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    Clinical Trial Results:
    Efficacy and safety of 2 doses of agomelatine (10mg, 25mg) given orally in children (from 7 to less than 12 years) and adolescents (from 12 to less than 18 years) with moderate to severe Major Depressive Disorder. A 12-week, randomized, double-blind, active (fluoxetine 10 mg/day with potential adjustment to 20 mg/day) and placebo-controlled, parallel groups, international, multicentre study followed by an optional open-labelled 21-month safety extension period.

    Summary
    EudraCT number
    2015-002181-23
    Trial protocol
    FI   HU   DE   BG   PL  
    Global end of trial date
    27 Oct 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    11 May 2022
    First version publication date
    24 Jul 2020
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Final results

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CL3-20098-076
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherche International Servier, 33 155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherche International Servier, 33 155724366, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001181-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate the antidepressant short-term efficacy of at least one of the two doses of agomelatine compared to placebo after 12 weeks of treatment in children (from 7 to less than 12 years of age) and adolescents (from 12 to less than 18 years of age) suffering from moderate to severe Major Depressive Disorder using Children Depression Rating Scale – Revised (CDRS-R).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Feb 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    21 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 17
    Country: Number of subjects enrolled
    Ukraine: 72
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    Hungary: 74
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 61
    Country: Number of subjects enrolled
    Russian Federation: 120
    Country: Number of subjects enrolled
    Serbia: 10
    Worldwide total number of subjects
    400
    EEA total number of subjects
    181
    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)
    80
    Adolescents (12-17 years)
    320
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Male or female, in-or-out patients: children (from 7 to less than 12 years old) and adolescents (from 12 to less than 18 years old). Primary diagnosis of Major Depressive Disorder (MDD), single or recurrent episode, of moderate to severe intensity, fulfilling DSM-IV-TR, CDRS-R Raw score > or = 45, CGI-S score > or = 4.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Agomelatine 10 mg - Total population
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime.

    Arm title
    Agomelatine 25 mg - Total population
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime.

    Arm title
    Placebo - Total population
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

    Arm title
    Fluoxetine - Total population
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Fluoxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL (10 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double leading to an increased dose: 5 mL (20 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

    Number of subjects in period 1
    Agomelatine 10 mg - Total population Agomelatine 25 mg - Total population Placebo - Total population Fluoxetine - Total population
    Started
    102
    95
    103
    100
    Completed
    94
    84
    87
    87
    Not completed
    8
    11
    16
    13
         Non medical reason
    3
    7
    12
    9
         Adverse event, non-fatal
    2
    3
    2
    3
         Lack of efficacy
    3
    1
    2
    -
         Protocol deviation
    -
    -
    -
    1
    Period 2
    Period 2 title
    Double-blind period - Adolescents
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Agomelatine 10 mg - Adolescents
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime.

    Arm title
    Agomelatine 25 mg - Adolescents
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime.

    Arm title
    Placebo - Adolescents
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

    Arm title
    Fluoxetine - Adolescents
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Fluoxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL (10 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double leading to an increased dose: 5 mL (20 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

    Number of subjects in period 2
    Agomelatine 10 mg - Adolescents Agomelatine 25 mg - Adolescents Placebo - Adolescents Fluoxetine - Adolescents
    Started
    81
    76
    82
    81
    Completed
    73
    68
    71
    71
    Not completed
    8
    8
    11
    10
         Non medical reason
    3
    5
    8
    6
         Adverse event, non-fatal
    2
    2
    1
    3
         Lack of efficacy
    3
    1
    2
    -
         Protocol deviation
    -
    -
    -
    1
    Period 3
    Period 3 title
    Double-blind period - Children
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Agomelatine 10 mg - Children
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime.

    Arm title
    Agomelatine 25 mg - Children
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime.

    Arm title
    Placebo - Children
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

    Arm title
    Fluoxetine - Children
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Fluoxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL (10 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double leading to an increased dose: 5 mL (20 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

    Number of subjects in period 3
    Agomelatine 10 mg - Children Agomelatine 25 mg - Children Placebo - Children Fluoxetine - Children
    Started
    21
    19
    21
    19
    Completed
    21
    16
    16
    16
    Not completed
    0
    3
    5
    3
         Non medical reason
    -
    2
    4
    3
         Adverse event, non-fatal
    -
    1
    1
    -
    Period 4
    Period 4 title
    Open-label Period - Total population
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in the agomelatine 10 mg or agomelatine 25 mg groups.

    Arm title
    Placebo / Agomelatine 10-25 mg - W012-W104 period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, all patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were on placebo.

    Arm title
    Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, all patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in the fluoxetine group (10 mg or 20 mg from W2 depending on the improvement of the patient).

    Arm title
    All - W012-W104 period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, all patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in agomelatine, fluoxetine or placebo groups.

    Number of subjects in period 4
    Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period Placebo / Agomelatine 10-25 mg - W012-W104 period Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period All - W012-W104 period
    Started
    170
    85
    84
    339
    Completed
    93
    48
    46
    187
    Not completed
    77
    37
    38
    152
         Recovery
    40
    14
    15
    69
         Non medical reason
    25
    12
    17
    54
         Adverse event, non-fatal
    6
    5
    3
    14
         Lost to follow-up
    1
    1
    -
    2
         Lack of efficacy
    4
    2
    2
    8
         Protocol deviation
    1
    3
    1
    5
    Period 5
    Period 5 title
    Open-label Period - Adolescents
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, adolescent patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in the agomelatine 10 mg or agomelatine 25 mg groups.

    Arm title
    Placebo / Agomelatine 10-25 mg - Ado - W012-W104
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, adolescents took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were on placebo.

    Arm title
    Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012-W104
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, adolescents took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in the fluoxetine group (10 mg or 20 mg from W2 depending on the improvement of the patient).

