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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.

    Summary
    EudraCT number
    		 2010-020467-21
    Trial protocol
    		 ES   DE   LT   LV   SK   NL  
    Global end of trial date
    09 Jun 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
    WN25309
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01192906
    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 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
    09 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objectives of this study are : • To evaluate the efficacy of 24 weeks treatment with bitopertin in the Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) in patients with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics • To evaluate the safety and tolerability of 24 weeks of treatment with bitopertin in patients with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics
    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
    		 This is an add-on therapy to selected typical and atypical antipsychotics treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 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
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 85
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Lithuania: 40
    Country: Number of subjects enrolled
    Turkey: 25
    Country: Number of subjects enrolled
    Ukraine: 58
    Country: Number of subjects enrolled
    Canada: 51
    Country: Number of subjects enrolled
    United States: 73
    Country: Number of subjects enrolled
    Brazil: 155
    Country: Number of subjects enrolled
    Chile: 26
    Country: Number of subjects enrolled
    Taiwan: 27
    Worldwide total number of subjects
    621
    EEA total number of subjects
    206
    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)
    609
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study enrolled outpatients aged 18 and above with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of schizophrenia with persistent, predominant negative symptoms and on current stable antipsychotic treatment.

    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
    Subjects and investigators remained blinded to the treatment they received throughout the study. In the Follow-up, subjects did not receive drug but they remained blinded to the treatment they had received previously.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo - Treatment Period 1
    Arm description
    		 Participants received placebo orally once daily 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 dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

    Arm title
    		 Bitopertin 5 mg - Treatment Period 1
    Arm description
    		 Participants received bitopertin 5 mg orally once daily 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
    5 mg taken orally once daily in the morning, with or without food

    Arm title
    		 Bitopertin 10 mg - Treatment Period 1
    Arm description
    		 Participants received bitopertin 10 mg orally once daily 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 taken orally once daily in the morning, with or without food

    Arm title
    		 Placebo - Treatment Period 2
    Arm description
    		 Participants received placebo orally once daily 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 dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

    Arm title
    		 Bitopertin 5 mg - Treatment Period 2
    Arm description
    		 Participants received bitopertin 5 mg orally once daily 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
    5 mg taken orally once daily in the morning, with or without food

    Arm title
    		 Bitopertin 10 mg - Treatment Period 2
    Arm description
    		 Participants received bitopertin 10 mg orally once daily 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 taken orally once daily in the morning, with or without food

    Arm title
    		 Placebo - Washout Period
    Arm description
    		 Participants received placebo orally once daily 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 dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

    Arm title
    		 Bitopertin 5 mg - Washout Period
    Arm description
    		 Participants received bitopertin 5 mg orally once daily 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
    5 mg taken orally once daily in the morning, with or without food

    Arm title
    		 Bitopertin 5 mg to placebo - Washout Period
    Arm description
    		 Participants received placebo orally once daily 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 dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

    Arm title
    		 Bitopertin 10 mg - Washout Period
    Arm description
    		 Participants received bitopertin 10 mg orally once daily 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 taken orally once daily in the morning, with or without food

    Arm title
    		 Bitopertin 10 mg to placebo - Washout Period
    Arm description
    		 Participants received placebo orally once daily 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 dose of 10 mg tablet taken once daily in the morning, with or without food

    Arm title
    		 Placebo to Bitopertin 10 mg - Long-Term Extension
    Arm description
    		 Participants received bitopertin 10 mg orally once daily 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 taken orally once daily in the morning, with or without food

    Arm title
    		 Bitopertin 5 mg to Bitopertin 10 mg - Long-Term Extension
    Arm description
    		 Participants received bitopertin 10 mg orally once daily 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 taken orally once daily in the morning, with or without food

    Arm title
    		 Bitopertin 10 mg - Long-Term Extension
    Arm description
    		 Participants received bitopertin 10 mg orally once daily 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 taken orally once daily in the morning, with or without food

