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    Clinical Trial Results:
    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
    2010-020696-23
    Trial protocol
    GB   HU   FI   SE  
    Global end of trial date
    08 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Apr 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN25307
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01235520
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    To Be Added In By Sponsor, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline , F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline , F. Hoffmann-La Roche AG, 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
    08 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives in this study were as follows: - To evaluate the efficacy after 12 weeks of treatment with bitopertin vs. placebo, as adjunct to antipsychotics, in the Positive and Negative Syndrome Scale (PANSS) Positive Symptom Factor Score (PSFS) in patients with sub-optimally controlled symptoms of schizophrenia; - To evaluate the safety and tolerability after 12 weeks of treatment with bitopertin vs. placebo, as adjunct to antipsychotics, in patients with sub-optimally controlled symptoms of schizophrenia. The key secondary objective in this study was: - To evaluate the efficacy after 12 weeks of treatment with bitopertin vs. placebo, as adjunct to antipsychotics, in the PANSS PSFS in the complement factor H-related protein 1 (CFHR1)-high subgroup of patients with sub-optimally controlled symptoms of schizophrenia.
    Protection of trial subjects
    Signed written informed consent after the scope and nature of the investigation had been explained to them before screening evaluations and willingness to comply with the study restrictions.
    Background therapy
    There was former psychiatric care given to a number of patients being treated. This previous psychiatric care was given prior to the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Nov 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Romania: 26
    Country: Number of subjects enrolled
    Russian Federation: 102
    Country: Number of subjects enrolled
    United States: 149
    Country: Number of subjects enrolled
    Argentina: 42
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Colombia: 22
    Country: Number of subjects enrolled
    India: 80
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Mexico: 44
    Worldwide total number of subjects
    588
    EEA total number of subjects
    99
    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)
    578
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Screened for a period of up to 37 days.

    Period 1
    Period 1 title
    Overall period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Blinding for Arms with the following designation in the name of the arm: Treatment Period 1, Treatment Period 2, and Washout Period. During the Long-Term Extension period, all patients received active treatment but remained blinded to their treatment during the double-blind treatment phase. Patients were blinded but did not receive treatment during follow-up period.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo, 12 weeks - Treatment Period 1
    Arm description
    Patients randomized to placebo (10 or 20 mg) taken orally, once daily for 12 weeks in double-blind treatment
    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
    10 or 20 mg tablet taken once daily for 12 weeks

    Arm title
    Bitopertin 10 mg, 12 weeks - Treatment Period 1
    Arm description
    Patients randomized to bitopertin 10 mg taken orally, once daily for 12 weeks in double-blind treatment
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet taken orally once daily for 12 weeks

    Arm title
    Bitopertin 20 mg, 12 weeks - Treatment Period 1
    Arm description
    Patients randomized to bitopertin 20 mg taken orally, once daily for 12 weeks in double-blind treatment
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg tablet taken orally once daily for 12 weeks

    Arm title
    Placebo, weeks 13-52 - Treatment Period 2
    Arm description
    Patients randomized to placebo taken orally, once daily from week 13 through week 52 in double-blind treatment
    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
    10 or 20 mg tablet taken once daily from week 13-52

    Arm title
    Bitopertin 10 mg, weeks 13-52 - Treatment Period 2
    Arm description
    Patients randomized to bitopertin (10 mg) taken orally, once daily from week 13 through week 52 in double-blind treatment
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet taken once daily, weeks 13-52

    Arm title
    Bitopertin 20 mg, weeks 13-52 - Treatment Period 2
    Arm description
    Patients randomized to bitopertin (20 mg) taken orally, once daily from week 13 through week 52 in double-blind treatment
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg tablet taken orally once daily, weeks 13-52

    Arm title
    Placebo - Washout Period
    Arm description
    -
    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
    10 or 20 mg tablet taken once daily

    Arm title
    Bitopertin 10 mg - Washout Period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet taken orally once daily

    Arm title
    Bitopertin 10 mg to Placebo - Washout Period
    Arm description
    -
    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
    10 tablet taken once daily

    Arm title
    Bitopertin 20 mg - Washout Period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg tablet taken orally once daily

    Arm title
    Bitopertin 20 mg to Placebo - Washout Period
    Arm description
    -
    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
    20 mg tablet taken once daily

    Arm title
    Placebo to Bitopertin 10 mg - Long-Term Extension Period
    Arm description
    Randomized - controlled, not blinded
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet taken orally once daily

