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

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2010-020370-42
    Trial protocol
    		 GB   HU   FI   SE  
    Global end of trial date
    26 May 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 May 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Quality Control of data already entered before access for sponsors was blocked on 31 July 2015

    Trial information

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    Trial identification
    Sponsor protocol code
    NN25310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01192867
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, 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
    15 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate efficacy of 24 weeks treatment with RO4917838 in the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score in subjects with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics. Evaluate safety and tolerability of 24 weeks treatment with RO4917838 in subjects with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 Stable antipsychotic treatment
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 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
    Romania: 36
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Hungary: 59
    Country: Number of subjects enrolled
    Russian Federation: 138
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Argentina: 70
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Colombia: 27
    Country: Number of subjects enrolled
    India: 53
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Mexico: 50
    Worldwide total number of subjects
    626
    EEA total number of subjects
    157
    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)
    616
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Diagnosis of schizophrenia, paranoid, disorganised, residual, undifferentiated or catatonic subtype. A score of 40 or greater on the sum of the 14 Positive and Negative Syndrome Scale (PANSS) negative and disorganised thought factor items and a score of 22 or less on the sum of the 8 PANSS positive symptom factor items.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Blinding only for Arms with the following designation in the name of the arm: Treatment period 1, Treatment period 2 and Washout period. Not applicable/not blinded for Longterm extension period and Safety follow-up period arms.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo - Treatment period 1
    Arm description
    		 Matching placebo adjunct to stable antipsychotic treatment for 24 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
    Matching placebo oral use (p.o.) once daily (q.d.) for 24 weeks

    Arm title
    		 Bitopertin 10 mg - Treatment period 1
    Arm description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral use (p.o.) once daily (q.d.) for 24 weeks

    Arm title
    		 Bitopertin 20 mg - Treatment period 1
    Arm description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg oral use (p.o.) once daily (q.d.) for 24 weeks

    Arm title
    		 Placebo - Treatment period 2
    Arm description
    		 Matching placebo adjunct to stable antipsychotic treatment for 28 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
    Matching placebo oral use (p.o.) once daily (q.d.) for 28 weeks

    Arm title
    		 Bitopertin 10 mg - Treatment period 2
    Arm description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for 28 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral use (p.o.) once daily (q.d.) for 28 weeks

    Arm title
    		 Bitopertin 20 mg - Treatment period 2
    Arm description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for 28 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg oral use (p.o.) once daily (q.d.) for 28 weeks

    Arm title
    		 Placebo - Washout period
    Arm description
    		 Matching placebo adjunct to stable antipsychotic treatment 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
    Matching placebo oral use (p.o.) once daily (q.d.) for 4 weeks

    Arm title
    		 Bitopertin 10 mg - Washout period
    Arm description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral use (p.o.) once daily (q.d.) for 4 weeks

    Arm title
    		 Bitopertin 10 mg to placebo - Washout period
    Arm description
    		 Bitopertin/RO4917838 10 mg switched to placebo for duration of washout period; adjunct to stable antipsychotic treatment 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
    Matching placebo oral use (p.o.) once daily (q.d.) for 4 weeks

    Arm title
    		 Bitopertin 20 mg - Washout period
    Arm description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg oral use (p.o.) once daily (q.d.) for 4 weeks

    Arm title
    		 Bitopertin 20 mg to placebo - Washout period
    Arm description
    		 Bitopertin/RO4917838 20 mg switched to placebo for duration of washout period; adjunct to antipsychotic treatment 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
    Matching placebo oral use (p.o.) once daily (q.d.) for 4 weeks

    Arm title
    		 Placebo - Longterm extension period
    Arm description
    		 Matching placebo during previous periods: switched to Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment up to 3 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral use (p.o.) once daily (q.d.) for up to 3 years

    Arm title
    		 Bitopertin 10 mg - Longterm extension period
    Arm description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for up to 3 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg oral use (p.o.) once daily (q.d.) for up to 3 years

    Arm title
    		 Bitopertin 20 mg - Longterm extension period
    Arm description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for up to 3 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bitopertin
    Investigational medicinal product code
    RO4917838
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg oral use (p.o.) once daily (q.d.) for up to 3 years