    Arm title
    		 Placebo - Safety Follow-Up Period
    Arm description
    		 Participants were not treated during the follow-up period
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Bitopertin 5 mg - Safety Follow-Up Period
    Arm description
    		 Participants were not treated during the follow-up period
    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
    		 Participants were not treated during the follow-up period
    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 5 mg - Treatment Period 1 Bitopertin 10 mg - Treatment Period 1 Placebo - Treatment Period 2 Bitopertin 5 mg - Treatment Period 2 Bitopertin 10 mg - Treatment Period 2 Placebo - Washout Period Bitopertin 5 mg - Washout Period Bitopertin 5 mg to placebo - Washout Period Bitopertin 10 mg - Washout Period Bitopertin 10 mg to placebo - Washout Period Placebo to Bitopertin 10 mg - Long-Term Extension Bitopertin 5 mg to Bitopertin 10 mg - Long-Term Extension Bitopertin 10 mg - Long-Term Extension Placebo - Safety Follow-Up Period Bitopertin 5 mg - Safety Follow-Up Period Bitopertin 10 mg - Safety Follow-Up Period
    Started
    209
    211
    201
    178
    181
    165
    133
    66
    66
    63
    63
    121
    116
    114
    88
    95
    438
    Completed
    181
    185
    166
    134
    136
    127
    129
    62
    66
    61
    61
    0
    0
    0
    53
    60
    370
    Not completed
    28
    26
    35
    44
    45
    38
    4
    4
    0
    2
    2
    121
    116
    114
    35
    35
    68
         Adverse event, non-fatal
    20
    12
    10
    6
    7
    5
    1
    1
    -
    -
    1
    1
    4
    7
    5
    4
    4
         Protocol violation
    -
    2
    2
    1
    1
    -
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Death
    -
    -
    -
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    2
    1
    -
         Non-compliance
    2
    1
    7
    4
    -
    2
    -
    1
    -
    -
    -
    2
    1
    1
    -
    -
    -
         Administrative/Other
    -
    3
    1
    28
    28
    23
    2
    2
    -
    2
    -
    112
    100
    100
    5
    14
    13
         Lost to follow-up
    2
    -
    1
    1
    1
    5
    -
    -
    -
    -
    -
    -
    1
    -
    8
    7
    22
         Withdrawal by subject
    3
    6
    12
    3
    6
    1
    -
    -
    -
    -
    1
    2
    8
    4
    15
    9
    29
         Lack of efficacy
    1
    2
    2
    -
    2
    2
    1
    -
    -
    -
    -
    3
    2
    2
    -
    -
    -

    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
    		 621 621
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.4 ± 11.7 -
    Gender categorical
    Units: Subjects
        Female
    		 191 191
        Male
    		 430 430

    End points

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    End points reporting groups
    Reporting group title
    Placebo - Treatment Period 1
    Reporting group description
    		 Participants received placebo orally once daily for 24 weeks

    Reporting group title
    Bitopertin 5 mg - Treatment Period 1
    Reporting group description
    		 Participants received bitopertin 5 mg orally once daily for 24 weeks

    Reporting group title
    Bitopertin 10 mg - Treatment Period 1
    Reporting group description
    		 Participants received bitopertin 10 mg orally once daily for 24 weeks

    Reporting group title
    Placebo - Treatment Period 2
    Reporting group description
    		 Participants received placebo orally once daily for 28 weeks

    Reporting group title
    Bitopertin 5 mg - Treatment Period 2
    Reporting group description
    		 Participants received bitopertin 5 mg orally once daily for 28 weeks

    Reporting group title
    Bitopertin 10 mg - Treatment Period 2
    Reporting group description
    		 Participants received bitopertin 10 mg orally once daily for 28 weeks

    Reporting group title
    Placebo - Washout Period
    Reporting group description
    		 Participants received placebo orally once daily for 4 weeks

    Reporting group title
    Bitopertin 5 mg - Washout Period
    Reporting group description
    		 Participants received bitopertin 5 mg orally once daily for 4 weeks