    Arm title
    Bitopertin 10 mg - Long-Term Extension Period
    Arm description
    Randomized - controlled, not blinded
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet taken orally once daily

    Arm title
    Bitopertin 20 mg - Long-Term Extension Period
    Arm description
    Randomized - controlled, not blinded
    Arm type
    Experimental

    Investigational medicinal product name
    RO4917838
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg tablet taken orally once daily

    Arm title
    Placebo - Follow-up Period
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Bitopertin 10 mg - Follow-up Period
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Bitopertin 20 mg - Follow-up Period
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Placebo, 12 weeks - Treatment Period 1 Bitopertin 10 mg, 12 weeks - Treatment Period 1 Bitopertin 20 mg, 12 weeks - Treatment Period 1 Placebo, weeks 13-52 - Treatment Period 2 Bitopertin 10 mg, weeks 13-52 - Treatment Period 2 Bitopertin 20 mg, weeks 13-52 - Treatment Period 2 Placebo - Washout Period 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 to Bitopertin 10 mg - Long-Term Extension Period Bitopertin 10 mg - Long-Term Extension Period Bitopertin 20 mg - Long-Term Extension Period Placebo - Follow-up Period Bitopertin 10 mg - Follow-up Period Bitopertin 20 mg - Follow-up Period
    Started
    196
    198
    194
    157
    170
    168
    75
    44
    42
    45
    43
    58
    66
    67
    138
    251
    192
    Completed
    161
    171
    171
    75
    86
    88
    70
    42
    39
    44
    39
    2
    3
    2
    67
    119
    116
    Not completed
    35
    27
    23
    82
    84
    80
    5
    2
    3
    1
    4
    56
    63
    65
    71
    132
    76
         Death
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Ongoing in follow-up period
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    12
    11
    10
         Protocol violation
    1
    2
    3
    1
    1
    2
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Lack of efficacy
    -
    1
    -
    2
    -
    6
    -
    -
    -
    -
    -
    1
    1
    -
    -
    -
    -
         Non-compliance
    4
    2
    4
    6
    4
    3
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Withdrawal by subject
    11
    10
    3
    12
    12
    7
    -
    -
    1
    -
    -
    2
    2
    4
    16
    15
    11
         Adverse event, non-fatal
    10
    7
    7
    9
    10
    15
    1
    -
    -
    -
    1
    -
    -
    1
    3
    6
    4
         Administrative/other
    6
    2
    5
    47
    51
    42
    4
    2
    2
    1
    3
    51
    59
    58
    13
    22
    16
         Lost to follow-up
    3
    3
    1
    5
    6
    5
    -
    -
    -
    -
    -
    -
    1
    2
    27
    77
    35

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period (overall period)
    Reporting group description
    -

    Reporting group values
    Overall period (overall period) Total
    Number of subjects
    588 588
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.7 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    215 215
        Male
    373 373

    End points

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    End points reporting groups
    Reporting group title
    Placebo, 12 weeks - Treatment Period 1
    Reporting group description
    Patients randomized to placebo (10 or 20 mg) taken orally, once daily for 12 weeks in double-blind treatment

    Reporting group title
    Bitopertin 10 mg, 12 weeks - Treatment Period 1
    Reporting group description
    Patients randomized to bitopertin 10 mg taken orally, once daily for 12 weeks in double-blind treatment

    Reporting group title
    Bitopertin 20 mg, 12 weeks - Treatment Period 1
    Reporting group description
    Patients randomized to bitopertin 20 mg taken orally, once daily for 12 weeks in double-blind treatment

    Reporting group title
    Placebo, weeks 13-52 - Treatment Period 2
    Reporting group description
    Patients randomized to placebo taken orally, once daily from week 13 through week 52 in double-blind treatment

    Reporting group title
    Bitopertin 10 mg, weeks 13-52 - Treatment Period 2
    Reporting group description
    Patients randomized to bitopertin (10 mg) taken orally, once daily from week 13 through week 52 in double-blind treatment

    Reporting group title
    Bitopertin 20 mg, weeks 13-52 - Treatment Period 2
    Reporting group description
    Patients randomized to bitopertin (20 mg) taken orally, once daily from week 13 through week 52 in double-blind treatment

    Reporting group title
    Placebo - Washout Period
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg - Washout Period
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg to Placebo - Washout Period
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg - Washout Period
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg to Placebo - Washout Period
    Reporting group description
    -

    Reporting group title
    Placebo to Bitopertin 10 mg - Long-Term Extension Period
    Reporting group description
    Randomized - controlled, not blinded

