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    Clinical Trial Results:
    A Phase III, multi-center, randomized, 12-week, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of RO4917838 in patients with sub-optimally controlled symptoms of schizophrenia treated with antipsychotics followed by a 40-week double-blind, parallel-group, placebo-controlled treatment period.

    Summary
    EudraCT number
    		 2010-020718-26
    Trial protocol
    		 CZ   IT   BG  
    Global end of trial date
    12 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2016
    First version publication date
    24 Jun 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WN25305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01235559
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a phase III, multi-center, randomized, 12-week, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of bitopertin (RO4917838) in participants with sub-optimally controlled symptoms of schizophrenia treated with anti-psychotics, followed by a 44-week double-blind, parallel-group, placebo-controlled treatment period (40-week treatment period followed by a 4-week washout period). The primary objectives of the study were to evaluate the efficacy after 12 weeks of treatment with bitopertin versus placebo, as adjunct to antipsychotics, in the Positive and Negative Syndrome Scale (PANSS) positive symptom factor score in participants with sub-optimally controlled symptoms of schizophrenia, and evaluate the safety and tolerability after 12 weeks of treatment with bitopertin versus placebo as adjunct to antipsychotics, in participants with sub-optimally controlled symptoms of schizophrenia.
    Protection of trial subjects
    The study was conducted in accordance with the principles of “Declaration of Helsinki” and Good Clinical Practice according to the regulations and procedures consistent with the protocol. Approval from the Institutional Review Board (IRB)/Ethics Committee (EC) was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval. An approval from the relevant regulatory authority was also obtained prior to the start of study. All the protocol amendments were submitted to the IRB/EC and to the regulatory authorities in accordance with the local regulatory requirements. A written informed consent was obtained from the participants and care givers prior to the participation in the study. All new safety information that resulted in significant changes in the risk/benefit assessment were reviewed and updated in the informed consent form, as necessary. Consent to the expanded pharmacokinetics (PK) assessments and long term extension period was also obtained from the participants and caregivers, as necessary.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 80
    Country: Number of subjects enrolled
    Czech Republic: 69
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    China: 182
    Country: Number of subjects enrolled
    Japan: 71
    Country: Number of subjects enrolled
    United States: 170
    Country: Number of subjects enrolled
    Russian Federation: 3
    Worldwide total number of subjects
    596
    EEA total number of subjects
    170
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    587
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study included 2 treatment periods, Treatment Period 1 (12-Week double blind treatment) and Treatment Period 2 (44-week double blind treatment), and Long Term Extension Period (for 3 years).

    Pre-assignment
    Screening details
    		 Out of 602 randomized participants, 2 were randomized to another bitopertin study first and not included in the safety population. A further 3 participants were randomized twice and only first randomization were analysed. One participant was randomized but not treated, and therefore, 596 participants were available in the safety population.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bitopertin 10 mg – Treatment Period 1
    Arm description
    		 Participants received bitopertin 10 milligrams (mg) oral tablet once a day (QD) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 10 mg oral tablet QD in the morning, with or without food for 12 weeks.

    Arm title
    		 Bitopertin 20 mg – Treatment Period 1
    Arm description
    		 Participants received bitopertin 20 mg oral tablet QD for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 20 mg oral tablet QD in the morning, with or without food for 12 weeks.

    Arm title
    		 Placebo – Treatment Period 1
    Arm description
    		 Participants received placebo-matched to bitopertin QD for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Biopterin oral tablet QD in the morning, with or without food for 12 weeks.

    Number of subjects in period 1
    		Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Started
    198
    199
    199
    Completed
    165
    173
    177
    Not completed
    33
    26
    22
         Consent withdrawn by subject
    9
    7
    1
         Death
    2
    -
    -
         Administrative/other
    2
    4
    3
         Adverse event
    4
    2
    7
         Non−compliance
    7
    4
    2
         Lost to follow-up
    6
    6
    6
         Lack of efficacy
    2
    -
    -
         Protocol deviation
    1
    3
    3
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Bitopertin 10 mg – Treatment Period 2
    Arm description
    		 Participants received bitopertin 10 mg oral tablet QD for 40 weeks (from Week 13 to Week 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 10 mg oral tablet QD in the morning, with or without food for 40 weeks (from Week 13 to Week 52).

