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    Clinical Trial Results:
    A randomized, double-blind, parallel-group study of the safety and efficacy of RO4917523 versus placebo, as adjunctive therapy in patients with major depressive disorder with inadequate response to ongoing antidepressant treatment.

    Summary
    EudraCT number
    		 2011-001436-33
    Trial protocol
    		 DE  
    Global end of trial date
    27 Sep 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NP25620
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01437657
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-LaRoche 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
    27 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of two fixed doses of RO4917523 (basimglurant) compared to placebo in a confirmatory manner over 6 weeks as adjunctive therapy in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressant treatment. The change will be measured based on the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
    Background therapy
    		 Ongoing treatment with a single antidepressant of the SSRI or SNRI class was continued for the duration of the double-blind treatment period without modification of the dosing schedule.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2011
    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
    Poland: 86
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Chile: 25
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    Romania: 16
    Worldwide total number of subjects
    333
    EEA total number of subjects
    127
    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)
    321
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were screened over a period of 2 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Matching placebo capsules

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RO4917523 0.5 mg
    Arm description
    		 Subjects received 0.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO4917523
    Investigational medicinal product code
    Other name
    basimglurant
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One basimglurant 0.5 mg capsule was administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule was administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.

    Arm title
    		 RO4917523 1.5 mg
    Arm description
    		 Subjects received 1.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO4917523
    Investigational medicinal product code
    Other name
    basimglurant
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One basimglurant 0.5 mg capsule and 1 basimglurant 1.0 mg capsule were administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo once daily for 6 weeks, then were followed for 3 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Two placebo capsules were administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.

    Number of subjects in period 1
    		RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Started
    112
    111
    110
    Completed treatment
    97 [1]
    96 [2]
    99 [3]
    Completed follow-up
    103
    105
    106
    Completed
    103
    105
    106
    Not completed
    9
    6
    4
         Not specified
    9
    6
    3
         Did not receive study drug
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects who discontinued treatment could enter the follow-up period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects who discontinued treatment could enter the follow-up period.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects who discontinued treatment could enter the follow-up period.

    Baseline characteristics

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

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 333 333
    Age categorical
    Units: Subjects
        Age =< 65 years
    		 326 326
        Age > 65 years
    		 7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.6 ( 11.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 217 217
        Male
    		 116 116

    End points

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    End points reporting groups
    Reporting group title
    RO4917523 0.5 mg
    Reporting group description
    		 Subjects received 0.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks.

    Reporting group title
    RO4917523 1.5 mg
    Reporting group description
    		 Subjects received 1.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo once daily for 6 weeks, then were followed for 3 weeks.

    Primary: Change From Baseline in The Montgomery Asberg Depression Rating Scale (MADRS) Total Score

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    End point title
    		 Change From Baseline in The Montgomery Asberg Depression Rating Scale (MADRS) Total Score
    End point description
    The clinician-rated MADRS is a 10-item instrument designed to assess the overall severity of depressive symptoms on a scale of 0 to 6, with 0 being the least amount of symptoms and 6 being the most amount of symptoms. The total score ranges from 0 to 60 and is equal to the sum of all items. A negative change from baseline indicates that symptoms improved.
    End point type
    Primary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: scores on a scale
        least squares mean (standard error)
    -14.1 ( 0.9 )
    -16.1 ( 0.9 )
    -14.6 ( 0.9 )
    Statistical analysis title
    		 Analysis of MADRS total score for RO4917523 0.5 mg
    Comparison groups
    Placebo v RO4917523 0.5 mg
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.742
    Method
    		 mixed-effect model repeat measures
    Confidence interval
    Statistical analysis title
    		 Analysis of MADRS total score for RO4917523 1.5 mg
    Comparison groups
    RO4917523 1.5 mg v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.416
    Method
    		 mixed-effect model repeat measures
    Confidence interval

    Secondary: Change From Baseline in The Quick Inventory of Depressive Symptomatology-Self Report 16-Item Version (QIDS-SR16) Total Score

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    End point title
    		 Change From Baseline in The Quick Inventory of Depressive Symptomatology-Self Report 16-Item Version (QIDS-SR16) Total Score
    End point description
    The QIDS-SR16 is a 16-item scale completed by patients to assess the severity of their depressive symptoms. The scale assesses all nine symptom domains selected by DSMIV to diagnose a major depressive episode. Each of the 16 items is scored on a 4-point anchored scale, representing least severe (0) to most severe (3). Specific instructions for calculating a total score are included in the scale. Total scores range from 0 to 27 with a higher score indicating greater severity. A negative change from baseline indicates that symptoms improved.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: scores on a scale
        least squares mean (standard error)
    -6 ( 0.5 )
    -7.5 ( 0.5 )
    -5.8 ( 0.5 )
    Statistical analysis title
    		 Analysis of QIDS-SR16 for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.362 [1]
    Method
    		 mixed-effect model repeat measures
    Confidence interval
    Notes
    [1] - Unadjusted 1-sided lower p-value
    Statistical analysis title
    		 Analysis of QIDS-SR16 for RO4917523 1.5 mg
    Comparison groups
    RO4917523 1.5 mg v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [2]
    Method
    		 mixed-effect model repeat measures
    Confidence interval
    Notes
    [2] - Unadjusted 1-sided lower p-value