    Reporting group title
    Bitopertin 10 mg - Long-Term Extension Period
    Reporting group description
    Randomized - controlled, not blinded

    Reporting group title
    Bitopertin 20 mg - Long-Term Extension Period
    Reporting group description
    Randomized - controlled, not blinded

    Reporting group title
    Placebo - Follow-up Period
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg - Follow-up Period
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg - Follow-up Period
    Reporting group description
    -

    Primary: Mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Symptom Factor Score (PSFS) at Week 12

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    End point title
    Mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Symptom Factor Score (PSFS) at Week 12 [1]
    End point description
    End point type
    Primary
    End point timeframe
    Timeframe is week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This final abbreviated Clinical Study Report (CSR) presents the data at Week 12 for the primary endpoint, PANSS PSFS, and one of the secondary endpoints, PANSS Total Score. The study did not meet its primary endpoint.
    End point values
    Placebo, 12 weeks - Treatment Period 1 Bitopertin 10 mg, 12 weeks - Treatment Period 1 Bitopertin 20 mg, 12 weeks - Treatment Period 1
    Number of subjects analysed
    186
    188
    186
    Units: Scores on a scale
        arithmetic mean (standard error)
    -4.88 ± 0.357
    -4.46 ± 0.327
    -4.67 ± 0.297
    Statistical analysis title
    Difference from placebo: 10 mg RO4917838
    Statistical analysis description
    Difference of treatment with 10 mg RO4917838 from placebo based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix
    Comparison groups
    Bitopertin 10 mg, 12 weeks - Treatment Period 1 v Placebo, 12 weeks - Treatment Period 1
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2169
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.34
         upper limit
    1.5
    Statistical analysis title
    Difference from placebo: 20 mg RO4917838 MMRM
    Statistical analysis description
    Difference of treatment with 20 mg RO4917838 from placebo based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix
    Comparison groups
    Placebo, 12 weeks - Treatment Period 1 v Bitopertin 20 mg, 12 weeks - Treatment Period 1
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3572
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.49
         upper limit
    1.36

    Secondary: Mean Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12

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    End point title
    Mean Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This final abbreviated Clinical Study Report (CSR) presents the data at Week 12 for the primary endpoint, PANSS PSFS, and one of the secondary endpoints, PANSS Total Score. The study did not meet its primary endpoint.
    End point values
    Placebo, 12 weeks - Treatment Period 1 Bitopertin 10 mg, 12 weeks - Treatment Period 1 Bitopertin 20 mg, 12 weeks - Treatment Period 1
    Number of subjects analysed
    186
    188
    186
    Units: Scores on a scale
        arithmetic mean (standard error)
    -13.36 ± 0.88
    -12.24 ± 0.804
    -13.05 ± 0.823
    Statistical analysis title
    Difference from placebo: 10 mg RO4917838
    Comparison groups
    Placebo, 12 weeks - Treatment Period 1 v Bitopertin 10 mg, 12 weeks - Treatment Period 1
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2789
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    3.64
    Statistical analysis title
    Difference from placebo: 20 mg RO4917838
    Comparison groups
    Placebo, 12 weeks - Treatment Period 1 v Bitopertin 20 mg, 12 weeks - Treatment Period 1
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.647
    Method
    Mixed Models Repeated Measures Analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    2.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    This abbreviated study report presents the final analysis of safety and includes all available safety data up to the time of the primary analysis and all available AE and laboratory assessment data for all study periods up to the LPLV.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Placebo - Treatment Periods 1 & 2
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg - Treatment Periods 1 & 2
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg - Treatment Periods 1 & 2
    Reporting group description
    -

    Reporting group title
    Placebo during washout period
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg during washout period
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg to placebo during washout period
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg during washout period
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg to placebo during washout period
    Reporting group description
    -

    Reporting group title
    Placebo to Bitopertin 10 mg during long-term extension
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg during long-term extension
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg during long-term extension
    Reporting group description
    -

    Reporting group title
    Placebo - follow-up period
    Reporting group description
    -

    Reporting group title
    Bitopertin 10 mg - follow-up period
    Reporting group description
    -

    Reporting group title
    Bitopertin 20 mg - follow-up period
    Reporting group description
    -

