇸
Oceanside, California, United States
Artemis Institute for Clinical Research, LLC
🇺🇸
San Diego, California, United States
Collaborative Neuroscience Network Inc.
🇺🇸
Torrance, California, United States
Behavioral Clinical Research Inc.
🇺🇸
Lauderhill, Florida, United States
University of Miami Miller School of Medicine
🇺🇸
Miami, Florida, United States
Medical Research Group of Central Florida
🇺🇸
Orange City, Florida, United States
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Clinical Innovtions Inc
🇺🇸Costa Mesa, California, United States