    Arm title
    		 Placebo - Safety follow-up period
    Arm description
    		 Matching placebo during previous periods: no intervention during this period; adjunct to stable antipsychotic treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Bitopertin 10 mg - Safety follow-up period
    Arm description
    		 Bitopertin/RO4917838 10 mg during previous periods: no intervention during this period; adjunct to antipsychotic treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Bitopertin 20 mg - Safety follow-up period
    Arm description
    		 20 mg Bitopertin/RO4917838 during previous periods: no intervention during this period; adjunct to stable antipsychotic treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Placebo - Treatment period 1 Bitopertin 10 mg - Treatment period 1 Bitopertin 20 mg - Treatment period 1 Placebo - Treatment period 2 Bitopertin 10 mg - Treatment period 2 Bitopertin 20 mg - 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 - Longterm extension period Bitopertin 10 mg - Longterm extension period Bitopertin 20 mg - Longterm extension period Placebo - Safety follow-up period Bitopertin 10 mg - Safety follow-up period Bitopertin 20 mg - Safety follow-up period
    Started
    210
    208
    208
    160
    174
    177
    119
    71
    71
    78
    77
    102
    116
    120
    108
    310
    208
    Completed
    163
    174
    180
    119
    142
    155
    113
    68
    68
    73
    71
    0
    0
    0
    61
    234
    148
    Not completed
    47
    34
    28
    41
    32
    22
    6
    3
    3
    5
    6
    102
    116
    120
    47
    76
    60
         Consent withdrawn by subject
    9
    11
    12
    7
    2
    3
    -
    -
    -
    -
    -
    4
    1
    6
    18
    25
    15
         Administrative
    4
    4
    4
    23
    21
    12
    3
    3
    3
    5
    3
    93
    109
    106
    11
    17
    15
         Adverse event, non-fatal
    19
    7
    5
    9
    5
    3
    -
    -
    -
    -
    1
    3
    3
    4
    5
    1
    2
         Death
    -
    1
    -
    -
    1
    -
    2
    -
    -
    -
    1
    -
    -
    -
    1
    2
    2
         Non-compliance
    7
    4
    1
    2
    1
    2
    1
    -
    -
    -
    1
    -
    1
    -
    -
    -
    -
         Lost to follow-up
    2
    3
    5
    -
    1
    -
    -
    -
    -
    -
    -
    1
    2
    3
    12
    31
    26
         Lack of efficacy
    1
    2
    -
    -
    -
    1
    -
    -
    -
    -
    -
    1
    -
    1
    -
    -
    -
         Protocol deviation
    5
    2
    1
    -
    1
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 626 626
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 616 616
        From 65-84 years
    		 10 10
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.3 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    		 203 203
        Male
    		 423 423

    End points

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    End points reporting groups
    Reporting group title
    Placebo - Treatment period 1
    Reporting group description
    		 Matching placebo adjunct to stable antipsychotic treatment for 24 weeks

    Reporting group title
    Bitopertin 10 mg - Treatment period 1
    Reporting group description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for 24 weeks

    Reporting group title
    Bitopertin 20 mg - Treatment period 1
    Reporting group description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for 24 weeks

    Reporting group title
    Placebo - Treatment period 2
    Reporting group description
    		 Matching placebo adjunct to stable antipsychotic treatment for 28 weeks

    Reporting group title
    Bitopertin 10 mg - Treatment period 2
    Reporting group description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for 28 weeks

    Reporting group title
    Bitopertin 20 mg - Treatment period 2
    Reporting group description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for 28 weeks

    Reporting group title
    Placebo - Washout period
    Reporting group description
    		 Matching placebo adjunct to stable antipsychotic treatment for 4 weeks

    Reporting group title
    Bitopertin 10 mg - Washout period
    Reporting group description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for 4 weeks

    Reporting group title
    Bitopertin 10 mg to placebo - Washout period
    Reporting group description
    		 Bitopertin/RO4917838 10 mg switched to placebo for duration of washout period; adjunct to stable antipsychotic treatment for 4 weeks

