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    Clinical Trial Results:
    Interventional, Randomized, Double-blind, Placebo-controlled, Active-reference (Fluoxetine), Fixed-dose Study of Vortioxetine in Paediatric Patients Aged 7 to 11 Years, With Major Depressive Disorder (MDD)

    Summary
    EudraCT number
    		 2008-005353-38
    Trial protocol
    		 LV   EE   GB   HU   FI   DE   IT   ES   BG   PL   FR  
    Global end of trial date
    21 Jan 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Sep 2022
    First version publication date
    31 Jul 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    12709A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02709655
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    H. Lundbeck A/S
    Sponsor organisation address
    Ottiliavej 9, Valby, Denmark, 2500
    Public contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, +45 36301311, LundbeckClinicalTrials@lundbeck.com
    Scientific contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, +45 36301311, LundbeckClinicalTrials@lundbeck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000455-PIP02-10
    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
    21 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the efficacy of vortioxetine 10 milligrams (mg)/day and 20 mg/day versus placebo after 8 weeks of treatment on depressive symptoms in children with a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5®) diagnosis of MDD.
    Protection of trial subjects
    This study was conducted in compliance with Good Clinical Practice and in accordance with the ethical principles described in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 22
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Colombia: 144
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Mexico: 109
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Serbia: 26
    Country: Number of subjects enrolled
    Russian Federation: 93
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United States: 179
    Country: Number of subjects enrolled
    South Africa: 1
    Worldwide total number of subjects
    683
    EEA total number of subjects
    107
    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)
    683
    Adolescents (12-17 years)
    0
    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
    		 This study included 2 periods: single-blind (SB) (treatment with standardized brief psychosocial intervention [BPI] and placebo) and double-blind (DB) (treatment with BPI and placebo, vortioxetine 10 mg/day, vortioxetine 20 mg/day, or fluoxetine 20 mg/day).

    Pre-assignment
    Screening details
    		 Prior to the interim analysis, participants were randomized in a 1:1:1:1 ratio to placebo, vortioxetine 10 mg/day, vortioxetine 20 mg/day, or fluoxetine 20 mg/day. After interim analysis, participants were randomized in a 1:1:1 ratio to placebo, vortioxetine 10 mg/day, or vortioxetine 20 mg/day.

    Period 1
    Period 1 title
    Single-Blind Phase (4 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Single-Blind: Placebo
    Arm description
    		 Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule was administered per schedule specified in the arm description.

    Number of subjects in period 1 [1]
    		Single-Blind: Placebo
    Started
    677
    Received at least 1 dose of study drug
    677
    Completed
    540
    Not completed
    137
         Consent withdrawn by subject
    15
         Failure to meet randomization criteria
    85
         Adverse event, non-fatal
    2
         Non-compliance with study drug
    3
         Other than specified
    20
         Lost to follow-up
    1
         Lack of efficacy
    8
         Protocol deviation
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 683 participants were enrolled, out of which 6 were not treated.
    Period 2
    Period 2 title
    Double-Blind Phase (8 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind: Placebo
    Arm description
    		 Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule was administered per schedule specified in the arm description.

    Arm title
    		 Double-Blind: Vortioxetine 10 mg
    Arm description
    		 Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vortioxetine
    Investigational medicinal product code
    Other name
    Brintellix ®, Lu AA21004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vortioxetine was administered per dose and schedule specified in the arm description.

    Arm title
    		 Double-Blind: Vortioxetine 20 mg
    Arm description
    		 Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vortioxetine
    Investigational medicinal product code
    Other name
    Brintellix ®, Lu AA21004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vortioxetine was administered per dose and schedule specified in the arm description.

    Arm title
    		 Double-Blind: Fluoxetine 20 mg
    Arm description
    		 Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluoxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Fluoxetine was administered per dose and schedule specified in the arm description.