    Secondary: Change From Baseline in The Clinician Global Impression-Severity (CGI-S) Rating Score-LOCF

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    End point title
    		 Change From Baseline in The Clinician Global Impression-Severity (CGI-S) Rating Score-LOCF
    End point description
    The CGI-S was used to evaluate the overall clinical status (severity of illness). The CGI-S is rated on a scale of 1 to 7 with 1 referring to “normal” and 7 referring to “most severely ill." A negative change from baseline indicates that symptoms have improved. The analysis was applied to the last observation carried forward (LOCF) values.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: scores on a scale
        arithmetic mean (standard error)
    -1.25 ( 0.11 )
    -1.49 ( 0.12 )
    -1.39 ( 0.11 )
    Statistical analysis title
    		 Analysis of CGI-S for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.775 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Unadjusted 1-sided lower p-value
    Statistical analysis title
    		 Analysis of CGI-S for RO4917523 1.5 mg
    Comparison groups
    Placebo v RO4917523 1.5 mg
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.268 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Unadjusted 1-sided lower p-value

    Secondary: Distribution of Rating Scores For The Clinician Global Impression-Improvement (CGI-I) Scale-LOCF

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    End point title
    		 Distribution of Rating Scores For The Clinician Global Impression-Improvement (CGI-I) Scale-LOCF
    End point description
    The CGI-I was used to evaluate the change from baseline in clinical status. The CGI-I is rated on a scale of 1 to 7 with 1 referring to “very much improved”and 7 referring to “very much worse." The analysis was applied to the last observation carried forward (LOCF) values.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: scores on a scale
        arithmetic mean (standard error)
    2.58 ( 0.11 )
    2.21 ( 0.1 )
    2.41 ( 0.1 )
    Statistical analysis title
    		 Analysis of CGI-I for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.851 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Unadjusted 1-sided lower p-value
    Statistical analysis title
    		 Analysis of CGI-I for RO4917523 1.5 mg
    Comparison groups
    RO4917523 1.5 mg v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Unadjusted 1-sided lower p-value

    Secondary: Distribution of Rating Scores For The Patient Global Impression-Improvement (PGI-I) Scale

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    End point title
    		 Distribution of Rating Scores For The Patient Global Impression-Improvement (PGI-I) Scale
    End point description
    The PGI-I is a self-reported instrument to record the patient’s own assessment of improvement since baseline. The patient is asked to rate their condition now, as compared to how it was before they began study medication, using a 7-point scale ranging from very much better (1) to very much worse (7). The PGI-I is essentially a patient-reported version of the CGI-I.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: scores on a scale
        arithmetic mean (standard error)
    2.7 ( 0.11 )
    2.41 ( 0.12 )
    2.63 ( 0.1 )
    Statistical analysis title
    		 Analysis of PGI-I for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.534 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Unadjusted 1-sided lower p-value
    Statistical analysis title
    		 Analysis of PGI-I for RO4917523 1.5 mg
    Comparison groups
    Placebo v RO4917523 1.5 mg
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Unadjusted 1-sided lower p-value

    Secondary: Percent of Subjects Exhibiting Response After 6 Weeks of Treatment

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    End point title
    		 Percent of Subjects Exhibiting Response After 6 Weeks of Treatment
    End point description
    Response was defined as a ≥ 50% improvement in the total score of the clinician-rated Montgomery Asberg Depression Rating Scale (MADRS) from Baseline to Day 42.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: percent of subjects
        number (not applicable)
    41.96
    50.45
    46.79
    Statistical analysis title
    		 Analysis of response for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.804 [9]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [9] - Unadjusted 1-sided upper p-value
    Statistical analysis title
    		 Analysis of response for RO4917523 1.5 mg
    Comparison groups
    Placebo v RO4917523 1.5 mg
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.342 [10]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [10] - Unadjusted 1-sided upper p-value

    Secondary: Percent of Subjects With Remission After 6 Weeks of Treatment

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    End point title
    		 Percent of Subjects With Remission After 6 Weeks of Treatment
    End point description
    Remission was defined as having a clinician-rated Montgomery Asberg Depression Rating Scale (MADRS) total score of ≤ 10 at Day 42
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: percent of subjects
        number (not applicable)
    26.79
    36.04
    30.28
    Statistical analysis title
    		 Analysis of remission for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.765 [11]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [11] - Unadjusted 1-sided upper p-value
    Statistical analysis title
    		 Analysis of remission for RO4917523 1.5 mg
    Comparison groups
    Placebo v RO4917523 1.5 mg
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.222 [12]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [12] - Unadjusted 1-sided upper p-value