    Serious adverse events
    Placebo - Treatment Periods 1 & 2 Bitopertin 10 mg - Treatment Periods 1 & 2 Bitopertin 20 mg - Treatment Periods 1 & 2 Placebo during washout period Bitopertin 10 mg during washout period Bitopertin 10 mg to placebo during washout period Bitopertin 20 mg during washout period Bitopertin 20 mg to placebo during washout period Placebo to Bitopertin 10 mg during long-term extension Bitopertin 10 mg during long-term extension Bitopertin 20 mg during long-term extension Placebo - follow-up period Bitopertin 10 mg - follow-up period Bitopertin 20 mg - follow-up period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 196 (5.10%)
    13 / 198 (6.57%)
    9 / 194 (4.64%)
    1 / 76 (1.32%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    2 / 58 (3.45%)
    5 / 66 (7.58%)
    1 / 67 (1.49%)
    2 / 138 (1.45%)
    5 / 251 (1.99%)
    6 / 192 (3.13%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    1 / 192 (0.52%)
         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 / 0
    0 / 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
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 198 (1.01%)
    3 / 194 (1.55%)
    1 / 76 (1.32%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    3 / 66 (4.55%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    1 / 251 (0.40%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    3 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 1
    2 / 4
         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
    Major Depression
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    1 / 194 (0.52%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Psychotic Disorder
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 198 (0.00%)
    1 / 194 (0.52%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    2 / 138 (1.45%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Mood altered
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Schizophrenia, paranoid type
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Suicidal ideation
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Anxiety
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    1 / 66 (1.52%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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 / 1
    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
    Insomnia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    1 / 192 (0.52%)
         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 / 0
    0 / 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
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Overdose
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    1 / 251 (0.40%)
    0 / 192 (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
    Post-traumatic pain
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    1 / 194 (0.52%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Atrial flutter
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Respiratory, thoracic and mediastinal disorders
    Sinus polyp
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    1 / 58 (1.72%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    1 / 194 (0.52%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Cerebral ischaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Dizziness
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    1 / 66 (1.52%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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 / 1
    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
    Ischaemic stroke
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    1 / 251 (0.40%)
    0 / 192 (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
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Musculoskeletal and connective tissue disorders
    Jaw cyst
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    1 / 58 (1.72%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    1 / 67 (1.49%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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 / 1
    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 / 196 (0.00%)
    0 / 198 (0.00%)
    1 / 194 (0.52%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    1 / 251 (0.40%)
    0 / 192 (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 / 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
    Pneumonia
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 198 (1.01%)
    1 / 194 (0.52%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    1 / 251 (0.40%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    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
    Bronchitis
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    1 / 44 (2.27%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    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
    Cellulitis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Otitis media chronic
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Tonsillitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    1 / 66 (1.52%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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 / 1
    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
    Tooth abscess
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    1 / 66 (1.52%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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 / 1
    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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    1 / 58 (1.72%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo - Treatment Periods 1 & 2 Bitopertin 10 mg - Treatment Periods 1 & 2 Bitopertin 20 mg - Treatment Periods 1 & 2 Placebo during washout period Bitopertin 10 mg during washout period Bitopertin 10 mg to placebo during washout period Bitopertin 20 mg during washout period Bitopertin 20 mg to placebo during washout period Placebo to Bitopertin 10 mg during long-term extension Bitopertin 10 mg during long-term extension Bitopertin 20 mg during long-term extension Placebo - follow-up period Bitopertin 10 mg - follow-up period Bitopertin 20 mg - follow-up period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 196 (12.24%)
    36 / 198 (18.18%)
    33 / 194 (17.01%)
    5 / 76 (6.58%)
    6 / 44 (13.64%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    11 / 58 (18.97%)
    25 / 66 (37.88%)
    19 / 67 (28.36%)
    11 / 138 (7.97%)
    27 / 251 (10.76%)