    Number of subjects in period 2
    		Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Started
    153
    151
    153
    83
    Received at least 1 dose of study drug
    153
    151
    153
    83
    Full analysis set (FAS)
    153
    148
    148
    81
    Completed
    138
    135
    133
    78
    Not completed
    15
    16
    20
    5
         Consent withdrawn by subject
    4
    4
    4
    1
         Adverse event, non-fatal
    1
    2
    3
    -
         Non-compliance with study drug
    1
    3
    6
    1
         Other than specified
    5
    7
    5
    2
         Lost to follow-up
    1
    -
    2
    -
         Lack of efficacy
    2
    -
    -
    1
         Protocol deviation
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Single-Blind: Placebo
    Reporting group description
    		 Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.

    Reporting group values
    		 Single-Blind: Placebo Total
    Number of subjects
    		 677 677
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 677 677
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.3 ( 1.42 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 312 312
        Male
    		 365 365
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 2 2
        Black or African American
    		 112 112
        Not Reported
    		 12 12
        Other
    		 229 229
        White
    		 321 321
    Children Depression Rating Scale - Revised (CDRS-R) Total Score
    The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression).
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 63.4 ( 9.12 ) -

    End points

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    End points reporting groups
    Reporting group title
    Single-Blind: Placebo
    Reporting group description
    		 Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.
    Reporting group title
    Double-Blind: Placebo
    Reporting group description
    		 Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.

    Reporting group title
    Double-Blind: Vortioxetine 10 mg
    Reporting group description
    		 Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.

    Reporting group title
    Double-Blind: Vortioxetine 20 mg
    Reporting group description
    		 Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.

    Reporting group title
    Double-Blind: Fluoxetine 20 mg
    Reporting group description
    		 Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.

    Subject analysis set title
    Vortioxetine Average (Avg. VOR)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Avg. VOR is the average dose effect of the 2 vortioxetine doses (Vortioxetine 10 mg and Vortioxetine 20 mg).

    Primary: Change From Baseline in Children Depression Rating Scale - Revised (CDRS-R) Total Score at Week 8 of Phase B

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    End point title
    		 Change From Baseline in Children Depression Rating Scale - Revised (CDRS-R) Total Score at Week 8 of Phase B
    End point description
    CDRS-R consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. Total score ranged from 17 (normal) to 113 (severe depression). Least square (LS) mean was estimated using a restricted maximum likelihood (REML)-based Mixed Model Repeated Measurements (MMRM) approach. Full analysis set (FAS) included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of CDRS-R total score. Overall number of participants analyzed = participants evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (Week 4 of Phase A), Week 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg Vortioxetine Average (Avg. VOR)
    Number of subjects analysed
    136
    132
    134
    78
    266
    Units: units on a scale
        least squares mean (standard error)
    -17.48 ( 1.35 )
    -19.20 ( 1.37 )
    -19.94 ( 1.37 )
    -20.78 ( 1.60 )
    -19.57 ( 1.16 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an REML-based MMRM approach with freely varying mean and covariance structure and with country, treatment (vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine, and placebo), and Week as fixed factors and Baseline CDRS-R total score as a continuous covariate, the treatment-by-week interaction, and Baseline CDRS-R-by-Week interaction.
    Comparison groups
    Double-Blind: Placebo v Vortioxetine Average (Avg. VOR)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0937
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.54
         upper limit
    		 0.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using an REML-based MMRM approach with freely varying mean and covariance structure and with country, treatment (vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine, and placebo), and Week as fixed factors and Baseline CDRS-R total score as a continuous covariate, the treatment-by-week interaction, and Baseline CDRS-R-by-Week interaction.
    Comparison groups
    Double-Blind: Placebo v Double-Blind: Vortioxetine 10 mg
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2336
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.56
         upper limit
    		 1.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.44
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Analysis was performed using an REML-based MMRM approach with freely varying mean and covariance structure and with country, treatment (vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine, and placebo), and Week as fixed factors and Baseline CDRS-R total score as a continuous covariate, the treatment-by-week interaction, and Baseline CDRS-R-by-Week interaction.
    Comparison groups
    Double-Blind: Placebo v Double-Blind: Vortioxetine 20 mg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0879
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.29
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.44
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Analysis was performed using an REML-based MMRM approach with freely varying mean and covariance structure and with country, treatment (vortioxetine 10 mg/day, vortioxetine 20 mg/day, fluoxetine, and placebo), and Week as fixed factors and Baseline CDRS-R total score as a continuous covariate, the treatment-by-week interaction, and Baseline CDRS-R-by-Week interaction.
    Comparison groups
    Double-Blind: Placebo v Double-Blind: Fluoxetine 20 mg
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0531
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.65
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7

