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

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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Bitopertin; Drug: Antipsychotics; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 625
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Bourgas, Bulgaria, 8000
    • DDPDS Prof Dr Ivan Temkov EOOD
  • Kazanlak, Bulgaria, 6100
    • MHAT Dr.Hristo Stambolski EOOD; Psychiatry Ward of Acute Psychotic Disiorders in Severe Stage
  • Novi Iskar, Bulgaria, 1282
    • State Psychiatric Hospital Sv. Ivan Rilski Novi Iskar; First Man Dept. and First Woman Dept.
  • Pazardzhik, Bulgaria, 4400
    • State Psychiatric Hospital - Pazardzhik AD; Department for active treatment of men and for women
  • Plovdiv, Bulgaria, 4002
    • UMHAT Dr Georgi Stranski; EAD; Psychiatry
  • Radnevo, Bulgaria, 6260
    • State Psychiatric Hospital Dr. G. Kissiov; 3-d Women Ward 1-st Men Ward
  • Rousse, Bulgaria, 7003
    • DDPDIU-Ruse; Men acute department Women acute department
  • Sofia, Bulgaria, 1606
    • Military Medical Academy- MHAT
• China
  • Baoding, China, 071000
    • Hebei Mental Health Centre
  • Beijing, China, 071000
    • Beijing Huilongguan Hospital; Department of Psychiatric
  • Beijing, China, 100083
    • Peking University Sixth Hospital; Department of Psychiatry
  • Beijing, China, 100088
    • Beijing An Ding Hosp.Capital Medical University; 5th Clinical Dept Depression Centre
  • Changsha, China, 410011
    • The Second Xiangya Hospital of Central South University
  • Chengdu, China, 610041
    • West China Hospital, Sichuan University
  • GuangzhouGuangdong, China, 510370
    • Guangzhou Brain Hospital
  • Hangzhou, China, 310009
    • The Second Affiliated Hospital of Zhejiang University College
  • Hangzhou, China, 310003
    • The First Affiliated Hospital of College of Medicine, Zhejiang University(First Hospital of Zhejiang
  • Kunming, China, 650032
    • The First Affilliated Hospital of Kunming Medical College
  • Nanjing, China, 210029
    • Nanjing Brain Hospital
  • Shanghai, China, 200030
    • Shanghai Mental Health Center
  • Shanghai, China, 200065
    • Tongji Hospital of Tongji University
  • Wuhan, China, 430060
    • Renmin Hospital of Wuhan University
  • Wuxi, China, 214151
    • Wuxi mental health center
  • Xi'an, China, 710061
    • First Affiliated Hospital of Medical College of Xi'an Jiaotong University
  • Xi'an, China, 710061
    • Xi'an Mental Health Center
  • Xi'an, China, 710032
    • The First Affiliated Hospital of The Fourth Military Medical University (Xijing Hospital)
• Czech Republic
  • Brno, Czech Republic, 602 00
    • Saint Anne s.r.o.
  • Liberec, Czech Republic, 460 63
    • Krajska nemocnice Liberec a.s.
  • Melnik, Czech Republic, 276 01
    • Psychiatricka ambulance
  • Plzen, Czech Republic, 312 00
    • A-shine s.r.o.
  • Praha 10, Czech Republic, 100 00
    • Clintrial,s.r.o.
  • Praha 6, Czech Republic, 160 00
    • Medical Services Prague s.r.o.
  • Praha 8 - Bohnice, Czech Republic, 181 03
    • Psychiatricke Centrum Praha
  • Sternberk, Czech Republic, 785 01
    • CTCenter MaVe s.r.o.