    Arm title
    All - Adolescents - W012-W104
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W12 to W14, adolescents took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in agomelatine, fluoxetine or placebo groups.

    Number of subjects in period 5
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104 Placebo / Agomelatine 10-25 mg - Ado - W012-W104 Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012-W104 All - Adolescents - W012-W104
    Started
    134
    69
    68
    271
    Completed
    71
    38
    36
    145
    Not completed
    63
    31
    32
    126
         Recovery
    31
    11
    13
    55
         Non medical reason
    23
    9
    14
    46
         Adverse event, non-fatal
    3
    5
    3
    11
         Lost to follow-up
    1
    1
    -
    2
         Protocol deviation
    1
    3
    1
    5
         Lack of efficacy
    4
    2
    1
    7
    Period 6
    Period 6 title
    Study period W000-W104
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W12 to W14, patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient.

    Arm title
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W12 to W14, adolescents took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient.

    Number of subjects in period 6
    Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
    Started
    170
    134
    Completed
    93
    71
    Not completed
    77
    63
         Recovery
    40
    31
         Non medical reason
    25
    23
         Adverse event, non-fatal
    6
    3
         Lost to follow-up
    1
    1
         Lack of efficacy
    4
    4
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Agomelatine 10 mg - Total population
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Total population
    Reporting group description
    -

    Reporting group title
    Placebo - Total population
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Total population
    Reporting group description
    -

    Reporting group values
    Agomelatine 10 mg - Total population Agomelatine 25 mg - Total population Placebo - Total population Fluoxetine - Total population Total
    Number of subjects
    102 95 103 100 400
    Age categorical
    Units: Subjects
        Children (2-11 years)
    21 19 21 19 80
        Adolescents (12-17 years)
    81 76 82 81 320
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.6 ± 2.9 13.4 ± 2.7 13.8 ± 2.6 13.8 ± 2.7 -
    Gender categorical
    Units: Subjects
        Female
    68 61 64 57 250
        Male
    34 34 39 43 150
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all patients of the Modified Randomised Set (MRS) having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint. MRS: All included and randomised patients (i.e. all included patients to whom a therapeutic unit was randomly assigned using IRS).

    Subject analysis set title
    Adolescents of the Full Analysis Set (FAS_ADO)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all adolescents patients of the MRS having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint.

    Subject analysis set title
    Children of the Full Analysis Set (FAS_CHILD)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all children patients of the MRS having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint.

    Subject analysis sets values
    Full Analysis Set (FAS) Adolescents of the Full Analysis Set (FAS_ADO) Children of the Full Analysis Set (FAS_CHILD)
    Number of subjects
    396
    317
    79
    Age categorical
    Units: Subjects
        Children (2-11 years)
    79
        Adolescents (12-17 years)
    317
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.7 ± 2.7
    14.8 ± 1.6
    9.2 ± 1.3
    Gender categorical
    Units: Subjects
        Female
    247
    216
    31
        Male
    149
    101
    48

    End points

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    End points reporting groups
    Reporting group title
    Agomelatine 10 mg - Total population
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Total population
    Reporting group description
    -

    Reporting group title
    Placebo - Total population
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Total population
    Reporting group description
    -
    Reporting group title
    Agomelatine 10 mg - Adolescents
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Adolescents
    Reporting group description
    -

    Reporting group title
    Placebo - Adolescents
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Adolescents
    Reporting group description
    -
    Reporting group title
    Agomelatine 10 mg - Children
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Children
    Reporting group description
    -

    Reporting group title
    Placebo - Children
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Children
    Reporting group description
    -
    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period
    Reporting group description
    -

    Reporting group title
    Placebo / Agomelatine 10-25 mg - W012-W104 period
    Reporting group description
    -

    Reporting group title
    Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period
    Reporting group description
    -

    Reporting group title
    All - W012-W104 period
    Reporting group description
    -
    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104
    Reporting group description
    -

    Reporting group title
    Placebo / Agomelatine 10-25 mg - Ado - W012-W104
    Reporting group description
    -

    Reporting group title
    Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012-W104
    Reporting group description
    -

    Reporting group title
    All - Adolescents - W012-W104
    Reporting group description
    -
    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all patients of the Modified Randomised Set (MRS) having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint. MRS: All included and randomised patients (i.e. all included patients to whom a therapeutic unit was randomly assigned using IRS).

    Subject analysis set title
    Adolescents of the Full Analysis Set (FAS_ADO)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all adolescents patients of the MRS having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint.

    Subject analysis set title
    Children of the Full Analysis Set (FAS_CHILD)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all children patients of the MRS having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint.

    Primary: CDRS-R raw total score: change from baseline to W12 (Total population of the FAS)