    Secondary: Change From Baseline in CDRS-R Total Score at Weeks 2, 4, and 6 of Phase B

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    End point title
    		 Change From Baseline in CDRS-R Total Score at Weeks 2, 4, and 6 of Phase B
    End point description
    The CDRS-R was rated by a clinician following interviews with the child and parent and consisted of 17 items out of which 3 items rated nonverbal observations (listless speech, hypoactivity, and depressed affect). Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this endpoint. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 2, 4, and 6 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    147
    146
    80
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 2 (n=153,147,146,80)
    -9.20 ( 1.17 )
    -9.54 ( 1.18 )
    -10.30 ( 1.19 )
    -10.17 ( 1.32 )
        Change at Week 4 (n=145,137,139,78)
    -13.15 ( 1.28 )
    -14.56 ( 1.30 )
    -15.62 ( 1.30 )
    -13.97 ( 1.50 )
        Change at Week 6 (n=143,136,137,78)
    -16.00 ( 1.32 )
    -17.64 ( 1.34 )
    -18.28 ( 1.34 )
    -17.75 ( 1.56 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B

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    End point title
    		 Change From Baseline in CDRS-R Subscores (Mood, Somatic, Subjective, and Behaviour) at Weeks 2, 4, 6, and 8 of Phase B
    End point description
    CDRS-R consisted of 17 items. Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. Four subscores were defined based on the CDRS-R: Mood: sum of items 8, 11, 14, 15; score range 4 to 28, Somatic: sum of items 4, 5, 6, 7, 16, 17; score range 6 to 36, Subjective: sum of items 9, 10, 12, 13; score range 4 to 28, and Behaviour: sum of items 1, 2, 3; score range 3 to 21. Higher scores indicated the most severe measure of depression. FAS: all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline assessment and at least 1 valid post-baseline assessment of CDRS-R total score. Overall number of participants analyzed = participants evaluated for this endpoint. n = participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 2, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    147
    146
    80
    Units: units on a scale
    least squares mean (standard error)
        Mood Score: Change at Week 2 (n=153,147,146,80)
    -2.82 ( 0.40 )
    -3.10 ( 0.40 )
    -3.47 ( 0.40 )
    -3.02 ( 0.45 )
        Mood Score: Change at Week 4 (n=145,137,139,78)
    -3.69 ( 0.42 )
    -4.39 ( 0.43 )
    -4.77 ( 0.43 )
    -3.73 ( 0.49 )
        Mood Score: Change at Week 6 (n=143,136,137,78)
    -4.67 ( 0.43 )
    -5.39 ( 0.44 )
    -5.52 ( 0.44 )
    -4.97 ( 0.51 )
        Mood Score: Change at Week 8 (n=136,132,134,78)
    -5.08 ( 0.44 )
    -5.64 ( 0.44 )
    -5.95 ( 0.45 )
    -5.84 ( 0.51 )
        Somatic Score: Change at Week 2 (n=153,147,146,80)
    -2.81 ( 0.44 )
    -2.61 ( 0.44 )
    -2.88 ( 0.44 )
    -3.02 ( 0.50 )
        Somatic Score: Change at Week 4 (n=145,137,139,78)
    -4.08 ( 0.47 )
    -4.30 ( 0.48 )
    -4.70 ( 0.48 )
    -4.26 ( 0.56 )
        Somatic Score: Change at Week 6 (n=143,136,137,78)
    -4.86 ( 0.48 )
    -5.53 ( 0.49 )
    -5.33 ( 0.49 )
    -5.57 ( 0.57 )
        Somatic Score: Change at Week 8 (n=136,132,134,78)
    -5.38 ( 0.49 )