    Reporting group title
    Bitopertin 20 mg - Washout period
    Reporting group description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for 4 weeks

    Reporting group title
    Bitopertin 20 mg to placebo - Washout period
    Reporting group description
    		 Bitopertin/RO4917838 20 mg switched to placebo for duration of washout period; adjunct to antipsychotic treatment for 4 weeks

    Reporting group title
    Placebo - Longterm extension period
    Reporting group description
    		 Matching placebo during previous periods: switched to Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment up to 3 years

    Reporting group title
    Bitopertin 10 mg - Longterm extension period
    Reporting group description
    		 Bitopertin/RO4917838 10 mg adjunct to stable antipsychotic treatment for up to 3 years

    Reporting group title
    Bitopertin 20 mg - Longterm extension period
    Reporting group description
    		 Bitopertin/RO4917838 20 mg adjunct to stable antipsychotic treatment for up to 3 years

    Reporting group title
    Placebo - Safety follow-up period
    Reporting group description
    		 Matching placebo during previous periods: no intervention during this period; adjunct to stable antipsychotic treatment

    Reporting group title
    Bitopertin 10 mg - Safety follow-up period
    Reporting group description
    		 Bitopertin/RO4917838 10 mg during previous periods: no intervention during this period; adjunct to antipsychotic treatment

    Reporting group title
    Bitopertin 20 mg - Safety follow-up period
    Reporting group description
    		 20 mg Bitopertin/RO4917838 during previous periods: no intervention during this period; adjunct to stable antipsychotic treatment

    Primary: Mean Change from Baseline Positive and Negative Syndrome Scale (PANSS)

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    End point title
    		 Mean Change from Baseline Positive and Negative Syndrome Scale (PANSS) [1]
    End point description
    Mean change from baseline to week 24 in the Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) in subjects with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics.
    End point type
    Primary
    End point timeframe
    Baseline to week 24
    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: Since this study has an adaptive trial design all periods had to be reported in the Overall Period to avoid errors in the subject disposition section. As indicated in the arm titles data were reported for all arms in the baseline period (Treatment period 1).
    End point values
    		 Placebo - Treatment period 1 Bitopertin 10 mg - Treatment period 1 Bitopertin 20 mg - Treatment period 1
    Number of subjects analysed
    197
    200
    197
    Units: Score
        arithmetic mean (standard error)
    -6.11 ± 0.369
    -5.77 ± 0.335
    -6.08 ± 0.379
    Statistical analysis title
    		 Difference from Placebo: 10 mg RO4917838 MMRM
    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
    Placebo - Treatment period 1 v Bitopertin 10 mg - Treatment period 1
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2706
    Method
    		 MMRM
    Confidence interval
    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 - Treatment period 1 v Bitopertin 20 mg - Treatment period 1
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6425
    Method
    		 MMRM
    Confidence interval
    Statistical analysis title
    		 Difference from placebo: 10 mg RO4917838 ANCOVA
    Statistical analysis description
    Difference of treatment with 10 mg RO4917838 from placebo using analysis of covariance (ANCOVA) model
    Comparison groups
    Bitopertin 10 mg - Treatment period 1 v Placebo - Treatment period 1
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3692
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Difference from placebo: 20 mg RO4917838 ANCOVA
    Statistical analysis description
    Difference of treatment with 20 mg RO4917838 from placebo using analysis of covariance (ANCOVA) model
    Comparison groups
    Placebo - Treatment period 1 v Bitopertin 20 mg - Treatment period 1
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean change from baseline in the Personal and Social Performance (PSP) total score