    Arm title
    		 Bitopertin 20 mg – Treatment Period 2
    Arm description
    		 Participants received bitopertin 20 mg oral tablet QD for 40 weeks (from Week 13 to Week 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 20 mg oral tablet QD in the morning, with or without food for 40 weeks.

    Arm title
    		 Placebo – Treatment Period 2
    Arm description
    		 Participants received placebo-matched to bitopertin QD for 40 weeks (from Week 13 to Week 52).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Biopterin oral tablet QD in the morning, with or without food for 40 weeks.

    Number of subjects in period 2
    		Bitopertin 10 mg – Treatment Period 2 Bitopertin 20 mg – Treatment Period 2 Placebo – Treatment Period 2
    Started
    165
    173
    177
    Completed
    110
    105
    111
    Not completed
    55
    68
    66
         Consent withdrawn by subject
    15
    10
    9
         Did not continue in Treatment Period 2
    2
    2
    3
         Death
    1
    -
    -
         Administrative/other
    22
    31
    25
         Adverse event
    7
    10
    9
         Non−compliance
    2
    3
    7
         Lost to follow-up
    4
    8
    6
         Lack of efficacy
    2
    2
    5
         Protocol deviation
    -
    2
    2
    Period 3
    Period 3 title
    Washout Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bitopertin 10 mg – Washout Period
    Arm description
    		 Participants received bitopertin 10 mg oral tablet QD for 4 weeks (Week 52 to Week 56).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 10 mg oral tablet QD in the morning, with or without food for 4 weeks (Week 52 to Week 56).

    Arm title
    		 Bitopertin 10 mg to Placebo – Washout Period
    Arm description
    		 Participants who received bitopertin 10 mg oral tablet QD during the treatment period 1 and 2 were switched to placebo for 4 weeks (Week 52 to Week 56).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Bitopertin 10 mg oral tablet QD in the morning, with or without food for 4 weeks.

    Arm title
    		 Bitopertin 20 mg – Washout Period
    Arm description
    		 Participants received bitopertin 20 mg oral tablet QD for 4 weeks (Week 52 to Week 56).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 20 mg oral tablet QD in the morning, with or without food for 4 weeks (Week 52 to Week 56).

    Arm title
    		 Bitopertin 20 mg to Placebo – Washout Period
    Arm description
    		 Participants who received bitopertin 20 mg oral tablet QD during the treatment period 1 and 2 were switched to placebo for 4 weeks (Week 52 to Week 56).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to bitopertin oral tablet QD in the morning, with or without food for 4 weeks (Week 52 to Week 56).

    Arm title
    		 Placebo – Washout Period
    Arm description
    		 Participants received placebo-matched to bitopertin QD for 4 weeks (Week 52 to Week 56).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Biopterin oral tablet QD in the morning, with or without food for 4 weeks.

    Number of subjects in period 3
    		Bitopertin 10 mg – Washout Period Bitopertin 10 mg to Placebo – Washout Period Bitopertin 20 mg – Washout Period Bitopertin 20 mg to Placebo – Washout Period Placebo – Washout Period
    Started
    56
    54
    53
    52
    110
    Completed
    54
    53
    49
    51
    107
    Not completed
    2
    1
    4
    1
    3
         Consent withdrawn by subject
    -
    -
    -
    -
    2
         Adverse event, non-fatal
    -
    -
    1
    1
    -
         Administrative/other
    1
    1
    1
    -
    1
         Lost to follow-up
    1
    -
    2
    -
    -
    Period 4
    Period 4 title
    Long-Term Extension
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Bitopertin 10 mg – Long-Term Extension
    Arm description
    		 Participants received bitopertin 10 mg oral tablet once a day (QD) for 3 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 10 mg oral tablet QD in the morning, with or without food for 3 years.

    Arm title
    		 Bitopertin 20 mg – Long-Term Extension
    Arm description
    		 Participants received bitopertin 20 mg oral tablet QD for 3 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 20 mg oral tablet QD in the morning, with or without food for 3 years.

    Arm title
    		 Placebo to Biopterin 10 mg – Long-Term Extension
    Arm description
    		 Participants received placebo-matched to bitopertin QD for 3 years.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Biopterin oral tablet QD in the morning, with or without food for 3 years.