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Azienda Ospedaliera Universitaria Federico Ii
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • Asst Degli Spedali Civili Di Brescia; Servizio di farmacia
    • Milano, Lombardia, Italy, 20122
      • Clinica Mangiagalli
    • Milano, Lombardia, Italy, 20124
      • ASST FATEBENEFRATELLI SACCO; Psichiatria (Fatebenefratelli)
  • Piemonte
    • Torino, Piemonte, Italy, 10126
      • Azienda Ospedaliero Universitaria Molinette San Giovanni Bat
  • Puglia
    • Bari, Puglia, Italy, 70124
      • Azienda Ospedaliero-Universitaria Consorziale Pol. di Bari; Neuroscienze e Organi di Senso
  • Toscana
    • Pisa, Toscana, Italy, 56126
      • A.O. Universitaria Pisana; Psichiatria
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Azienda Ospedaliera di Padova
• Japan
  • Chiba, Japan, 272-8516
    • Kohnodai Hp., National Center for Global Health and Medicine
  • Funabashi-shi, Japan, 273-8540
    • Fukkokai Soubu Hospital
  • Gunma, Japan, 370-2455
    • Daiwakai Seimou Hospital
  • Hiroshima-shi, Japan, 733-0864
    • Koseikai Kusatsu Hospital
  • Hokkaido, Japan, 060-8648
    • Hokkaido University Hospital
  • Kanzaki-gun, Japan, 842-0192
    • NHO Hizen Psychiatric Medical Center
  • Kita-Ku, Japan, 114-0024
    • Sankeikai Nishigahara Hospital
  • Kitakyushu-shi, Japan, 807-8556
    • Hospital of the University of Occupational and Environmental Health,Japan
  • Kochi-shi, Japan, 780-8535
    • Jinseikai Hosogi Unity Hospital
  • Koshi-shi, Japan, 861-1116
    • NHO Kikuchi National Hospital
  • Kumamoto-shi, Japan, 861-8002
    • Yuge Hospital
  • Kurayoshi-shi, Japan, 682-0023
    • Jinkokai Kurayoshi Hospital
  • Nagoya-Shi, Japan, 463-0802
    • NHO Higashiowari Hospital
  • Omuta-shi, Japan, 836-0004
    • Shinkokai Shiranui Hospital
  • Sakai-shi, Japan, 590-0018
    • Asakayama General Hospital
  • Sapporo-shi, Japan, 004-0841
    • Tonankai Ashirbetsu Hospital
  • Sapporo-shi, Japan, 006-0816
    • Sawayamakai Teine Hospital
  • Sendai-shi, Japan, 983-0836
    • Tohoku Seishin Hokenkai Aoba Hospital
  • Shirakawa-shi, Japan, 961-0021
    • Jisenkai Nanko Psychiatric Institute
  • Tokyo, Japan, 162-8666
    • Tokyo Women's Medical University Hospital
  • Tokyo, Japan, 187-8551
    • National Center Of Neurology And Psychiatry Hospital
  • Toyama-shi, Japan, 939-8073
    • Korenkai Minamitoyama Nakagawa Hospital
  • Toyoake-shi, Japan, 470-1192
    • Fujita Health University Hospital
  • Yokohama-shi, Japan, 223-0062
    • Deep Intention Hiyoshi Hospital
  • Yokohama-shi, Japan, 233-0006
    • Kanagawa Prefectural Psychiatric Center Kinko Hospital
  • Yokohama-shi, Japan, 246-0026
    • Yokohama Aihara Hospital
• Russian Federation
  • Kemerovo, Russian Federation, 650036
    • Kemerovo Regional Clinical Psychiatric Hospital
  • Lipetsk, Russian Federation, 399313
    • GUZ Lipetsk Regional psychoneurological Hospital #1; Dispansary Department
  • Moscow, Russian Federation, 115522
    • Institution of RAMS (Mental Health Research Center of RAMS); Psychopharmacology laboratory
  • Moscow, Russian Federation, 127083
    • Central Moscow Regional Clinical Psychiatric Hospital
  • Sartatov, Russian Federation, 410028
    • MHI City Clinical Hospital #2 named after V.I. Razumovsky; Psychiatric
  • St. Petersburg, Russian Federation, 190121
    • City Psychiatric Hospital #2 of St. Nikolay Chudotvorets
  • St. Petersburg, Russian Federation, 192019
    • StP SR Psychoneurological Institute n.a.V.M.Bekhterev of MoH
  • Talagi, Russian Federation, 163530
    • Arkhangelsk Regional Clinical Psychiatric Hospital
• United States
  • California
    • Costa Mesa, California, United States, 92626
      • Clinical Innovtions Inc
    • Escondido, California, United States, 92025
      • Synergy Clinical Research of Escondido
    • Granada Hills, California, United States, 91344
      • San Fernando Mental Health Center
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Oceanside, California, United States, 92056
      • Excell Research
    • San Diego, California, United States, 92103
      • Artemis Institute for Clinical Research, LLC
    • Torrance, California, United States, 90502
      • Collaborative Neuroscience Network Inc.