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    End point title
    CDRS-R raw total score: change from baseline to W12 (Total population of the FAS)
    End point description
    The superiority of each agomelatine dose as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. The CDRS-R was used to assess the diagnosis and severity of the current depressed episode in children and adolescents. This is a 17-item clinician rated instrument integrating multiple-source information. Each of them can be rated within the ranges of 1-5 or 1-7. The total score ranges from 17 (normal) to 113 (severe depression). The rater has to: - complete the rating scale during 2 separate interviews: 1 with the patient and 1 with the parent(s)/legally authorized representative(s). - fill in the rating comments for each item, from both sources. - evaluate the symptoms rating from both sources and provide/define the “best description of the child”. - enter in the e-CRF the final rated values of each item corresponding to the “best description of the child” an
    End point type
    Primary
    End point timeframe
    The Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski & Mokros, 1996) was assessed by the investigator at each visit from the selection visit to W12.
    End point values
    Agomelatine 10 mg - Total population Agomelatine 25 mg - Total population Placebo - Total population Fluoxetine - Total population
    Number of subjects analysed
    102
    94
    101
    99
    Units: No unit
        arithmetic mean (standard deviation)
    -20.9 ± 14.0
    -22.5 ± 15.2
    -19.7 ± 14.4
    -21.7 ± 14.1
    Statistical analysis title
    Placebo minus agomelatine 10 mg
    Statistical analysis description
    The superiority of agomelatine 10 mg as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. A three-way analysis of covariance (ANCOVA) model was used. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.
    Comparison groups
    Agomelatine 10 mg - Total population v Placebo - Total population
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079 [1]
    Method
    ANCOVA
    Parameter type
    Estimate of the adjusted difference
    Point estimate
    3.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    6.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.81
    Notes
    [1] - Dunnett-adjusted p-value
    Statistical analysis title
    Placebo minus agomelatine 25 mg
    Statistical analysis description
    The superiority of agomelatine 25 mg as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. A three-way analysis of covariance (ANCOVA) model was used. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.
    Comparison groups
    Agomelatine 25 mg - Total population v Placebo - Total population
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.04 [2]
    Method
    ANCOVA
    Parameter type
    Estimate of the adjusted difference
    Point estimate
    4.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    7.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.83
    Notes
    [2] - Dunnett-adjusted p-value
    Statistical analysis title
    Placebo minus fluoxetine
    Statistical analysis description
    An assay sensitivity was studied with a three-way analysis of covariance (ANCOVA) model using the comparison of fluoxetine to placebo. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.
    Comparison groups
    Placebo - Total population v Fluoxetine - Total population
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.039
    Method
    ANCOVA
    Parameter type
    Estimate of the difference
    Point estimate
    3.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    7.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.81

    Primary: CDRS-R raw total score: change from baseline to W12 (Adolescents of the FAS)

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    End point title
    CDRS-R raw total score: change from baseline to W12 (Adolescents of the FAS)
    End point description
    The superiority of each agomelatine dose as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. The CDRS-R was used to assess the diagnosis and severity of the current depressed episode in children and adolescents. This is a 17-item clinician rated instrument integrating multiple-source information. Each of them can be rated within the ranges of 1-5 or 1-7. The total score ranges from 17 (normal) to 113 (severe depression). The rater has to: - complete the rating scale during 2 separate interviews: 1 with the patient and 1 with the parent(s)/legally authorized representative(s). - fill in the rating comments for each item, from both sources. - evaluate the symptoms rating from both sources and provide/define the “best description of the child”. - enter in the e-CRF the final rated values of each item corresponding to the “best description of the child”
    End point type
    Primary
    End point timeframe
    The Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski & Mokros, 1996) was assessed by the investigator at each visit from the selection visit to W12.
    End point values
    Agomelatine 10 mg - Adolescents Agomelatine 25 mg - Adolescents Placebo - Adolescents Fluoxetine - Adolescents
    Number of subjects analysed
    81
    75
    81
    80
    Units: No unit
        arithmetic mean (standard error)
    -21.1 ± 14.1
    -23.8 ± 15.4
    -19.8 ± 13.4
    -22.0 ± 14.2
    Statistical analysis title
    Placebo minus agomelatine 10 mg
    Statistical analysis description
    The superiority of agomelatine 10 mg as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. A three-way analysis of covariance (ANCOVA) model was used. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.
    Comparison groups
    Placebo - Adolescents v Agomelatine 10 mg - Adolescents
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.132 [3]
    Method
    ANCOVA
    Parameter type
    Estimate of the adjusted difference
    Point estimate
    3.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    7.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.11
    Notes
    [3] - Dunnett-adjusted p-value
    Statistical analysis title
    Placebo minus agomelatine 25 mg
    Statistical analysis description
    The superiority of agomelatine 25 mg as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. A three-way analysis of covariance (ANCOVA) model was used. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.
    Comparison groups
    Placebo - Adolescents v Agomelatine 25 mg - Adolescents
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.028 [4]
    Method
    ANCOVA
    Parameter type
    Estimate of the adjusted difference
    Point estimate
    5.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    9.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13
    Notes
    [4] - Dunnett-adjusted p-value
    Statistical analysis title
    Placebo minus fluoxetine
    Statistical analysis description
    An assay sensitivity was studied with a three-way analysis of covariance (ANCOVA) model using the comparison of fluoxetine to placebo. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.
    Comparison groups
    Placebo - Adolescents v Fluoxetine - Adolescents
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079
    Method
    ANCOVA
    Parameter type
    Estimate of the difference
    Point estimate
    3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    7.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1

    Primary: CDRS-R raw total score: change from baseline to W12 (Children of the FAS)

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    End point title
    CDRS-R raw total score: change from baseline to W12 (Children of the FAS) [5]
    End point description
    The CDRS-R was used to assess the diagnosis and severity of the current depressed episode in children and adolescents. This is a 17-item clinician rated instrument integrating multiple-source information. Each of them can be rated within the ranges of 1-5 or 1-7. The total score ranges from 17 (normal) to 113 (severe depression). The rater has to: - complete the rating scale during 2 separate interviews: 1 with the patient and 1 with the parent(s)/legally authorized representative(s). - fill in the rating comments for each item, from both sources. - evaluate the symptoms rating from both sources and provide/define the “best description of the child”. - enter in the e-CRF the final rated values of each item corresponding to the “best description of the child” and the corresponding Raw summary score.
    End point type
    Primary
    End point timeframe
    The Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski & Mokros, 1996) was assessed by the investigator at each visit from the selection visit to W12.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical inferences for children
    End point values
    Agomelatine 10 mg - Children Agomelatine 25 mg - Children Placebo - Children Fluoxetine - Children
    Number of subjects analysed
    21
    19
    20
    19
    Units: No unit
        arithmetic mean (standard deviation)
    -20.0 ± 13.9
    -17.1 ± 13.3
    -19.0 ± 18.3
    -20.7 ± 14.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events which occurred or worsen or became serious according to the investigator, or upgraded by the Sponsor, between the first IMP intake date (included) and the last IMP intake date + 1 day (included).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Agomelatine 10 mg - Total population
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Total population
    Reporting group description
    -