    -6.15 ( 0.50 )
    -6.08 ( 0.50 )
    -6.44 ( 0.57 )
        Subjective Score:Change at Week 2(n=153,147,146,80
    -1.44 ( 0.22 )
    -1.46 ( 0.22 )
    -1.43 ( 0.22 )
    -1.56 ( 0.25 )
        Subjective Score:Change at Week 4(n=145,137,139,78
    -2.04 ( 0.23 )
    -2.12 ( 0.23 )
    -2.20 ( 0.23 )
    -2.17 ( 0.27 )
        Subjective Score:Change at Week 6(n=143,136,137,78
    -2.43 ( 0.24 )
    -2.42 ( 0.24 )
    -2.65 ( 0.24 )
    -2.38 ( 0.28 )
        Subjective Score:Change at Week 8(n=136,132,134,78
    -2.56 ( 0.24 )
    -2.59 ( 0.24 )
    -2.84 ( 0.24 )
    -2.65 ( 0.28 )
        Behaviour Score:Change at Week 2(n=153,147,146,80)
    -2.16 ( 0.34 )
    -2.40 ( 0.34 )
    -2.56 ( 0.35 )
    -2.61 ( 0.39 )
        Behaviour Score:Change at Week 4(n=145,137,139,78)
    -3.39 ( 0.38 )
    -3.77 ( 0.39 )
    -4.00 ( 0.39 )
    -3.80 ( 0.45 )
        Behaviour Score:Change at Week 6(n=143,136,137,78)
    -4.09 ( 0.39 )
    -4.31 ( 0.39 )
    -4.83 ( 0.40 )
    -4.80 ( 0.46 )
        Behaviour Score:Change at Week 8(n=136,132,134,78)
    -4.47 ( 0.40 )
    -4.80 ( 0.41 )
    -5.09 ( 0.41 )
    -5.83 ( 0.48 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With CDRS-R Response

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    End point title
    		 Percentage of Participants With CDRS-R Response
    End point description
    CDRS-R response was defined as a ≥50% decrease in CDRS-R total score, calculated as: (change from baseline [Randomization])/(baseline value – 17). The CDRS-R consisted of 17 items out of which 3 items rated nonverbal observations. Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    147
    146
    80
    Units: percentage of participants
    number (not applicable)
        Week 2 (n = 153, 147, 146, 80)
    7.8
    10.2
    11.6
    16.3
        Week 4 (n = 145, 137, 139, 78)
    20.7
    23.4
    26.6
    26.9
        Week 6 (n = 143, 136, 137, 78)
    30.8
    31.6
    37.2
    33.3
        Week 8 (n = 136, 132, 134, 78)
    29.4
    36.4
    41.0
    47.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With CDRS-R Remission

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    End point title
    		 Percentage of Participants With CDRS-R Remission
    End point description
    CDRS-R remission was defined as a CDRS-R total score ≤28. The CDRS-R consisted of 17 items out of which 3 items rated nonverbal observations. Fourteen items were rated on a 7-point scale from 1 to 7, and 3 items (sleep disturbance, appetite disturbance, and listless speech) were scored on a 5-point scale from 1 to 5. A rating of 1 indicated normal functioning and a higher number indicated a greater degree of depression. The total score ranged from 17 (normal) to 113 (severe depression). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    147
    146
    80
    Units: percentage of participants
    number (not applicable)
        Week 2 (n = 153, 147, 146, 80)
    2.0
    5.4
    2.7
    3.8
        Week 4 (n = 145, 137, 139, 78)
    9.0
    9.5
    10.1
    9.0
        Week 6 (n = 143, 136, 137, 78)
    14.7
    15.4
    15.3
    14.1
        Week 8 (n = 136, 132, 134, 78)
    14.7
    16.7
    20.1
    26.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B