    Reporting group title
    Bitopertin 5 mg to placebo - Washout Period
    Reporting group description
    		 Participants received placebo orally once daily for 4 weeks

    Reporting group title
    Bitopertin 10 mg - Washout Period
    Reporting group description
    		 Participants received bitopertin 10 mg orally once daily for 4 weeks

    Reporting group title
    Bitopertin 10 mg to placebo - Washout Period
    Reporting group description
    		 Participants received placebo orally once daily for 4 weeks

    Reporting group title
    Placebo to Bitopertin 10 mg - Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 10 mg orally once daily for up to 3 years

    Reporting group title
    Bitopertin 5 mg to Bitopertin 10 mg - Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 10 mg orally once daily for up to 3 years

    Reporting group title
    Bitopertin 10 mg - Long-Term Extension
    Reporting group description
    		 Participants received bitopertin 10 mg orally once daily for up to 3 years

    Reporting group title
    Placebo - Safety Follow-Up Period
    Reporting group description
    		 Participants were not treated during the follow-up period

    Reporting group title
    Bitopertin 5 mg - Safety Follow-Up Period
    Reporting group description
    		 Participants were not treated during the follow-up period

    Reporting group title
    Bitopertin 10 mg - Safety Follow-Up Period
    Reporting group description
    		 Participants were not treated during the follow-up period

    Primary: Mean Change from Baseline in the PANSS Negative Symptom Factor Score at Week 24

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    End point title
    		 Mean Change from Baseline in the PANSS Negative Symptom Factor Score at Week 24 [1]
    End point description
    The PANSS is a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. Each of the 30 items is rated on a 7-point scale, from 1 to 7 (absence of to extreme psychopathology). The negative symptom subscale is composed of 7 items: Blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The score on the negative symptom subscale can range from 0 to 49, with a higher score indicating more negative symptom psychopathology. A negative change score indicates improvement. Intent-to-treat population: All randomized participants who received at least 1 dose of double-blind study drug and had at least one post-baseline assessment of the primary efficacy variable. For all analyses of PANSS data, the scores were transformed into 0-6 points to express “absent” as 0.
    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: This final abbreviated Clinical Study Report (CSR) presents the data at Week 24 for the key primary endpoint, Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS), and the key secondary endpoint, Personal and Social Performance (PSP) total score. The study did not meet its primary endpoint.
    End point values
    		 Placebo - Treatment Period 1 Bitopertin 5 mg - Treatment Period 1 Bitopertin 10 mg - Treatment Period 1
    Number of subjects analysed
    203
    205
    197
    Units: number
        arithmetic mean (standard error)
    -5.25 ± 0.365
    -5.53 ± 0.33
    -5.87 ± 0.366
    Statistical analysis title
    		 Placebo vs. Bitopertin 5 mg - PANSS at Week 24
    Statistical analysis description
    Primary analysis population was ITT population. For all analyses of PANSS data, scores were transformed into 0-6 points to express “absent” as 0. Mean change from baseline in PANSS NSFS and PSP at Week 24 was analyzed using an MMRM incorporating data collected up to 24 weeks of treatment to assess all data collected over time with consideration of the variance−covariance matrix of repeated measures. No imputation for missing data were used in primary analyses.
    Comparison groups
    Placebo - Treatment Period 1 v Bitopertin 5 mg - Treatment Period 1
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4742
    Method
    		 Mixed Models Repeated Measures Analysis
    Confidence interval
    Statistical analysis title
    		 Placebo vs. Bitopertin 10 mg - PANSS at Week 24
    Statistical analysis description
    Primary analysis population was ITT population. For all analyses of PANSS data, scores were transformed into 0-6 points to express “absent” as 0. Mean change from baseline in PANSS NSFS and PSP at Week 24 was analyzed using an MMRM incorporating data collected up to 24 weeks of treatment to assess all data collected over time with consideration of the variance−covariance matrix of repeated measures. No imputation for missing data was used in primary analyses.
    Comparison groups
    Placebo - Treatment Period 1 v Bitopertin 10 mg - Treatment Period 1
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0989
    Method
    		 Mixed Models Repeated Measures Analysis
    Confidence interval