    Number of subjects in period 4
    		Bitopertin 10 mg – Long-Term Extension Bitopertin 20 mg – Long-Term Extension Placebo to Biopterin 10 mg – Long-Term Extension
    Started
    95
    90
    94
    Completed
    0
    0
    0
    Not completed
    95
    90
    94
         Consent withdrawn by subject
    11
    5
    6
         Death
    -
    -
    1
         Administrative/other
    75
    77
    73
         Adverse event
    3
    2
    4
         Non−compliance
    3
    1
    4
         Lost to follow-up
    1
    3
    2
         Protocol deviation
    1
    1
    1
         Lack of efficacy
    1
    1
    3
    Period 5
    Period 5 title
    Safety Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Bitopertin 10 mg – Safety Follow-up
    Arm description
    		 Participants received bitopertin 10 mg oral tablet QD for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 10 mg oral tablet QD in the morning, with or without food for 4 weeks.

    Arm title
    		 Bitopertin 20 mg – Safety Follow-up
    Arm description
    		 Participants received bitopertin 20 mg oral tablet QD for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bitopertin 20 mg oral tablet QD in the morning, with or without food for 4 weeks.

    Arm title
    		 Placebo – Safety Follow-up
    Arm description
    		 Participants received placebo-matched to bitopertin QD for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Biopterin 10 or 20 mg oral tablet QD in the morning, with or without food for 4 weeks.

    Number of subjects in period 5
    		Bitopertin 10 mg – Safety Follow-up Bitopertin 20 mg – Safety Follow-up Placebo – Safety Follow-up
    Started
    292
    199
    105
    Completed
    218
    137
    63
    Not completed
    74
    62
    42
         Consent withdrawn by subject
    29
    17
    13
         Death
    4
    -
    -
         Administrative/other
    9
    12
    3
         Adverse event
    5
    4
    2
         Lost to follow-up
    27
    29
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bitopertin 10 mg – Treatment Period 1
    Reporting group description
    		 Participants received bitopertin 10 milligrams (mg) oral tablet once a day (QD) for 12 weeks.

    Reporting group title
    Bitopertin 20 mg – Treatment Period 1
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD for 12 weeks.

    Reporting group title
    Placebo – Treatment Period 1
    Reporting group description
    		 Participants received placebo-matched to bitopertin QD for 12 weeks.

    Reporting group values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1 Total
    Number of subjects
    		 198 199 199 596
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.2 ± 12.4 39.1 ± 12.2 39.7 ± 12.7 -
    Gender categorical
    Units: Subjects
        Female
    		 85 85 65 235
        Male
    		 113 114 134 361

    End points

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    End points reporting groups
    Reporting group title
    Bitopertin 10 mg – Treatment Period 1
    Reporting group description
    		 Participants received bitopertin 10 milligrams (mg) oral tablet once a day (QD) for 12 weeks.

    Reporting group title
    Bitopertin 20 mg – Treatment Period 1
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD for 12 weeks.

    Reporting group title
    Placebo – Treatment Period 1
    Reporting group description
    		 Participants received placebo-matched to bitopertin QD for 12 weeks.
    Reporting group title
    Bitopertin 10 mg – Treatment Period 2
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD for 40 weeks (from Week 13 to Week 52).

    Reporting group title
    Bitopertin 20 mg – Treatment Period 2
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD for 40 weeks (from Week 13 to Week 52).

    Reporting group title
    Placebo – Treatment Period 2
    Reporting group description
    		 Participants received placebo-matched to bitopertin QD for 40 weeks (from Week 13 to Week 52).
    Reporting group title
    Bitopertin 10 mg – Washout Period
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD for 4 weeks (Week 52 to Week 56).

    Reporting group title
    Bitopertin 10 mg to Placebo – Washout Period
    Reporting group description
    		 Participants who received bitopertin 10 mg oral tablet QD during the treatment period 1 and 2 were switched to placebo for 4 weeks (Week 52 to Week 56).

    Reporting group title
    Bitopertin 20 mg – Washout Period
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD for 4 weeks (Week 52 to Week 56).

    Reporting group title
    Bitopertin 20 mg to Placebo – Washout Period
    Reporting group description
    		 Participants who received bitopertin 20 mg oral tablet QD during the treatment period 1 and 2 were switched to placebo for 4 weeks (Week 52 to Week 56).