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    End point title
    		 Mean change from baseline in the Personal and Social Performance (PSP) total score [2]
    End point description
    Mean change from baseline at week 24 in personal and social functioning using Personal and Social Performance (PSP) total score in subjects with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    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: Since this study has an adaptive trial design all periods had to be reported in the Overall Period to avoid errors in the subject disposition section. As indicated in the arm titles data were reported for all arms in the baseline period (Treatment period 1).
    End point values
    		 Placebo - Treatment period 1 Bitopertin 10 mg - Treatment period 1 Bitopertin 20 mg - Treatment period 1
    Number of subjects analysed
    197
    200
    197
    Units: Score
        arithmetic mean (standard error)
    8.41 ± 0.802
    9.48 ± 0.848
    8.38 ± 0.804
    Statistical analysis title
    		 Difference from placebo: 10 mg RO4917838 MMRM
    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
    Placebo - Treatment period 1 v Bitopertin 10 mg - Treatment period 1
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4697
    Method
    		 MMRM
    Confidence interval
    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 - Treatment period 1 v Bitopertin 20 mg - Treatment period 1
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8982
    Method
    		 MMRM
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization to the end of the study (up to 4 years, 2 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo - Treatment periods 1 and 2
    Reporting group description
    		 Matching placebo, Treatment periods 1 and 2: 52 weeks

    Reporting group title
    Bitopertin 10 mg - Treatment periods 1 and 2
    Reporting group description
    		 Bitopertin 10 mg, Treatment periods 1 and 2: 52 weeks

    Reporting group title
    Bitopertin 20 mg - Treatment periods 1 and 2
    Reporting group description
    		 Bitopertin 20 mg, Treatment periods 1 and 2: 52 weeks

    Reporting group title
    Placebo - Washout period
    Reporting group description
    		 Matching placebo, oral administration, once daily for 4 weeks following the treatment period 2 starting at week 52

    Reporting group title
    Bitopertin 10 mg - Washout period
    Reporting group description
    		 Bitopertin 10 mg, oral administration, once daily for 4 weeks following treatment period 2 starting at week 52

    Reporting group title
    Bitopertin 10 mg to Placebo - Washout period
    Reporting group description
    		 Bitopertin 10 mg switched to placebo: oral administration, once daily for 4 weeks following treatment period 2 starting at week 52

    Reporting group title
    Bitopertin 20 mg - Washout period
    Reporting group description
    		 Bitopertin 20 mg, oral administration, once daily for 4 weeks following treatment period 2 starting at week 52

    Reporting group title
    Bitopertin 20 mg to Placebo - Washout period
    Reporting group description
    		 Bitopertin 20 mg switched to placebo: oral administration, once daily for 4 weeks following treatment period 2 starting at week 52

    Reporting group title
    Placebo - Long term extension period
    Reporting group description
    		 Placebo group in treatment and washout periods switched to Bitopertin/RO4917838 10 mg, oral administration, once daily for up to 3 years following washout period

    Reporting group title
    Biopertin 10 mg - Long term extension period
    Reporting group description
    		 Bitopertin 10 mg, oral administration, once daily up to 3 years following washout period

    Reporting group title
    Bitopertin 20 mg - Long term extension period
    Reporting group description
    		 Bitopertin 20 mg, oral administration, once daily up to 3 years following the washout period

    Reporting group title
    Placebo - Safety follow up period
    Reporting group description
    		 Placebo group in prior periods: no intervention during 4 week safety follow up period

    Reporting group title
    Bitopertin 10 mg - Safety follow up period
    Reporting group description
    		 Bitopertin 10 mg in prior periods: no intervention during 4 week safety follow up period

    Reporting group title
    Bitopertin 20 mg - Safety follow up period
    Reporting group description
    		 Bitopertin 20 mg in prior periods: no intervention during 4 week safety follow up period