    Secondary: Mean Change from Baseline in the Personal and Social Performance (PSP) Total Score at Week 24

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    End point title
    		 Mean Change from Baseline in the Personal and Social Performance (PSP) Total Score at Week 24 [2]
    End point description
    The PSP is a clinician-rated 100-point rating scale subdivided into 10 equal intervals, enabling the determination of small changes in levels of functioning. The ratings are based upon assessment of the patient’s functioning in 4 areas: 1) Socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviors. Each of the 4 areas is rated in 6 degrees of severity (absent, mild, manifest, marked, severe, very severe). Higher scores represent better personal and social functioning, with ratings from 91-100 referring to more than adequate functioning, while scores under 30 refer to poor functioning that intensive supervision is required. A higher score indicates better functioning. A positive change score indicates improvement. Intent-to-treat population: All randomized participants who received at least 1 dose of double-blind study drug and had at least one post-baseline assessment of the primary efficacy variable.
    End point type
    Secondary
    End point timeframe
    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: This final abbreviated Clinical Study Report (CSR) presents the data at Week 24 for the key primary endpoint, Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS), and the key secondary endpoint, Personal and Social Performance (PSP) total score. The study did not meet its primary endpoint.
    End point values
    		 Placebo - Treatment Period 1 Bitopertin 5 mg - Treatment Period 1 Bitopertin 10 mg - Treatment Period 1
    Number of subjects analysed
    203
    205
    197
    Units: number
        arithmetic mean (standard error)
    8.64 ± 0.752
    6.64 ± 0.712
    8.24 ± 0.733
    Statistical analysis title
    		 Placebo vs. Bitopertin 5 mg - PSP at Week 24
    Statistical analysis description
    Primary analysis population was ITT population. For all analyses of PANSS data, scores were transformed into 0-6 points to express “absent” as 0. Mean change from baseline in PSP at Week 24 was analyzed using an MMRM incorporating data collected up to 24 weeks of treatment to assess all data collected over time with consideration of the variance−covariance matrix of repeated measures. No imputation for missing data were used in primary analyses.
    Comparison groups
    Placebo - Treatment Period 1 v Bitopertin 5 mg - Treatment Period 1
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1288
    Method
    		 Mixed Models Repeated Measures Analysis
    Confidence interval
    Statistical analysis title
    		 Placebo vs. Bitopertin 10 mg - PSP at Week 24
    Statistical analysis description
    Primary analysis population was ITT population. For all analyses of PANSS data, scores were transformed into 0-6 points to express “absent” as 0. Mean change from baseline in PSP at Week 24 was analyzed using an MMRM incorporating data collected up to 24 weeks of treatment to assess all data collected over time with consideration of the variance−covariance matrix of repeated measures. No imputation for missing data were used in primary analyses.
    Comparison groups
    Placebo - Treatment Period 1 v Bitopertin 10 mg - Treatment Period 1
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6471
    Method
    		 Mixed Models Repeated Measures Analysis
    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
    Reporting groups
    Reporting group title
    Placebo through Week 52
    Reporting group description
    		 -

    Reporting group title
    Bitopertin 5 mg through Week 52
    Reporting group description
    		 -

    Reporting group title
    Bitopertin 10 mg through Week 52
    Reporting group description
    		 -

    Reporting group title
    Placebo during washout period
    Reporting group description
    		 -

    Reporting group title
    Bitopertin 5 mg during washout period
    Reporting group description
    		 -

    Reporting group title
    Bitopertin 5 mg to 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
    Placebo to bitopertin 10 mg during long-term extension
    Reporting group description
    		 -

    Reporting group title
    Bitopertin 5 mg 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
    Placebo during follow-up period
    Reporting group description
    		 -

    Reporting group title
    Bitopertin 5 mg during follow-up period
    Reporting group description
    		 -