    Post-hoc: Change From Baseline in The Patient-Rated Montgomery Asberg Depression Rating Scale (MADRS) Total Score

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    End point title
    		 Change From Baseline in The Patient-Rated Montgomery Asberg Depression Rating Scale (MADRS) Total Score
    End point description
    Following the assessment of the MADRS by the rater, the patient then completed the MADRS as a self-assessment using the same laptop computer (the “patient-rated MADRS”; Sachs et al., 2011). The assessment of the patient-rated MADRS was made at all visits where the clinician-rated MADRS was assessed (excluding follow up). It was administered as a computerized, interactive interview, involving a series of probe and follow-up questions with multiple choice response options. A negative change from baseline indicates that symptoms improved.
    End point type
    Post-hoc
    End point timeframe
    From Baseline to Day 42
    End point values
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Number of subjects analysed
    112
    111
    109
    Units: scores on a scale
        least squares mean (standard error)
    -13.1 ( 1 )
    -16.2 ( 1 )
    -13.3 ( 1 )
    Statistical analysis title
    		 Analysis of MADRS total score for RO4917523 0.5 mg
    Comparison groups
    RO4917523 0.5 mg v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.547 [13]
    Method
    		 mixed-effect model repeat measures
    Confidence interval
    Notes
    [13] - Unadjusted 1-sided lower p-value
    Statistical analysis title
    		 Analysis of MADRS total score for RO4917523 1.5 mg
    Comparison groups
    RO4917523 1.5 mg v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021 [14]
    Method
    		 mixed-effect model repeat measures
    Confidence interval
    Notes
    [14] - Unadjusted 1-sided lower p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    9 weeks after start of treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    RO4917523 0.5 mg
    Reporting group description
    		 Subjects received 0.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks.

    Reporting group title
    RO4917523 1.5 mg
    Reporting group description
    		 Subjects received 1.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo once daily for 6 weeks, then were followed for 3 weeks.

    Serious adverse events
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 111 (0.90%)
    2 / 109 (1.83%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Tibia Fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 111 (0.90%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major Depression
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure Acute
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 111 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RO4917523 0.5 mg RO4917523 1.5 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 112 (30.36%)
    44 / 111 (39.64%)
    39 / 109 (35.78%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 112 (4.46%)
    26 / 111 (23.42%)
    6 / 109 (5.50%)
         occurrences all number
    7
    32
    8
    Headache
         subjects affected / exposed
    12 / 112 (10.71%)
    8 / 111 (7.21%)
    8 / 109 (7.34%)
         occurrences all number
    14
    8
    10
    Somnolence
         subjects affected / exposed
    13 / 112 (11.61%)
    7 / 111 (6.31%)
    10 / 109 (9.17%)
         occurrences all number
    15
    7
    10
    Gastrointestinal disorders
    Dry Mouth
         subjects affected / exposed
    4 / 112 (3.57%)
    6 / 111 (5.41%)
    4 / 109 (3.67%)
         occurrences all number
    4
    6
    6
    Nausea
         subjects affected / exposed
    6 / 112 (5.36%)
    8 / 111 (7.21%)
    13 / 109 (11.93%)
         occurrences all number
    6
    8
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 112 (6.25%)
    6 / 111 (5.41%)
    2 / 109 (1.83%)
         occurrences all number
    7
    6
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 111 (0.00%)
    8 / 109 (7.34%)
         occurrences all number
    1
    0
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2011
    This amendment introduced the following key changes: -Blood sampling for the purpose of clinical genoptying was added to the collection of specimens from patients during the study (3 mL blood sample on Day 1). -An electrocardiogram (ECG) measurement on Day 14 was added to the schedule of assessments. -Individuals whose occupation is to drive or operate mass transportation (i.e., buses, trains), large vehicles (i.e., trucks), or heavy machinery were added to the exclusion criteria. -Fluvoxamine, pregabalin and gabapentin were added to the list of prohibited concomitant medications.
    02 Apr 2012
    This amendment introduced the following key changes: -The inclusion criteria were amended to enable enrollment of patients up to 70 years of age, and patients with a body mass index (BMI) between 18 and 38 kg/m2 inclusive. -By health authority request, patients with a positive finding on the Columbia-Suicide Severity Rating Scale (C-SSRS) or with liver function test abnormalities that met Hy’s law were required to be withdrawn. -Assumptions for sample size calculation were clarified, and the description of handling of missing data was updated. -The option for the Drug Safety Monitoring Board (DSMB) to review efficacy data during safety reviews was added.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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