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    Clinical Trial Results:
    Pharmacokinetics and safety of agomelatine in children (from 7 to less than 12 years) and adolescents (from 12 to less than 18 years) with Depressive or Anxiety Disorder. An open-labelled, multicenter, three-dose level, non-comparative study.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2012-003404-12
    Trial protocol
    		 FI   SE   HU   EE   RO   PL  
    Global end of trial date
    14 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Feb 2016
    First version publication date
    21 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-20098-075
    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 Cedex
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, 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
    14 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate pharmacokinetics of 3 doses (5, 10 and 25 mg) of agomelatine in patients from 7 to less than 18 years suffering from Depressive or Anxiety Disorder.
    Protection of trial subjects
    This open-labelled PK and safety study was done before placebo-controlled studies are conducted, in order to provide information on agomelatine PK and preliminary safety data in children and adolescents. ­­Based on the PK characteristics of agomelatine, a single administration was considered sufficient to assess the PK parameters, as steady state is reached from the first day of administration. Due to the rapid elimination of agomelatine, an interval of 24 hours was considered sufficient between doses. The oral film-coated tablet formulation was used, as agomelatine tablet shape and size was acceptable for this age-range and this formulation offers the best profile in terms of expected palatability, safety, compliance and efficacy. Saliva samples were collected for evaluating the agomelatine PK, as this was a non-invasive procedure. Only one PK blood sample was drawn, in order to check the correlation between plasma and saliva agomelatine concentrations. The total of blood collected was not superior to maximum tolerated volume. In addition to standard study withdrawal criteria, the following led to a mandatory withdrawal from the study: -Hospitalisation of the patient for aggravation of depression/psychiatric disorder -Worsening of Major Depressive Episode/psychiatric disorder, according to investigator’s clinical judgment. -High suicidal risk, according to investigator’s judgement. -Any suicide attempt during the study, whatever its severity. -Occurrence of psychotic features. -AST and/or ALT > 3 x ULN, confirmed at re-test. -Any symptoms or signs of potential liver injury. -Pregnancy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    Hungary: 26
    Country: Number of subjects enrolled
    Romania: 18
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    24
    Adolescents (12-17 years)
    27
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There was a screening period of 3 to 7 days between the selection and inclusion (Day 0) visits: this period, without IMP administration, was to be as short as possible. It allowed investigators to perform electrocardiogram (ECG) and laboratory examinations. The results of the examinations had to be available at the inclusion visit.

    Period 1
    Period 1 title
    Treatment Period (Day 1)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Agomelatine 5 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    S 20098
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral film-coated tablet of agomelatine 5 mg on Day 1 between 6.00 p.m. and 7.00 p.m.

    Number of subjects in period 1
    		Agomelatine 5 mg
    Started
    51
    Completed
    51
    Period 2
    Period 2 title
    Treatment Period (Day 2)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

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

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    S 20098
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral film-coated tablet of agomelatine 10 mg on Day 2 between 6.00 p.m. and 7.00 p.m.

    Number of subjects in period 2
    		Agomelatine 10 mg
    Started
    51
    Completed
    49
    Not completed
    2
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
    Period 3
    Period 3 title
    Treatment Period (Day 3)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

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

    Investigational medicinal product name
    Agomelatine
    Investigational medicinal product code
    S 20098
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral film-coated tablet of agomelatine 25 mg on Day 3 between 6.00 p.m. and 7.00 p.m.

    Number of subjects in period 3
    		Agomelatine 25 mg
    Started
    49
    Completed
    49

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period (Day 1)
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period (Day 1) Total
    Number of subjects
    		 51 51
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 24 24
        Adolescents (12-17 years)
    		 27 27
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.4 ( 3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 26 26
    Subject analysis sets

    Subject analysis set title
    Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants from 12 to less than 18 years of age

    Subject analysis set title
    Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants from 7 to less than 12 years of age

    Subject analysis sets values
    		 Adolescents Children
    Number of subjects
    27
    24
    Age categorical
    Units: Subjects
        Children (2-11 years)
        Adolescents (12-17 years)
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.8 ( 1.8 )
    9.8 ( 1 )
    Gender categorical
    Units: Subjects
        Female
    15
    10
        Male
    12
    14