    Reporting group title
    Placebo – Washout Period
    Reporting group description
    		 Participants received placebo-matched to bitopertin QD for 4 weeks (Week 52 to Week 56).
    Reporting group title
    Bitopertin 10 mg – Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet once a day (QD) for 3 years.

    Reporting group title
    Bitopertin 20 mg – Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD for 3 years.

    Reporting group title
    Placebo to Biopterin 10 mg – Long-Term Extension
    Reporting group description
    		 Participants received placebo-matched to bitopertin QD for 3 years.
    Reporting group title
    Bitopertin 10 mg – Safety Follow-up
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD for 4 weeks.

    Reporting group title
    Bitopertin 20 mg – Safety Follow-up
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD for 4 weeks.

    Reporting group title
    Placebo – Safety Follow-up
    Reporting group description
    		 Participants received placebo-matched to bitopertin QD for 4 weeks.

    Primary: Change From Baseline in the PANSS Positive Symptom Factor Score (PSFS) at Week 12

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    End point title
    		 Change From Baseline in the PANSS Positive Symptom Factor Score (PSFS) at Week 12
    End point description
    PANSS was a 30-item scale designed to capture degree of severity for many symptoms in schizophrenia. Symptoms and each item of the PANSS was rated on a 7-point scale: 1=Absent; 2=Minimal; 3=Mild; 4=Moderate; 5=Moderately severe; 6=Severe; 7=Extreme. Further assessment of symptoms using a factor analysis of the PANSS were calculated for PSFS which consisted of the following items: Delusions [P1], Hallucinatory behaviour[P3], Grandiosity [P5], Suspiciousness [P6], Stereotyped thinking [N7], Somatic concern [G1], Unusual thought content [G9], Lack of judgment and insight [G12]. Scores were transformed to 0-6 points with higher scores indicating greater severity of symptoms and 0 as absent. If any item score contributing to the factor score was missing then the factor was set to missing. Intent-to-Treat (ITT) population: All randomized participants who received at least 1 dose of double-blind study medication and had at least 1 post-baseline assessment of the primary efficacy variable.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    190
    190
    189
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -5.14 (-5.78 to -4.5)
    -4.22 (-4.85 to -3.6)
    -3.77 (-4.4 to -3.14)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bitopertin 10 mg – Treatment Period 1 v Placebo – Treatment Period 1
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.27
         upper limit
    		 -0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.457
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo – Treatment Period 1 v Bitopertin 20 mg – Treatment Period 1
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3142
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.452

    Primary: Change From Baseline in the PANSS-PSFS at Week 12 - Complement factor H-related protein 1 (CFHR1)-High Subgroup

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    End point title
    		 Change From Baseline in the PANSS-PSFS at Week 12 - Complement factor H-related protein 1 (CFHR1)-High Subgroup
    End point description
    PANSS was a 30-item scale designed to capture degree of severity for many symptoms in schizophrenia. Symptoms and each item of the PANSS was rated on a 7-point scale: 1=Absent; 2=Minimal; 3=Mild; 4=Moderate; 5=Moderately severe; 6=Severe; 7=Extreme. Further assessment of symptoms using a factor analysis of the PANSS were calculated for PSFS which consisted of the following items: Delusions [P1], Hallucinatory behaviour[P3], Grandiosity [P5], Suspiciousness [P6], Stereotyped thinking [N7], Somatic concern [G1], Unusual thought content [G9], Lack of judgment and insight [G12]. Scores were transformed to 0-6 points with higher scores indicating greater severity of symptoms and 0 as absent. If any item score contributing to the factor score was missing then the factor was set to missing. ITT population(CFHR1-High Subgroup):All randomized participants who received at least 1 dose of double-blind study medication and had at least 1 post-baseline assessment of the primary efficacy variable.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    110
    127
    129
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -5.16 (-6 to -4.31)
    -3.64 (-4.42 to -2.86)
    -3.58 (-4.35 to -2.81)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bitopertin 10 mg – Treatment Period 1 v Placebo – Treatment Period 1
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0069
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.72
         upper limit
    		 -0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.581
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo – Treatment Period 1 v Bitopertin 20 mg – Treatment Period 1
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9099
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 1.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.558