    Reporting group title
    Placebo - Total population
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Total population
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 mg - Adolescents
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Adolescents
    Reporting group description
    -

    Reporting group title
    Placebo - Adolescents
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Adolescents
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 mg - Children
    Reporting group description
    -

    Reporting group title
    Agomelatine 25 mg - Children
    Reporting group description
    -

    Reporting group title
    Placebo - Children
    Reporting group description
    -

    Reporting group title
    Fluoxetine - Children
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period
    Reporting group description
    -

    Reporting group title
    Placebo / Agomelatine 10-25 mg - W012-W104 period
    Reporting group description
    -

    Reporting group title
    Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period
    Reporting group description
    -

    Reporting group title
    All - W012-W104 period
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104
    Reporting group description
    -

    Reporting group title
    Placebo / Agomelatine 10-25 mg - Ado - W012-W104
    Reporting group description
    -

    Reporting group title
    Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012- W104
    Reporting group description
    -

    Reporting group title
    All - Adolescents - W012-W104
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period
    Reporting group description
    -

    Reporting group title
    Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
    Reporting group description
    -

    Serious adverse events
    Agomelatine 10 mg - Total population Agomelatine 25 mg - Total population Placebo - Total population Fluoxetine - Total population Agomelatine 10 mg - Adolescents Agomelatine 25 mg - Adolescents Placebo - Adolescents Fluoxetine - Adolescents Agomelatine 10 mg - Children Agomelatine 25 mg - Children Placebo - Children Fluoxetine - Children Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period Placebo / Agomelatine 10-25 mg - W012-W104 period Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period All - W012-W104 period Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104 Placebo / Agomelatine 10-25 mg - Ado - W012-W104 Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012- W104 All - Adolescents - W012-W104 Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 102 (5.88%)
    3 / 94 (3.19%)
    0 / 103 (0.00%)
    7 / 100 (7.00%)
    5 / 81 (6.17%)
    2 / 75 (2.67%)
    0 / 82 (0.00%)
    7 / 81 (8.64%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    8 / 170 (4.71%)
    12 / 85 (14.12%)
    9 / 84 (10.71%)
    29 / 339 (8.55%)
    7 / 134 (5.22%)
    11 / 69 (15.94%)
    8 / 68 (11.76%)
    26 / 271 (9.59%)
    11 / 170 (6.47%)
    8 / 134 (5.97%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    2 / 339 (0.59%)
    0 / 134 (0.00%)
    2 / 69 (2.90%)
    0 / 68 (0.00%)
    2 / 271 (0.74%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    2 / 271 (0.74%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver contusion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Haemorrhagic vasculitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (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 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    2 / 100 (2.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    2 / 81 (2.47%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    2 / 271 (0.74%)
    2 / 170 (1.18%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 2
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (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
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anorexia nervosa
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    1 / 68 (1.47%)
    2 / 271 (0.74%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    1 / 81 (1.23%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    3 / 85 (3.53%)
    1 / 84 (1.19%)
    4 / 339 (1.18%)
    0 / 134 (0.00%)
    3 / 69 (4.35%)
    1 / 68 (1.47%)
    4 / 271 (1.48%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 3
    0 / 1
    0 / 4
    0 / 0
    0 / 3
    0 / 1
    0 / 4
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adjustment disorder
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    anger
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    drug abuse
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emotional disorder of childhood
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mood swings
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    self-injurious ideation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (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 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    2 / 271 (0.74%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Latent tetany
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         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
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    0 / 170 (0.00%)