    End points

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    End points reporting groups
    Reporting group title
    Agomelatine 5 mg
    Reporting group description
    		 -
    Reporting group title
    Agomelatine 10 mg
    Reporting group description
    		 -
    Reporting group title
    Agomelatine 25 mg
    Reporting group description
    		 -

    Subject analysis set title
    Adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants from 12 to less than 18 years of age

    Subject analysis set title
    Children
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants from 7 to less than 12 years of age

    Primary: AUC

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    End point title
    		 AUC [1]
    End point description
    End point type
    Primary
    End point timeframe
    D1, D2 and D3
    Notes
    [1] - 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: Descriptive statistical analysis was planned in the protocol.
    End point values
    		 Agomelatine 5 mg Agomelatine 10 mg Agomelatine 25 mg
    Number of subjects analysed
    51
    51
    49
    Units: ng.h/mL
        median (confidence interval 90%)
    4.18 (1.97 to 19.1)
    7.09 (3.9 to 41.7)
    19 (7.76 to 147)
    No statistical analyses for this end point

    Primary: Cmax

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    End point title
    		 Cmax [2]
    End point description
    End point type
    Primary
    End point timeframe
    D1, D2 and D3
    Notes
    [2] - 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: Descriptive statistical analysis was planned in the protocol.
    End point values
    		 Agomelatine 5 mg Agomelatine 10 mg Agomelatine 25 mg
    Number of subjects analysed
    51
    51
    49
    Units: ng/mL
        median (confidence interval 90%)
    1.63 (0.766 to 10.8)
    2.69 (1.1 to 19.4)
    9.68 (1.97 to 87.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between screening and the last visit (run-out)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Overall: all patients
    Reporting group description
    		 All AEs in all patients throughout the study

    Reporting group title
    Overall: adolescents
    Reporting group description
    		 All AEs in all adolescent patients throughout the study

    Reporting group title
    Overall: children
    Reporting group description
    		 All AEs in all children patients throughout the study

    Reporting group title
    Agomelatine 5 mg: all patients
    Reporting group description
    		 AEs associated with the 5 mg dose intake (Day 1) in all patients

    Reporting group title
    Agomelatine 5 mg: adolescents
    Reporting group description
    		 AEs associated with the 5 mg dose intake (Day 1) in adolescent patients

    Reporting group title
    Agomelatine 5 mg: children
    Reporting group description
    		 AEs associated with the 5 mg dose intake (Day 1) in children patients

    Reporting group title
    Agomelatine 10 mg: all patients
    Reporting group description
    		 AEs associated with the 10 mg dose intake (Day 2) in all patients

    Reporting group title
    Agomelatine 10 mg: adolescents
    Reporting group description
    		 AEs associated with the 10 mg dose intake (Day 2) in adolescent patients

    Reporting group title
    Agomelatine 10 mg: children
    Reporting group description
    		 AEs associated with the 10 mg dose intake (Day 2) in children patients

    Reporting group title
    Agomelatine 25 mg: all patients
    Reporting group description
    		 AEs associated with the 25 mg dose intake (Day 3) in all patients

    Reporting group title
    Agomelatine 25 mg: adolescents
    Reporting group description
    		 AEs associated with the 25 mg dose intake (Day 3) in adolescent patients

    Reporting group title
    Agomelatine 25 mg: children
    Reporting group description
    		 AEs associated with the 25 mg dose intake (Day 3) in children patients