  • Florida
    • Lauderhill, Florida, United States, 33319
      • Behavioral Clinical Research Inc.
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Orange City, Florida, United States, 3273
      • Medical Research Group of Central Florida
    • Plantation, Florida, United States, 33317
      • Berma Research Group
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Center for Medical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46222
      • Indiana University; LaRue Carter Memorial Hospital-Research Unit
  • Maryland
    • Glen Burnie, Maryland, United States, 21061
      • Clinical Insights, Inc.
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Precise Research Centers
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Altea Research Institute
  • New Jersey
    • Toms River, New Jersey, United States, 08775
      • Ocean Rheumatology
  • New York
    • Buffalo, New York, United States, 14215
      • State University of New York at Buffalo; Department of Psychiatry
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute; Psychiatry Dept of Columbia University
    • Rochester, New York, United States, 14618
      • Finger Lakes Clinical Research
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Pennsylvania
    • Norristown, Pennsylvania, United States, 19403
      • Keystone Clinical Studies, LLC
    • Scranton, Pennsylvania, United States, 18503
      • Scranton Medical Institutes Llc.
  • Texas
    • Austin, Texas, United States, 78754
      • Community Clinical Research Inc.
    • Irving, Texas, United States, 75062
      • University Hills Clinical Research
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Lifetree Clinical Research
  • Washington
    • Kirkland, Washington, United States, 98033
      • Eastside Therapeutic Resource

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bitopertin 10 mg + 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.	Drug: Bitopertin; Participants will receive 10 mg or 20 mg of bitopertin.; Other Names: RO4917838; Drug: Antipsychotics; Participants will continue to receive their stable antipsychotic regiment throughout the study. Study protocol does not specify any particular antipsychotic drug and regimen.
Experimental: Bitopertin 20 mg + 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.	Drug: Bitopertin; Participants will receive 10 mg or 20 mg of bitopertin.; Other Names: RO4917838; Drug: Antipsychotics; Participants will continue to receive their stable antipsychotic regiment throughout the study. Study protocol does not specify any particular antipsychotic drug and regimen.
Placebo Comparator: 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.	Drug: Antipsychotics; Participants will continue to receive their stable antipsychotic regiment throughout the study. Study protocol does not specify any particular antipsychotic drug and regimen.; Drug: Placebo; Participants will receive bitopertin matching placebo once daily for 56 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Georgiades A, Davis VG, Atkins AS, Khan A, Walker TW, Loebel A, Haig G, Hilt DC, Dunayevich E, Umbricht D, Sand M, Keefe RSE. Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients. Schizophr Res. 2017 Dec;190:172-179. doi: 10.1016/j.schres.2017.03.040. Epub 2017 Apr 20.
• Bugarski-Kirola D, Blaettler T, Arango C, Fleischhacker WW, Garibaldi G, Wang A, Dixon M, Bressan RA, Nasrallah H, Lawrie S, Napieralski J, Ochi-Lohmann T, Reid C, Marder SR. Bitopertin in Negative Symptoms of Schizophrenia-Results From the Phase III FlashLyte and DayLyte Studies. Biol Psychiatry. 2017 Jul 1;82(1):8-16. doi: 10.1016/j.biopsych.2016.11.014. Epub 2016 Dec 15.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: August 30, 2010
• First Submitted That Met QC Criteria: August 30, 2010
• First Posted (Estimate): September 1, 2010

Study Record Updates

• Last Update Posted (Actual): February 15, 2017
• Last Update Submitted That Met QC Criteria: February 14, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Antipsychotic Agents
• Other Study ID Numbers: WN25308; 2010-020470-42