    Serious adverse events
    		 Placebo - Treatment periods 1 and 2 Bitopertin 10 mg - Treatment periods 1 and 2 Bitopertin 20 mg - Treatment periods 1 and 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 - Long term extension period Biopertin 10 mg - Long term extension period Bitopertin 20 mg - Long term extension period Placebo - Safety follow up period Bitopertin 10 mg - Safety follow up period Bitopertin 20 mg - Safety follow up period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 210 (8.10%)
    13 / 208 (6.25%)
    7 / 208 (3.37%)
    0 / 119 (0.00%)
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    1 / 78 (1.28%)
    2 / 77 (2.60%)
    1 / 102 (0.98%)
    7 / 116 (6.03%)
    5 / 120 (4.17%)
    7 / 108 (6.48%)
    2 / 310 (0.65%)
    2 / 208 (0.96%)
         number of deaths (all causes)
    1
    2
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid cancer
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    1 / 120 (0.83%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    1 / 208 (0.48%)
         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 / 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
    Metastases to lung
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    1 / 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
    Renal neoplasm
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    1 / 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
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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
    Social circumstances
    Physical assault
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Social problem
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Uterine polyp
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    1 / 120 (0.83%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    7 / 210 (3.33%)
    3 / 208 (1.44%)
    1 / 208 (0.48%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 102 (0.98%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    1 / 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
    Psychotic disorder
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    2 / 208 (0.96%)
    0 / 119 (0.00%)
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    1 / 120 (0.83%)
    2 / 108 (1.85%)
    1 / 310 (0.32%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    1 / 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
    Anxiety
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    1 / 120 (0.83%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    Completed suicide
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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
    1 / 1
    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
    Hallucination
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Investigations
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    1 / 208 (0.48%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Fall
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Forearm fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Gun shot wound
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Joint dislocation
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Radius fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Road traffic accident
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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 / 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
    Stab wound
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Toxicity to various agents
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    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
    Multiple fractures
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    1 / 120 (0.83%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Eye contusion
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    1 / 208 (0.48%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    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
    Bradycardia
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Multiple sclerosis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Post-injection delirium sedation syndrome
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Oromandibular dystonia
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    1 / 310 (0.32%)
    0 / 208 (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
    1 / 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
    Eye disorders
    Oculogyric crisis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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
    1 / 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
    Uveitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Infections and infestations
    Tuberculosis
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    1 / 208 (0.48%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Bronchitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 208 (0.48%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Pneumonia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    1 / 108 (0.93%)
    0 / 310 (0.00%)
    0 / 208 (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 / 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
    Sepsis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    hepatitis A
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Cervicitis
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Bronchitis chronic
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    1 / 208 (0.48%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 116 (0.00%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 210 (0.00%)
    0 / 208 (0.00%)
    0 / 208 (0.00%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    1 / 116 (0.86%)
    0 / 120 (0.00%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    0 / 208 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo - Treatment periods 1 and 2 Bitopertin 10 mg - Treatment periods 1 and 2 Bitopertin 20 mg - Treatment periods 1 and 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 - Long term extension period Biopertin 10 mg - Long term extension period Bitopertin 20 mg - Long term extension period Placebo - Safety follow up period Bitopertin 10 mg - Safety follow up period Bitopertin 20 mg - Safety follow up period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    116 / 210 (55.24%)