    Serious adverse events
    		 Overall: all patients Overall: adolescents Overall: children Agomelatine 5 mg: all patients Agomelatine 5 mg: adolescents Agomelatine 5 mg: children Agomelatine 10 mg: all patients Agomelatine 10 mg: adolescents Agomelatine 10 mg: children Agomelatine 25 mg: all patients Agomelatine 25 mg: adolescents Agomelatine 25 mg: children
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall: all patients Overall: adolescents Overall: children Agomelatine 5 mg: all patients Agomelatine 5 mg: adolescents Agomelatine 5 mg: children Agomelatine 10 mg: all patients Agomelatine 10 mg: adolescents Agomelatine 10 mg: children Agomelatine 25 mg: all patients Agomelatine 25 mg: adolescents Agomelatine 25 mg: children
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 51 (33.33%)
    10 / 27 (37.04%)
    7 / 24 (29.17%)
    10 / 51 (19.61%)
    6 / 27 (22.22%)
    4 / 24 (16.67%)
    8 / 51 (15.69%)
    5 / 27 (18.52%)
    3 / 24 (12.50%)
    11 / 49 (22.45%)
    8 / 27 (29.63%)
    3 / 22 (13.64%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Blood prolactin increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 49 (2.04%)
    1 / 27 (3.70%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
    1 / 27 (3.70%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    0
    0
    0
    2
    1
    1
    Nervous system disorders
    Hypersomnia
         subjects affected / exposed
    5 / 51 (9.80%)
    4 / 27 (14.81%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    4 / 49 (8.16%)
    3 / 27 (11.11%)
    1 / 22 (4.55%)
         occurrences all number
    6
    5
    1
    1
    1
    0
    1
    1
    0
    4
    3
    1
    Somnolence
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
    1 / 27 (3.70%)
    1 / 22 (4.55%)
         occurrences all number
    5
    4
    1
    2
    2
    0
    1
    1
    0
    2
    1
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    2
    2
    1
    0
    1
    3
    2
    1
    0
    0
    0
    Dyskinesia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    1 / 49 (2.04%)
    1 / 27 (3.70%)
    0 / 22 (0.00%)
         occurrences all number
    5
    3
    2
    2
    1
    1
    2
    1
    1
    1
    1
    0
    Hunger
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    2
    2
    1
    1
    1
    0
    1
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Thirst
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Vessel puncture site reaction
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
    1 / 27 (3.70%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    0
    0
    0
    2
    1
    1
    Neutropenia
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
    1 / 27 (3.70%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    0
    0
    0
    2
    1
    1
    Lymphocytosis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 49 (2.04%)
    0 / 27 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    2
    1
    2
    1
    1
    1
    1
    0
    0
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    1 / 49 (2.04%)
    1 / 27 (3.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    1
    0
    1
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Breast disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Sexual dysfunction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 49 (2.04%)
    1 / 27 (3.70%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Depressed mood
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    2
    1
    0
    1
    2
    1
    1
    0
    0
    0
    Emotional disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Mood swings
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Disorientation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    2 / 51 (3.92%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    1
    2
    1
    1
    0
    0
    0
    0
    0
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 51 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 51 (1.96%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 49 (0.00%)
    0 / 27 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2013
    -Addition of Estonia, Hungary, Poland and Romania. -Removal of Sweden; no longer part of the study. -Since January 2011, the National Institute for Health and Welfare recommendation on the usage of vitamin D in children and adolescents has been taken into consideration by the Ministry of Health in Finland. Accordingly, vitamin D administration is recommended in the prophylaxis of vitamin D-deficiency from 2 to 18 years old. Therefore, the administration of vitamin D as concomitant treatment during the study was authorised up to 1.000 IU per day. -The Total Reaction Time was removed from the evaluation criteria since the 2 other criteria obtained from the Choice Reaction Time (Recognition Reaction Time and Motor Reaction Time) are the most relevant criteria to be analysed in order to assess the vigilance/sedation. -The description of safety analysis relative to Adverse Events was adapted in accordance with international guidance. -The Declaration of Helsinki was reviewed at the last WMA meeting (Fortaleza, Brazil, October 2013).
    08 Jul 2014
    -Extension of the recruitment period until March 2015. -Change in selection and inclusion criteria. -Deletion of criteria of moderate or severe intensity for Major Depressive Episode, addition of Dysthymic Disorder, Generalized Anxiety Disorder, Separation Anxiety Disorder, Social Phobia and Specific Phobia. -Harmonisation of the inclusion- and non-inclusion criteria regarding the levels of liver enzymes and serum total bilirubin tests results with studies in adult population. -Minor clarifications.

    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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