    0 / 134 (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 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    Agomelatine 10 mg - Total population Agomelatine 25 mg - Total population Placebo - Total population Fluoxetine - Total population Agomelatine 10 mg - Adolescents Agomelatine 25 mg - Adolescents Placebo - Adolescents Fluoxetine - Adolescents Agomelatine 10 mg - Children Agomelatine 25 mg - Children Placebo - Children Fluoxetine - Children Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period Placebo / Agomelatine 10-25 mg - W012-W104 period Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period All - W012-W104 period Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104 Placebo / Agomelatine 10-25 mg - Ado - W012-W104 Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012- W104 All - Adolescents - W012-W104 Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 102 (59.80%)
    59 / 94 (62.77%)
    63 / 103 (61.17%)
    55 / 100 (55.00%)
    50 / 81 (61.73%)
    47 / 75 (62.67%)
    49 / 82 (59.76%)
    45 / 81 (55.56%)
    11 / 21 (52.38%)
    12 / 19 (63.16%)
    14 / 21 (66.67%)
    10 / 19 (52.63%)
    102 / 170 (60.00%)
    51 / 85 (60.00%)
    49 / 84 (58.33%)
    202 / 339 (59.59%)
    77 / 134 (57.46%)
    43 / 69 (62.32%)
    39 / 68 (57.35%)
    159 / 271 (58.67%)
    136 / 170 (80.00%)
    106 / 134 (79.10%)
    General disorders and administration site conditions
    Drug interaction
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    5 / 102 (4.90%)
    6 / 94 (6.38%)
    7 / 103 (6.80%)
    2 / 100 (2.00%)
    4 / 81 (4.94%)
    6 / 75 (8.00%)
    4 / 82 (4.88%)
    2 / 81 (2.47%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 19 (0.00%)
    6 / 170 (3.53%)
    4 / 85 (4.71%)
    2 / 84 (2.38%)
    12 / 339 (3.54%)
    5 / 134 (3.73%)
    4 / 69 (5.80%)
    1 / 68 (1.47%)
    10 / 271 (3.69%)
    14 / 170 (8.24%)
    12 / 134 (8.96%)
         occurrences all number
    5
    6
    9
    2
    4
    6
    6
    2
    1
    0
    3
    0
    6
    4
    4
    14
    5
    4
    1
    10
    14
    12
    Thirst
         subjects affected / exposed
    16 / 102 (15.69%)
    13 / 94 (13.83%)
    10 / 103 (9.71%)
    15 / 100 (15.00%)
    15 / 81 (18.52%)
    11 / 75 (14.67%)
    9 / 82 (10.98%)
    13 / 81 (16.05%)
    1 / 21 (4.76%)
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    2 / 19 (10.53%)
    7 / 170 (4.12%)
    3 / 85 (3.53%)
    2 / 84 (2.38%)
    12 / 339 (3.54%)
    5 / 134 (3.73%)
    3 / 69 (4.35%)
    2 / 68 (2.94%)
    10 / 271 (3.69%)
    26 / 170 (15.29%)
    21 / 134 (15.67%)
         occurrences all number
    16
    15
    10
    15
    15
    13
    9
    13
    1
    2
    1
    2
    8
    3
    2
    13
    6
    3
    2
    11
    31
    26
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    1
    2
    1
    0
    0
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    2 / 339 (0.59%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    0
    1
    3
    0
    0
    1
    1
    3
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    1 / 103 (0.97%)
    5 / 100 (5.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    3 / 81 (3.70%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    2 / 19 (10.53%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    1
    5
    0
    1
    0
    3
    0
    0
    1
    2
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Anxiety
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    2 / 103 (1.94%)
    3 / 100 (3.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    2 / 19 (10.53%)
    3 / 170 (1.76%)
    1 / 85 (1.18%)
    2 / 84 (2.38%)
    6 / 339 (1.77%)
    2 / 134 (1.49%)
    1 / 69 (1.45%)
    1 / 68 (1.47%)
    4 / 271 (1.48%)
    4 / 170 (2.35%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    2
    3
    0
    1
    2
    1
    0
    0
    0
    2
    3
    1
    2
    6
    2
    1
    1
    4
    4
    3
    Impulsive behaviour
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    2 / 100 (2.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Learning disability
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    2 / 100 (2.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    4 / 170 (2.35%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    5 / 339 (1.47%)
    4 / 134 (2.99%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    5 / 271 (1.85%)
    4 / 170 (2.35%)
    4 / 134 (2.99%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    0
    1
    0
    0
    0
    1
    4
    1
    0
    5
    4
    1
    0
    5
    4
    4
    Blood glucose increased
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 94 (2.13%)
    2 / 103 (1.94%)
    2 / 100 (2.00%)
    0 / 81 (0.00%)
    2 / 75 (2.67%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    3 / 170 (1.76%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    3 / 339 (0.88%)
    3 / 134 (2.24%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    3 / 271 (1.11%)
    6 / 170 (3.53%)
    5 / 134 (3.73%)
         occurrences all number
    1
    2
    2
    2
    0
    2
    2
    1
    1
    0
    0
    1
    3
    0
    0
    3
    3
    0
    0
    3
    6
    5
    Electrocardiogram PR shortened
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    1 / 85 (1.18%)
    2 / 84 (2.38%)
    4 / 339 (1.18%)
    1 / 134 (0.75%)
    1 / 69 (1.45%)
    2 / 68 (2.94%)
    4 / 271 (1.48%)
    2 / 170 (1.18%)
    1 / 134 (0.75%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    1
    1
    2
    4
    1
    1
    2
    4
    3
    2
    Weight increased
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 94 (5.32%)
    0 / 103 (0.00%)
    2 / 100 (2.00%)
    4 / 81 (4.94%)
    4 / 75 (5.33%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    2 / 21 (9.52%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    8 / 170 (4.71%)
    4 / 85 (4.71%)
    1 / 84 (1.19%)
    13 / 339 (3.83%)
    7 / 134 (5.22%)
    3 / 69 (4.35%)
    0 / 68 (0.00%)
    10 / 271 (3.69%)
    15 / 170 (8.82%)
    12 / 134 (8.96%)