    25 / 192 (13.02%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 196 (4.08%)
    12 / 198 (6.06%)
    11 / 194 (5.67%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences all number
    13
    19
    14
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    4 / 66 (6.06%)
    3 / 67 (4.48%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    4
    3
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 196 (4.59%)
    7 / 198 (3.54%)
    10 / 194 (5.15%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    0 / 58 (0.00%)
    0 / 66 (0.00%)
    0 / 67 (0.00%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences all number
    9
    7
    11
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 198 (0.00%)
    0 / 194 (0.00%)
    0 / 76 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
    0 / 43 (0.00%)
    4 / 58 (6.90%)
    2 / 66 (3.03%)
    2 / 67 (2.99%)
    0 / 138 (0.00%)
    0 / 251 (0.00%)
    0 / 192 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    4
    3
    2
    0
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2010
    Amendment A: Clarified study duration; Clarification on procedures collecting data for the Roche Clinical Repository (RCR) for exploratory objective; Changes to Work Readiness Questionnaire (WoRQ); Addition of inclusion criteria; Clarification of data collection: no details required on non-psychotropic medication; Change to the process to collect data in the eCRF for screened patient; Addition of Pharmacogenomic assessments to Other Endpoints; Clarification in Laboratory Assessments section to spell out "mean corpuscular volume" (MCV), and "mean corpuscular hemoglobin" (MCH); Clarification of urinalysis: to be performed at central laboratory; Addition of creatine phosphokinase for laboratory testing.
    22 Sep 2010
    Amendment B: Clarification on exclusion: to exclude patients who may have pre-existing potentially clinically significant hepatic dysfunction; Clarification of the secondary objective time point for safety and tolerability: 52 weeks randomized study treatment; Clarification of processes around patient randomization; Clarification of study duration; Clarification of Laboratory Assessments: guidelines added around fasting prior to blood sampling; Changes to schedule of assessment and procedure: Physical Examination changed from Week 16 to Week 12, ECG at Week 4 added, Clinical Global Impression – Improvement (CGI-I) assessment were assigned to the Baseline/Randomization visit-Day 1 was removed, Examination of Vital signs were added at Week 68, Week 80 and to be assessed every 12 weeks, Physical Examination, Smoking status, ESRS-A, and Eye Examination will be assessed in addition at Week 80, and Assessment of C-SSRS was added at Week 58.
    21 Apr 2011
    Amendment C: Further information on Long Term Extension regarding withdrawal effect based on the data collected during washout, safety and tolerability of long term use (beyond 56 weeks) of RO4917838 in combination with anti-psychotics and long-term treatment effects (beyond 56 weeks) on symptoms, functioning, quality of life and caregivers’ burden; Change in requirements for female contraception methods; Change in method for pregnancy testing; Initiation of psychotherapy and/or rehabilitative therapy permitted from Treatment Period 2 (TP2) onwards; Adding of exclusion criterion 21: Both cannabis and barbiturates can be retested if positive at screening; Adding of exclusion criterion 22: as glycine supplementation and other products may have an effect on Nmethyl-D aspartate (NMDA)-type glutamate receptors these substances will be prohibited during study participation to avoid confounding study results; Extension of visit window of prospective stabilization period; Clarification of repeating screening assessments and rescreening; Changes to Schedule of Assessments section: Addition of questionnaire and Patient Assessment Form (PAF) for screening visit, removal of abbreviated inclusion/exclusion criteria assessment, addition of ECG assessment at week 12, efficacy measures/rating scales were better aligned to key visits in TP2, addition of blood chemistry assessments to week 60 and week 68 of LTE, adding questionnaire and clarification of questionnaire timing; Analysis of iron inclusion bodies and completion of iron related parameters; Correction of blood volumes; Clarification of reporting of serious adverse events; Clarification of non-serious adverse events of special interest and reporting process; Addition of risk benefit section; Clarification of restricted and prohibited concomitant medication.
    20 Feb 2012
    Amendment D: Addition of biomarker defined subpopulation as secondary objective; Clarification of timing of screening and prospective stabilization period; Clarification of exclusion criterion 3: decrease of exclusionary hemoglobin criterion in males; Updated dosing of concomitant antipsychotics for inclusion criterion 12; Clarification of exclusion criterion for body mass index; Revision of caregiver definition in inclusion criterion 5; Additional follow-up for treatment withdrawal and at week 52 initiation of washout and clarification of withdrawal process; clarified exclusion criterion regarding concomitant medication; Updated requirements for past use of clozapine; Added eszopiclone to list of restricted medications; Updated definition of postmenopausal; Inclusion of description of exploratory substudy open to eligible patients from certain sites in United Kingdom; Addition of new guidelines regarding withdrawal for hepatic laboratory abnormalities.
    18 Oct 2012
    Amendment E: Modification of caregiver burden assessment/ questionnaire; Inclusion of a futility analysis; Addition of biomarker defined subpopulation analysis to the objectives; Change in data safety monitoring board; Modification of exclusion criteria 2: update to patient demographics in Asian countries; Modification of exclusion criteria 18: clarification on eligibility of patients with prior history of clozapine; Addition of 12-Lead ECG assessment in long-term extension period; Change in serious adverse event (SAE) reporting to require SAEs to be reported within 24 hours of investigator becoming aware of event; Change in definition of safety population; Changes in definition of study duration; Removal of reference to per protocol population as all efficacy analyses will be performed on intent-to-treat population.

    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.
    None reported
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