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

    Serious adverse events
    		 Placebo through Week 52 Bitopertin 5 mg through Week 52 Bitopertin 10 mg through Week 52 Placebo during washout period Bitopertin 5 mg during washout period Bitopertin 5 mg to Placebo during washout period Bitopertin 10 mg during washout period Bitopertin 10 mg to placebo during washout period Placebo to bitopertin 10 mg during long-term extension Bitopertin 5 mg to bitopertin 10 mg during long-term extension Bitopertin 10 mg during long-term extension Placebo during follow-up period Bitopertin 5 mg during follow-up period Bitopertin 10 mg during follow-up period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 209 (7.18%)
    11 / 211 (5.21%)
    16 / 201 (7.96%)
    1 / 133 (0.75%)
    0 / 66 (0.00%)
    2 / 66 (3.03%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
    2 / 121 (1.65%)
    3 / 116 (2.59%)
    5 / 114 (4.39%)
    5 / 88 (5.68%)
    4 / 95 (4.21%)
    9 / 438 (2.05%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    1 / 121 (0.83%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Benign ovarian tumour
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    1 / 116 (0.86%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Uterine leiomyoma
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    1 / 438 (0.23%)
         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
    General disorders and administration site conditions
    Mass
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    1 / 121 (0.83%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Sudden death
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Victim of homicide
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    1 / 88 (1.14%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    1 / 438 (0.23%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    1 / 438 (0.23%)
         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
    Pulmonary embolism
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    3 / 201 (1.49%)
    1 / 133 (0.75%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
    0 / 121 (0.00%)
    1 / 116 (0.86%)
    1 / 114 (0.88%)
    1 / 88 (1.14%)
    1 / 95 (1.05%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    5 / 209 (2.39%)
    3 / 211 (1.42%)
    3 / 201 (1.49%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    2 / 114 (1.75%)
    3 / 88 (3.41%)
    2 / 95 (2.11%)
    3 / 438 (0.68%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 3
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 3
    0 / 2
    1 / 3
         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
    Alcohol abuse
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Anxiety disorder
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    1 / 438 (0.23%)
         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
    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
    Hallucination
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         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
    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
    Thinking abnormal
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    1 / 438 (0.23%)
         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
    Anxiety
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Suicidal Ideation
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Depression
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    1 / 116 (0.86%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    1 / 114 (0.88%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Multiple fractures
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    1 / 114 (0.88%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Foot fracture
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    1 / 121 (0.83%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Hand fracture
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Wound
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Carbon monoxide poisoning
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Tendon injury
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Congenital, familial and genetic disorders
    Dermoid Cyst
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    1 / 95 (1.05%)
    0 / 438 (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
    Cardiomyopathy
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    1 / 95 (1.05%)
    0 / 438 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Duodenal ulcer
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    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
    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
    Jaw cyst
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    2 / 201 (1.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Necrotising fasciitis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 201 (0.50%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Ehinococciasis
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Pneumonia
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    1 / 121 (0.83%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    2 / 95 (2.11%)
    0 / 438 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 201 (0.00%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    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