         occurrences all number
    6
    5
    0
    2
    4
    4
    0
    1
    2
    1
    0
    1
    8
    4
    1
    13
    7
    3
    0
    10
    16
    13
    Blood prolactin increased
         subjects affected / exposed
    4 / 102 (3.92%)
    1 / 94 (1.06%)
    1 / 103 (0.97%)
    0 / 100 (0.00%)
    3 / 81 (3.70%)
    1 / 75 (1.33%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    8 / 170 (4.71%)
    1 / 85 (1.18%)
    3 / 84 (3.57%)
    12 / 339 (3.54%)
    4 / 134 (2.99%)
    1 / 69 (1.45%)
    2 / 68 (2.94%)
    7 / 271 (2.58%)
    11 / 170 (6.47%)
    6 / 134 (4.48%)
         occurrences all number
    4
    1
    1
    0
    3
    1
    1
    0
    1
    0
    0
    0
    8
    1
    3
    12
    4
    1
    2
    7
    12
    7
    Blood bilirubin increased
         subjects affected / exposed
    3 / 102 (2.94%)
    2 / 94 (2.13%)
    1 / 103 (0.97%)
    0 / 100 (0.00%)
    3 / 81 (3.70%)
    2 / 75 (2.67%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    2 / 170 (1.18%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    3 / 339 (0.88%)
    2 / 134 (1.49%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    3 / 271 (1.11%)
    7 / 170 (4.12%)
    7 / 134 (5.22%)
         occurrences all number
    3
    2
    1
    0
    3
    2
    1
    0
    0
    0
    0
    0
    2
    1
    0
    3
    2
    1
    0
    3
    7
    7
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    0 / 170 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    2 / 103 (1.94%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
    1 / 170 (0.59%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    2 / 339 (0.59%)
    1 / 134 (0.75%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    2 / 271 (0.74%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    2
    1
    0
    1
    1
    0
    0
    0
    1
    1
    1
    1
    0
    2
    1
    1
    0
    2
    1
    1
    Dizziness postural
         subjects affected / exposed
    2 / 102 (1.96%)
    5 / 94 (5.32%)
    1 / 103 (0.97%)
    2 / 100 (2.00%)
    2 / 81 (2.47%)
    5 / 75 (6.67%)
    1 / 82 (1.22%)
    2 / 81 (2.47%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    3 / 170 (1.76%)
    0 / 85 (0.00%)
    2 / 84 (2.38%)
    5 / 339 (1.47%)
    5 / 134 (3.73%)
    0 / 69 (0.00%)
    2 / 68 (2.94%)
    5 / 271 (1.85%)
    9 / 170 (5.29%)
    9 / 134 (6.72%)
         occurrences all number
    2
    5
    1
    2
    2
    5
    1
    2
    0
    0
    0
    0
    3
    0
    2
    5
    5
    0
    2
    5
    9
    9
    Headache
         subjects affected / exposed
    16 / 102 (15.69%)
    11 / 94 (11.70%)
    14 / 103 (13.59%)
    11 / 100 (11.00%)
    13 / 81 (16.05%)
    7 / 75 (9.33%)
    12 / 82 (14.63%)
    9 / 81 (11.11%)
    3 / 21 (14.29%)
    4 / 19 (21.05%)
    2 / 21 (9.52%)
    2 / 19 (10.53%)
    21 / 170 (12.35%)
    10 / 85 (11.76%)
    9 / 84 (10.71%)
    40 / 339 (11.80%)
    19 / 134 (14.18%)
    9 / 69 (13.04%)
    9 / 68 (13.24%)
    37 / 271 (13.65%)
    40 / 170 (23.53%)
    32 / 134 (23.88%)
         occurrences all number
    21
    15
    14
    11
    17
    9
    12
    9
    4
    6
    2
    2
    32
    11
    11
    54
    30
    10
    11
    51
    65
    54
    Dizziness
         subjects affected / exposed
    4 / 102 (3.92%)
    3 / 94 (3.19%)
    4 / 103 (3.88%)
    3 / 100 (3.00%)
    4 / 81 (4.94%)
    3 / 75 (4.00%)
    3 / 82 (3.66%)
    3 / 81 (3.70%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    5 / 170 (2.94%)
    2 / 85 (2.35%)
    4 / 84 (4.76%)
    11 / 339 (3.24%)
    5 / 134 (3.73%)
    2 / 69 (2.90%)
    3 / 68 (4.41%)
    10 / 271 (3.69%)
    10 / 170 (5.88%)
    10 / 134 (7.46%)
         occurrences all number
    5
    3
    4
    3
    5
    3
    3
    3
    0
    0
    1
    0
    6
    2
    4
    12
    6
    2
    3
    11
    13
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 102 (7.84%)
    7 / 94 (7.45%)
    7 / 103 (6.80%)
    4 / 100 (4.00%)
    5 / 81 (6.17%)
    5 / 75 (6.67%)
    6 / 82 (7.32%)
    3 / 81 (3.70%)
    3 / 21 (14.29%)
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
    5 / 170 (2.94%)
    5 / 85 (5.88%)
    1 / 84 (1.19%)
    11 / 339 (3.24%)
    4 / 134 (2.99%)
    3 / 69 (4.35%)
    1 / 68 (1.47%)
    8 / 271 (2.95%)
    17 / 170 (10.00%)
    11 / 134 (8.21%)
         occurrences all number
    9
    8
    10
    4
    6
    5
    8
    3
    3
    3
    2
    1
    5
    7
    1
    13
    4
    3
    1
    8
    21
    14
    Diarrhoea
         subjects affected / exposed
    6 / 102 (5.88%)
    4 / 94 (4.26%)
    6 / 103 (5.83%)
    8 / 100 (8.00%)
    5 / 81 (6.17%)
    3 / 75 (4.00%)
    5 / 82 (6.10%)
    8 / 81 (9.88%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    2 / 170 (1.18%)
    4 / 85 (4.71%)
    2 / 84 (2.38%)
    8 / 339 (2.36%)
    2 / 134 (1.49%)
    4 / 69 (5.80%)
    1 / 68 (1.47%)
    7 / 271 (2.58%)
    11 / 170 (6.47%)
    9 / 134 (6.72%)
         occurrences all number
    6
    5
    7
    9
    5
    4
    6
    9
    1
    1
    1
    0
    2
    5
    4
    11
    2
    5
    2
    9
    13
    11
    Dry mouth
         subjects affected / exposed
    21 / 102 (20.59%)
    13 / 94 (13.83%)
    11 / 103 (10.68%)
    13 / 100 (13.00%)
    18 / 81 (22.22%)
    10 / 75 (13.33%)
    10 / 82 (12.20%)
    11 / 81 (13.58%)
    3 / 21 (14.29%)
    3 / 19 (15.79%)
    1 / 21 (4.76%)
    2 / 19 (10.53%)
    7 / 170 (4.12%)
    0 / 85 (0.00%)
    2 / 84 (2.38%)
    9 / 339 (2.65%)
    5 / 134 (3.73%)
    0 / 69 (0.00%)
    2 / 68 (2.94%)
    7 / 271 (2.58%)
    31 / 170 (18.24%)
    24 / 134 (17.91%)
         occurrences all number
    21
    14