    Secondary: Change From Baseline in the PANSS Total Score at Week 12

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    End point title
    		 Change From Baseline in the PANSS Total Score at Week 12
    End point description
    PANSS total score (sum of 30 items) assessed the positive symptoms (delusions, hallucination, grandiosity, suspiciousness, stereotyped thinking, somatic concern, unusual thought content, lack of judgment and insight), negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation, motor retardation, active social avoidance), general psychopathology (somatic concern, anxiety, guilt feelings, tension, mannerisms/posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment/insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Each item was rated on a 7 point scale (1=Absent; 2=Minimal; 3=Mild; 4=Moderate; 5=Moderately severe; 6=Severe; 7=Extreme). Total score ranged from 30 to 210; higher score indicated greater severity. ITT population were used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    190
    190
    189
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -14.44 (-16.14 to -12.74)
    -11.81 (-13.48 to -10.14)
    -11.65 (-13.32 to -9.98)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bitopertin 10 mg – Treatment Period 1 v Placebo – Treatment Period 1
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0217
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -2.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.17
         upper limit
    		 -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.213
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo – Treatment Period 1 v Bitopertin 20 mg – Treatment Period 1
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8954
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.52
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.202

    Secondary: Change From Baseline in the PANSS Negative, Positive, and Psychopathology Subscale Score at Week 12

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    End point title
    		 Change From Baseline in the PANSS Negative, Positive, and Psychopathology Subscale Score at Week 12
    End point description
    The PANSS was a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. PANSS subscales include (Negative subscale, positive subscale and generalized psychopathology). Negative and positive subscale score included 7-items each and generalized psychopathology included 16 items. Each item was rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total negative and positive scores = 1 to 7 each, with higher score indicating greater severity and total generalized psychopathology score = 1 to 16, higher score indicating greater severity. The study program was terminated early, after the primary endpoint since the primary endpoint was not reached at higher doses of bitopertin. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [1] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [2] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [3] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the PANSS Negative Symptom Factor Score at Week 12

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    End point title
    		 Change From Baseline in the PANSS Negative Symptom Factor Score at Week 12
    End point description
    The PANSS was a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. PANSS factor score included negative symptoms factor score (7-items), disorganized thought/cognition factor score (7-items), uncontrolled hostility/excitement factor score (4-items), and anxiety/depression factor score (4-items). Each item was rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total negative symptoms and disorganized thought/cognition factor scores = 1 to 7 each, with higher score indicating greater severity and total uncontrolled hostility/excitement and anxiety/depression factor score = 1 to 4 each, with higher score indicating greater severity. The study program was terminated early, after the primary endpoint since the primary endpoint was not reached at higher doses of bitopertin. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [4] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [5] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [6] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PANSS-PSFS

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    End point title
    		 Percentage of Participants With PANSS-PSFS
    End point description
    Percentage of responders: Participants who have at least 20 percent (%) improvement from baseline in the PANSS PSFS (percentage decrease from baseline greater than or equal to [>=] 20%). Percentage of responders = Positive symptoms factor score at Week 12 minus Positive symptoms factor score at baseline divided by Positive symptoms factor score at baseline multiplied by 100. The study program was terminated early, after the primary endpoint since the primary endpoint was not reached at higher doses of bitopertin. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [7] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [8] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [9] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Symptoms Scale Score

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    End point title
    		 Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Symptoms Scale Score
    End point description
    Percentage of responders: Participants with “much” or “very much” improvement in the CGI-I overall and positive symptoms from baseline. Participants with a rating of either “much” or “very much” improvement in at least two of the three last post-baseline assessments (separated by at least 2 weeks) during the initial 12 weeks. Each of the CGI-I scales were rated on a 7-point scale. Ratings were based on degree of improvement from baseline. A CGI-I score of 1 refers to “very much improved” and a score of 7 refers to “very much worse.” Higher score = more affected. The study program was terminated early, after the primary endpoint since the primary endpoint was not reached at higher doses of Bitopertin. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [10] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [11] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [12] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression - Improvement (CGI-I) Symptoms Scale Score at Week 12

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    End point title
    		 Change From Baseline in Clinical Global Impression - Improvement (CGI-I) Symptoms Scale Score at Week 12
    End point description
    CGI-I: 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Improvement was defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved) on the scale. Higher score = more affected. The study program was terminated early, after the primary endpoint since the primary endpoint was not reached at higher doses of Bitopertin. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [13] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [14] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [15] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Personal and Social Performance (PSP) Total Score at Week 12