    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 through Week 52 Bitopertin 5 mg through Week 52 Bitopertin 10 mg through Week 52 Placebo during washout period Bitopertin 5 mg during washout period Bitopertin 5 mg to Placebo during washout period Bitopertin 10 mg during washout period Bitopertin 10 mg to placebo during washout period Placebo to bitopertin 10 mg during long-term extension Bitopertin 5 mg to bitopertin 10 mg during long-term extension Bitopertin 10 mg during long-term extension Placebo during follow-up period Bitopertin 5 mg during follow-up period Bitopertin 10 mg during follow-up period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    153 / 209 (73.21%)
    138 / 211 (65.40%)
    122 / 201 (60.70%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    47 / 121 (38.84%)
    49 / 116 (42.24%)
    40 / 114 (35.09%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
    Investigations
    Weight increased
         subjects affected / exposed
    12 / 209 (5.74%)
    9 / 211 (4.27%)
    8 / 201 (3.98%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    14
    10
    10
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 209 (10.53%)
    18 / 211 (8.53%)
    13 / 201 (6.47%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    7 / 121 (5.79%)
    4 / 116 (3.45%)
    3 / 114 (2.63%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    32
    39
    24
    0
    0
    0
    0
    0
    7
    4
    3
    0
    0
    0
    Somnolence
         subjects affected / exposed
    11 / 209 (5.26%)
    9 / 211 (4.27%)
    10 / 201 (4.98%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    11
    10
    11
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    11 / 209 (5.26%)
    5 / 211 (2.37%)
    8 / 201 (3.98%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    11
    6
    8
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 209 (5.26%)
    11 / 211 (5.21%)
    3 / 201 (1.49%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    13
    12
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 209 (4.78%)
    11 / 211 (5.21%)
    10 / 201 (4.98%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    3 / 116 (2.59%)
    6 / 114 (5.26%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    13
    18
    16
    0
    0
    0
    0
    0
    0
    3
    6
    0
    0
    0
    Insomnia
         subjects affected / exposed
    11 / 209 (5.26%)
    10 / 211 (4.74%)
    6 / 201 (2.99%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 121 (0.00%)
    0 / 116 (0.00%)
    0 / 114 (0.00%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    14
    12
    6
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    20 / 209 (9.57%)
    17 / 211 (8.06%)
    13 / 201 (6.47%)
    0 / 133 (0.00%)
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    7 / 121 (5.79%)
    5 / 116 (4.31%)
    2 / 114 (1.75%)
    0 / 88 (0.00%)
    0 / 95 (0.00%)
    0 / 438 (0.00%)
         occurrences all number
    23
    19
    19
    0
    0
    0
    0
    0
    8
    6
    3
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2010
    Version A: Staggered start approach was removed, increased safety monitoring per Special Protocol Assessment (SPA) feedback, various sections of the protocol were clarified.
    15 Sep 2010
    Version B: Clarification for dosing during Long-term Extension Period, addition of criteria to exclude patients who may have pre-existing potentially clinically significant hepatic dysfunction, addition of creatinine phosphokinase (was not listed in the standard laboratory list by error), clarification on procedures for Roche Clinical Repository (RCR), Work Readiness Questionnaire included as exploratory efficacy endpoint, corrected errors in the schedule of assessments and procedures.
    21 Apr 2011
    Version C: Inclusion of FDA’s requirements for analysis of iron inclusion bodies, changes to safety reporting of adverse events, clarification of screening/rescreening procedures, minor changes to study design (permission of psychosocial/rehabilitative therapies, addition of questionnaire to ensure exclusion of treatment resistant patients, minor changes to schedule of assessments and procedures), description of the VERIFIED™ system (Video Enhancement of Rater Interviewing for Independent Evaluation of Data) part of the rater quality assurance program.
    30 May 2012
    Version D: Addition of biomarker defined subpopulations as a secondary objective, clarification of hemoglobin exclusion criterion, additional follow-up for treatment withdrawal and at Week 52 initiation of washout, and clarification of withdrawal process, clarification of timing of screening and prospective stabilization period
    25 Jan 2013
    Version E: Inclusion of futility analysis, addition of biomarker defined subpopulation analysis as a key secondary objective, change in Data Safety Monitoring Board (DSMB) to Independent Data Monitoring Committee (IDMC), modification of body mass index (BMI) criterion, changes in serious adverse event (SAE) reporting timeframe, and other changes (addition of electrocardiogram [ECG] at Week 58, clarification of safety population, clarification of length of study, removal of analysis of the per protocol population)

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Nov 2013
    While bitopertin was generally well tolerated and its overall safety profile was similar to that seen in the previously reported phase II trial (NN20372), the study failed to meet its primary endpoint at week 24 (treatment period 1). These results do not support continuation of patients’ treatment (treatment period 2, until week 56 and long-term extension), and the decision was made to terminate this study early.
    -

    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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