    12
    13
    18
    11
    11
    11
    3
    3
    1
    2
    7
    0
    2
    9
    5
    0
    2
    7
    37
    29
    Nausea
         subjects affected / exposed
    10 / 102 (9.80%)
    12 / 94 (12.77%)
    14 / 103 (13.59%)
    9 / 100 (9.00%)
    9 / 81 (11.11%)
    10 / 75 (13.33%)
    12 / 82 (14.63%)
    8 / 81 (9.88%)
    1 / 21 (4.76%)
    2 / 19 (10.53%)
    2 / 21 (9.52%)
    1 / 19 (5.26%)
    5 / 170 (2.94%)
    9 / 85 (10.59%)
    4 / 84 (4.76%)
    18 / 339 (5.31%)
    3 / 134 (2.24%)
    8 / 69 (11.59%)
    4 / 68 (5.88%)
    15 / 271 (5.54%)
    24 / 170 (14.12%)
    19 / 134 (14.18%)
         occurrences all number
    11
    14
    17
    9
    10
    12
    15
    8
    1
    2
    2
    1
    5
    12
    5
    22
    3
    9
    5
    17
    28
    23
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    3 / 102 (2.94%)
    4 / 94 (4.26%)
    2 / 103 (1.94%)
    2 / 100 (2.00%)
    2 / 81 (2.47%)
    4 / 75 (5.33%)
    2 / 82 (2.44%)
    2 / 81 (2.47%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    4 / 170 (2.35%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    6 / 339 (1.77%)
    2 / 134 (1.49%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    3 / 271 (1.11%)
    9 / 170 (5.29%)
    6 / 134 (4.48%)
         occurrences all number
    4
    4
    2
    2
    3
    4
    2
    2
    1
    0
    0
    0
    4
    2
    0
    6
    2
    1
    0
    3
    10
    7
    Dermatitis allergic
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 94 (2.13%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    1 / 75 (1.33%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 339 (0.00%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Endocrine disorders
    Hyperprolactinaemia
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    2 / 170 (1.18%)
    1 / 85 (1.18%)
    3 / 84 (3.57%)
    6 / 339 (1.77%)
    1 / 134 (0.75%)
    1 / 69 (1.45%)
    2 / 68 (2.94%)
    4 / 271 (1.48%)
    2 / 170 (1.18%)
    1 / 134 (0.75%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    1
    2
    2
    3
    7
    1
    2
    2
    5
    2
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    2 / 102 (1.96%)
    3 / 94 (3.19%)
    6 / 103 (5.83%)
    1 / 100 (1.00%)
    1 / 81 (1.23%)
    3 / 75 (4.00%)
    5 / 82 (6.10%)
    1 / 81 (1.23%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    0 / 271 (0.00%)
    5 / 170 (2.94%)
    4 / 134 (2.99%)
         occurrences all number
    2
    3
    6
    1
    1
    3
    5
    1
    1
    0
    1
    0
    0
    2
    0
    2
    0
    0
    0
    0
    5
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    1 / 103 (0.97%)
    2 / 100 (2.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    3 / 170 (1.76%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    3 / 339 (0.88%)
    2 / 134 (1.49%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    2 / 271 (0.74%)
    3 / 170 (1.76%)
    2 / 134 (1.49%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    1
    1
    0
    0
    0
    1
    3
    0
    0
    3
    2
    0
    0
    2
    3
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    1 / 100 (1.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    2 / 21 (9.52%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    1
    2
    0
    0
    0
    0
    0
    1
    1
    0
    0
    1
    1
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    1 / 103 (0.97%)
    2 / 100 (2.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    2 / 170 (1.18%)
    2 / 134 (1.49%)
         occurrences all number
    1
    0
    1
    2
    1
    0
    0
    1
    0
    0
    1
    1
    2
    0
    0
    2
    2
    0
    0
    2
    3
    3
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 94 (1.06%)
    4 / 103 (3.88%)
    0 / 100 (0.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    3 / 21 (14.29%)
    0 / 19 (0.00%)
    1 / 170 (0.59%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    1 / 134 (0.75%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    2 / 170 (1.18%)
    1 / 134 (0.75%)
         occurrences all number
    1
    1
    4
    0
    1
    0
    1
    0
    0
    1
    3
    0
    1
    0
    0
    1
    1
    0
    0
    1
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 102 (2.94%)
    5 / 94 (5.32%)
    3 / 103 (2.91%)
    1 / 100 (1.00%)
    1 / 81 (1.23%)
    4 / 75 (5.33%)
    3 / 82 (3.66%)
    1 / 81 (1.23%)
    2 / 21 (9.52%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    11 / 170 (6.47%)
    9 / 85 (10.59%)
    4 / 84 (4.76%)
    24 / 339 (7.08%)
    8 / 134 (5.97%)
    7 / 69 (10.14%)
    2 / 68 (2.94%)
    17 / 271 (6.27%)
    19 / 170 (11.18%)
    13 / 134 (9.70%)
         occurrences all number
    3
    5
    3
    1
    1
    4
    3
    1
    2
    1
    0
    0
    15
    11
    4
    30
    12
    8
    2
    22
    23
    17
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 94 (0.00%)
    0 / 103 (0.00%)
    2 / 100 (2.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    1 / 170 (0.59%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    2 / 339 (0.59%)
    1 / 134 (0.75%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    2 / 271 (0.74%)
    1 / 170 (0.59%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    1
    0
    0
    0
    1
    1
    1
    0
    2
    1
    1
    0
    2
    1
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 94 (1.06%)
    3 / 103 (2.91%)
    2 / 100 (2.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    2 / 82 (2.44%)
    1 / 81 (1.23%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    1 / 19 (5.26%)
    6 / 170 (3.53%)
    2 / 85 (2.35%)