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    End point title
    		 Change From Baseline in Personal and Social Performance (PSP) Total Score at Week 12
    End point description
    The PSP scale was designed to assess the degree of dysfunction a participant exhibits within 4 domains of behavior: a) socially useful activities, b) personal and social relationships, c) self-care, and d) disturbing and aggressive behavior, each rated on 6-point scale (1=absent to 6=very severe). Total transformed score from 1 to 100 is generated from raw score based on clinical interpretation of scores generated in 4 areas of functioning. A score lying between 71 and 100 indicated a good functioning; one between 31 and 70 indicated varying degrees of difficulty, and a score of <=30 indicated functioning so poor that participant required intensive supervision. The study program was terminated early, after the primary endpoint since the primary endpoint was not reached at higher doses of Bitopertin. Analysis of the incomplete data set was not performed because it could potentially produce skewed or statistically irrelevant data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Bitopertin 10 mg – Treatment Period 1 Bitopertin 20 mg – Treatment Period 1 Placebo – Treatment Period 1
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [16] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [17] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    [18] - Due to early termination of study, insufficient data were available to perform all planned analyses.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Safety follow-up period (approximately 4 years)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Bitopertin 10 mg – Treatment Period
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD in the morning with/without food for 12 weeks (Week 0 to Week 12) in Treatment Period 1 and for 40 weeks (Week 13 to Week 52) in Treatment Period 2.

    Reporting group title
    Bitopertin 20mg – Treatment Period
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD in the morning with/without food for 12 weeks (Week 0 to Week 12) in Treatment Period 1 and for 40 weeks (Week 13 to Week 52) in Treatment Period 2.

    Reporting group title
    Placebo – Treatment Period
    Reporting group description
    		 Participants received placebo-matched to bitopertin taken QD in the morning with/without food for 12 weeks (Week 0 to Week 12) in Treatment Period 1 and for 40 weeks (Week 13 to Week 52) in Treatment Period 2.

    Reporting group title
    Bitopertin 10 mg – Washout Period
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

    Reporting group title
    Bitopertin 10 mg to Placebo – Washout Period
    Reporting group description
    		 Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

    Reporting group title
    Bitopertin 20mg – Washout Period
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

    Reporting group title
    Bitopertin 20mg to Placebo – Washout Period
    Reporting group description
    		 Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

    Reporting group title
    Placebo – Washout Period
    Reporting group description
    		 Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

    Reporting group title
    Placebo to Bitopertin 10mg – Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD, up to 3 years.

    Reporting group title
    Bitopertin 10mg – Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 10 mg oral tablet QD up to 3 years.

    Reporting group title
    Bitopertin 20mg – Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 20 mg oral tablet QD up to 3 years.

    Reporting group title
    Bitopertin 10 mg - Safety Follow-up
    Reporting group description
    		 All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 10 mg QD, for 4 weeks.

    Reporting group title
    Bitopertin 20 mg - Safety Follow-up
    Reporting group description
    		 All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 20 mg QD, for 4 weeks.

    Reporting group title
    Placebo - Safety Follow-up
    Reporting group description
    		 All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received placebo-matched to bitopertin, for 4 weeks.