    23 / 208 (11.06%)
    105 / 208 (50.48%)
    16 / 119 (13.45%)
    0 / 71 (0.00%)
    15 / 71 (21.13%)
    14 / 78 (17.95%)
    9 / 77 (11.69%)
    33 / 102 (32.35%)
    38 / 116 (32.76%)
    39 / 120 (32.50%)
    14 / 108 (12.96%)
    19 / 310 (6.13%)
    23 / 208 (11.06%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 210 (7.14%)
    11 / 208 (5.29%)
    6 / 208 (2.88%)
    1 / 119 (0.84%)
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    1 / 78 (1.28%)
    1 / 77 (1.30%)
    1 / 102 (0.98%)
    2 / 116 (1.72%)
    2 / 120 (1.67%)
    3 / 108 (2.78%)
    3 / 310 (0.97%)
    2 / 208 (0.96%)
         occurrences all number
    20
    16
    6
    1
    0
    1
    1
    1
    1
    2
    2
    3
    3
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 210 (2.38%)
    3 / 208 (1.44%)
    11 / 208 (5.29%)
    0 / 119 (0.00%)
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    2 / 116 (1.72%)
    1 / 120 (0.83%)
    0 / 108 (0.00%)
    0 / 310 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    6
    3
    11
    0
    0
    0
    1
    0
    0
    2
    1
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 210 (4.29%)
    9 / 208 (4.33%)
    8 / 208 (3.85%)
    2 / 119 (1.68%)
    0 / 71 (0.00%)
    2 / 71 (2.82%)
    2 / 78 (2.56%)
    0 / 77 (0.00%)
    7 / 102 (6.86%)
    0 / 116 (0.00%)
    2 / 120 (1.67%)
    1 / 108 (0.93%)
    1 / 310 (0.32%)
    1 / 208 (0.48%)
         occurrences all number
    10
    11
    10
    2
    0
    2
    2
    0
    8
    0
    2
    1
    1
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2010
    Amendment B: Addition of creatine phosphokinase for laboratory testing; Clarification on procedures collecting data for the Roche Clinical Repository (RCR) for exploratory objective; Changes to Work Readiness Questionnaire (WoRQ); Changes to schedule of assessments and procedures: physical examination changed from Week 28 to Week 24, during Long Term Extension period examination of vital signs were added at Week 68, Week 80 and to be assessed every 12 weeks; Clarification of data collection: no details required on non-psychotropic medication; Clarification of urinalysis: to be performed at central laboratory; Liver enzymes: changes to exclusion criteria excluding subjects with hepatic dysfunction
    21 Apr 2011
    Amendment C: Further information on Long Term Extension period regarding safety and tolerability of long term use (beyond 56 weeks) of RO4917838 in combination with antipsychotics as well as long-term treatment effects (beyond 56 weeks) on the symptoms, functioning, quality of life and caregivers’ burden; Addition of questionnaire; Initiation of psychosocial and/or rehabilitative therapy permitted from Treatment Period 2 (TP2) onwards; Adding of exclusion criterion 22: as glycine supplementation and other products may have an effect on the N-methyl-D aspartate (NMDA)-type glutamate receptors these substances will be prohibited during the study participation to avoid confounding the study results; Clarification of reporting of serious adverse events: elective hospitalisation or hospitalisation due to social reasons does not meet the criteria of Serious Adverse Event; Inclusion of risk and benefit assessment section: during this clinical development program the subject’s safety profile will be closely monitored. The risk for the individual subject due to treatment with RO4917838 or study related procedures are considered low because of the proposed doses and careful monitoring of all critical safety parameters. The current risk/benefit profile of the drug justifies continued assessment of RO4917838 in Phase III clinical studies. The participation in the study itself will not deprive subjects from standard treatment as their antipsychotic therapy is maintained.
    04 Oct 2011
    Amendment C-1: Description of the proton Magnetic Resonance Spectroscopy (1H-MRS) and functional magnetic resonance imaging (fMRI) sub study.
    20 Feb 2012
    Amendment D: Addition of biomarker defined subpopulations as a secondary objective; Clarification of timing of screening and prospective stabilisation period; Clarification of exclusion criterion 3 decreasing the exclusionary hemoglobin criterion in males from 13 g/dL to 12g/dL as per Data and Safety Monitoring Board (DSMB) endorsement; Updated dosing of concomitant antipsychotics for inclusion criterion 12: equivalent dose of the primary and secondary antipsychotic treatments can be the same; Clarification of exclusion criterion for Body Mass Index (BMI) < 18.5 or > 40; Revision of the definition of caregiver in inclusion criterion 5 to someone being able to support the subject through the study and who has sufficient knowledge and understanding of the subject to be able to identify changes in the subject’s condition or symptoms; Additional follow-up for treatment withdrawal and at week-52 initiation of wash-out, and clarification of withdrawal process to ensure close monitoring of reported adverse events; Definition of postmenopausal; New guidelines regarding withdrawal for hepatic laboratory abnormalities.
    30 May 2012
    Amendment D-1: Modification of caregiver burden assessment/questionnaire in the following countries: Canada, United Kingdom (UK), United States (USA), Australia, Finland, France, Germany, Italy, Netherlands, Spain and Sweden
    18 Oct 2012
    Amendment E: Modification of the caregiver burden assessment/questionnaire combining the approach related to Protocol version D and Protocol version D-1, the latest one applying locally to the following countries: Canada, United Kingdom, United States, Australia, Finland, France, Germany, Italy, Netherlands, Spain, and Sweden.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 May 2014
    Study was terminated prematurely after the primary analysis at Week 24. The study ended once the last randomised subject completed the last assessment (LPLV), which was planned for 4 weeks after the last dose taken, i.e., at the 4-week safety follow-up visit.
    -

    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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