    1 / 84 (1.19%)
    9 / 339 (2.65%)
    2 / 134 (1.49%)
    1 / 69 (1.45%)
    1 / 68 (1.47%)
    4 / 271 (1.48%)
    7 / 170 (4.12%)
    3 / 134 (2.24%)
         occurrences all number
    2
    1
    3
    2
    2
    0
    2
    1
    0
    1
    1
    1
    7
    2
    1
    10
    2
    1
    1
    4
    9
    4
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 94 (0.00%)
    1 / 103 (0.97%)
    1 / 100 (1.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    4 / 170 (2.35%)
    2 / 85 (2.35%)
    3 / 84 (3.57%)
    9 / 339 (2.65%)
    2 / 134 (1.49%)
    2 / 69 (2.90%)
    2 / 68 (2.94%)
    6 / 271 (2.21%)
    5 / 170 (2.94%)
    3 / 134 (2.24%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    1
    0
    0
    0
    0
    1
    6
    3
    4
    13
    3
    3
    2
    8
    7
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 94 (1.06%)
    2 / 103 (1.94%)
    0 / 100 (0.00%)
    1 / 81 (1.23%)
    0 / 75 (0.00%)
    2 / 82 (2.44%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    6 / 170 (3.53%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    8 / 339 (2.36%)
    3 / 134 (2.24%)
    2 / 69 (2.90%)
    0 / 68 (0.00%)
    5 / 271 (1.85%)
    8 / 170 (4.71%)
    4 / 134 (2.99%)
         occurrences all number
    1
    2
    2
    0
    1
    0
    2
    0
    0
    2
    0
    0
    7
    2
    0
    9
    3
    2
    0
    5
    10
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 102 (2.94%)
    5 / 94 (5.32%)
    7 / 103 (6.80%)
    5 / 100 (5.00%)
    1 / 81 (1.23%)
    4 / 75 (5.33%)
    4 / 82 (4.88%)
    4 / 81 (4.94%)
    2 / 21 (9.52%)
    1 / 19 (5.26%)
    3 / 21 (14.29%)
    1 / 19 (5.26%)
    8 / 170 (4.71%)
    2 / 85 (2.35%)
    3 / 84 (3.57%)
    13 / 339 (3.83%)
    8 / 134 (5.97%)
    1 / 69 (1.45%)
    3 / 68 (4.41%)
    12 / 271 (4.43%)
    15 / 170 (8.82%)
    12 / 134 (8.96%)
         occurrences all number
    3
    5
    7
    5
    1
    4
    4
    4
    2
    1
    3
    1
    8
    2
    3
    13
    8
    1
    3
    12
    16
    13
    Food intolerance
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 94 (1.06%)
    0 / 103 (0.00%)
    0 / 100 (0.00%)
    0 / 81 (0.00%)
    0 / 75 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 21 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    0 / 170 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 339 (0.29%)
    0 / 134 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
    1 / 271 (0.37%)
    1 / 170 (0.59%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    1
    0
    1
    1
    0
    Increased appetite
         subjects affected / exposed
    7 / 102 (6.86%)
    6 / 94 (6.38%)
    0 / 103 (0.00%)
    3 / 100 (3.00%)
    5 / 81 (6.17%)
    6 / 75 (8.00%)
    0 / 82 (0.00%)
    3 / 81 (3.70%)
    2 / 21 (9.52%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 19 (0.00%)
    5 / 170 (2.94%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    5 / 339 (1.47%)
    4 / 134 (2.99%)
    0 / 69 (0.00%)
    0 / 68 (0.00%)
    4 / 271 (1.48%)
    13 / 170 (7.65%)
    11 / 134 (8.21%)
         occurrences all number
    7
    6
    0
    3
    5
    6
    0
    3
    2
    0
    0
    0
    5
    0
    0
    5
    4
    0
    0
    4
    15
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2016
    It mainly concerned: - Supplementary non-inclusion criteria for liver function: *Free bilirubin > 2 ULN (criterion n°63), to exclude patients with Gilbert-syndrome who could present unpredictable timing and level of free bilirubin levels. *ALP and GGT > 1 ULN (criterion n°65), to exclude patients in normal growth but with potential hepatic enzyme alterations. *In the inclusion criteria (n°56): the selection criteria on scales scores which had to be still fulfilled were specified in the text. - Measures concerning liver function tests: *Liver function tests (AST, ALT, total bilirubin, free bilirubin, conjugated bilirubin, ALP, GGT) were added during double-blind period (W004) and during open label extension period (W014, W048 and W068). *Close monitoring through blood samplings re-tests in case of abnormalities observed on ALT/AST, bilirubin, ALP or GGT was defined as a monitoring every two weeks. *In case of ALT/AST > 2ULN under study treatment, a monitoring was organized every two weeks until values return to normal/baseline values. *Additional investigations which were to be performed in case of AST and/or ALT > 3 ULN were described in detail. - PAERS scale was added as individual safety assessment in addition to AEs. - Data of the PAERS scale (clinician part) were to be reported in the e-CRF and adverse events from the PAERS were to be reported in the AE form of the e-CRF. - Period of time i.e. “in the morning” was defined to perform biological sampling required in the seven days after the selection visit. - ECG recording was to be done under the supervision of the qualified specialist.
    13 Dec 2019
    It mainly concerned: - Integration of agreed modifications on the Paediatric Investigation Plan by EMA: decreased sample size (at least 390 patients instead of 484) and adapted statistical analysis including the modifications of subgroup analyses of primary endpoint and the update of statistical patient sets (at least 312 adolescents, with no requirement on children population). - Update of the total number of centres (63 instead of 67) and the list of participating countries (deletion of Germany and addition of Serbia). - Modifications of centres’ downloads of participants’ data from the e-CRF for archiving.

    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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