    Serious adverse events
    		 Bitopertin 10 mg – Treatment Period Bitopertin 20mg – Treatment Period Placebo – Treatment Period Bitopertin 10 mg – Washout Period Bitopertin 10 mg to Placebo – Washout Period Bitopertin 20mg – Washout Period Bitopertin 20mg to Placebo – Washout Period Placebo – Washout Period Placebo to Bitopertin 10mg – Long-Term Extension Bitopertin 10mg – Long-Term Extension Bitopertin 20mg – Long-Term Extension Bitopertin 10 mg - Safety Follow-up Bitopertin 20 mg - Safety Follow-up Placebo - Safety Follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 198 (4.04%)
    7 / 199 (3.52%)
    6 / 199 (3.02%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    6 / 94 (6.38%)
    1 / 95 (1.05%)
    0 / 90 (0.00%)
    4 / 292 (1.37%)
    6 / 199 (3.02%)
    1 / 105 (0.95%)
         number of deaths (all causes)
    4
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer metastatic
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    1 / 199 (0.50%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    1 / 292 (0.34%)
    1 / 199 (0.50%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    1 / 292 (0.34%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    1 / 292 (0.34%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric Symptom
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 198 (1.01%)
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    1 / 292 (0.34%)
    1 / 199 (0.50%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
    2 / 199 (1.01%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    3 / 94 (3.19%)
    1 / 95 (1.05%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    2 / 199 (1.01%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    1 / 292 (0.34%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anger
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    1 / 94 (1.06%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    2 / 94 (2.13%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizoaffective disorder bipolar type
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    1 / 94 (1.06%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    1 / 94 (1.06%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    1 / 199 (0.50%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 198 (0.00%)
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bitopertin 10 mg – Treatment Period Bitopertin 20mg – Treatment Period Placebo – Treatment Period Bitopertin 10 mg – Washout Period Bitopertin 10 mg to Placebo – Washout Period Bitopertin 20mg – Washout Period Bitopertin 20mg to Placebo – Washout Period Placebo – Washout Period Placebo to Bitopertin 10mg – Long-Term Extension Bitopertin 10mg – Long-Term Extension Bitopertin 20mg – Long-Term Extension Bitopertin 10 mg - Safety Follow-up Bitopertin 20 mg - Safety Follow-up Placebo - Safety Follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 198 (16.16%)
    37 / 199 (18.59%)
    32 / 199 (16.08%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    12 / 94 (12.77%)
    11 / 95 (11.58%)
    15 / 90 (16.67%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 198 (5.56%)
    6 / 199 (3.02%)
    4 / 199 (2.01%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    5 / 94 (5.32%)
    3 / 95 (3.16%)
    6 / 90 (6.67%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    18
    8
    5
    0
    0
    0
    0
    0
    6
    3
    8
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 198 (8.08%)
    18 / 199 (9.05%)
    22 / 199 (11.06%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    8 / 94 (8.51%)
    10 / 95 (10.53%)
    11 / 90 (12.22%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    25
    27
    35
    0
    0
    0
    0
    0
    11
    16
    16
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 198 (4.04%)
    15 / 199 (7.54%)
    9 / 199 (4.52%)
    0 / 56 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 110 (0.00%)
    0 / 94 (0.00%)
    0 / 95 (0.00%)
    0 / 90 (0.00%)
    0 / 292 (0.00%)
    0 / 199 (0.00%)
    0 / 105 (0.00%)
         occurrences all number
    9
    17
    10
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2010
    Version B: Protocol was amended to clarify the exclusion criteria of hepatic dysfunction, secondary objective time point for safety and tolerability.
    21 Apr 2011
    Version C: Protocol was amended to clarify on the long term extension period, female contraception method and pregnancy testing, initiation of psychotherapy/rehabilitative, non-serious adverse events of special interest and reporting process, restricted and prohibited concomitant medication.
    20 Feb 2012
    Version D: Protocol was amended to clarify on addition of biomarker defined subpopulations as a secondary objective, timing of screening and prospective stabilization period, exclusion criteria (haemoglobin criterion, body mass index, requirement for past use of clonazepam), inclusion criteria (dosing of concomitant antipsychotics, definition of caregivers and burden assessment/questionnaire), updated list of restricted medications, updated definition of postmenopausal, and duration of the study. Added new guideline regarding withdrawal for hepatic laboratory abnormalities.
    30 May 2012
    Version D-1: Protocol was amended to include a revised version of the Zarit Burden Interview (ZBI) questionnaire, the Schizophrenia Caregiver Questionnaire (SCQ) to optimize assessment of caregiver burden for caregivers of patients with schizophrenia. Additionally, the Caregiver Global Impression scale was added.
    30 Oct 2012
    Version E: Protocol was amended to clarify on inclusion of futility analysis and addition of biomarker defined subpopulation analysis to the objectives, exclusion criteria (body mass index, patients with prior history of clozapine treatment), addition of 12-lead electrocardiogram (ECG) assessment in long term extension period, changes in serious adverse event (SAE) reporting, definition of safety population, and definition of length of the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Results of many secondary endpoints were not reported as the study was terminated early due to failure in demonstration of adjunctive therapy with bitopertin in primary endpoint.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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