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    End point title
    		 Change From Baseline in General Behaviour Inventory (GBI) Depression Subscale Score, Using the 10-Item Depression Subscale Assessed by Parent (PGBI-10D) and Child (CGBI-10D) at Weeks 2, 4, 6, and 8 of Phase B
    End point description
    The GBI 10-item depression scale was developed to screen for depressive symptoms in children and adolescents. Two versions of the GBI 10-item depression scale were used, the child rated version (CGBI) and the parent rated version (PGBI). The 10 depression items were rated on a 4-point scale from 0 (never or hardly ever) to 3 (very often or almost constantly). The total score ranged from 0 to 30, with higher scores indicating greater pathology. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 2, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    152
    147
    146
    80
    Units: units on a scale
    least squares mean (standard error)
        PGBI: Change at Week 2 (n=152,147,146,80)
    -3.33 ( 0.55 )
    -3.38 ( 0.55 )
    -3.78 ( 0.56 )
    -3.78 ( 0.63 )
        PGBI: Change at Week 4 (n=143,137,137,78)
    -4.11 ( 0.58 )
    -4.72 ( 0.59 )
    -5.33 ( 0.59 )
    -4.45 ( 0.68 )
        PGBI: Change at Week 6 (n=142,136,137,78)
    -5.32 ( 0.58 )
    -5.58 ( 0.59 )
    -5.82 ( 0.59 )
    -6.05 ( 0.68 )
        PGBI: Change at Week 8 (n=136,132,134,78)
    -5.81 ( 0.61 )
    -6.51 ( 0.62 )
    -6.46 ( 0.62 )
    -6.56 ( 0.72 )
        CGBI: Change at Week 2 (n=149,145,143,76)
    -2.66 ( 0.61 )
    -3.32 ( 0.61 )
    -3.27 ( 0.61 )
    -2.94 ( 0.70 )
        CGBI: Change at Week 4 (n=141,136,134,75)
    -3.65 ( 0.65 )
    -4.15 ( 0.65 )
    -4.16 ( 0.65 )
    -3.16 ( 0.76 )
        CGBI: Change at Week 6 (n=139,134,135,75)
    -4.62 ( 0.63 )
    -5.43 ( 0.64 )
    -5.17 ( 0.63 )
    -5.14 ( 0.73 )
        CGBI: Change at Week 8 (n=134,131,132,75)
    -5.26 ( 0.65 )
    -6.12 ( 0.66 )
    -5.48 ( 0.65 )
    -5.46 ( 0.76 )
    No statistical analyses for this end point

    Secondary: Parent Global Assessment (PGA) Score

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    End point title
    		 Parent Global Assessment (PGA) Score
    End point description
    The PGA is a parent-rated variation of the CGI-I to evaluate the severity of the child’s symptoms. The PGA reflects assessments of symptoms using a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    152
    147
    145
    80
    Units: units on a scale
    least squares mean (standard error)
        Week 2 (n = 152, 147, 145, 80)
    3.31 ( 0.09 )
    3.25 ( 0.09 )
    3.18 ( 0.09 )
    3.13 ( 0.11 )
        Week 4 (n = 143, 137, 136, 78)
    2.97 ( 0.10 )
    2.90 ( 0.10 )
    2.84 ( 0.10 )
    2.90 ( 0.12 )
        Week 6 (n = 142, 136, 136, 78)
    2.73 ( 0.10 )
    2.73 ( 0.10 )
    2.68 ( 0.10 )
    2.80 ( 0.12 )
        Week 8 (n = 136, 132, 133, 78)
    2.68 ( 0.11 )
    2.62 ( 0.11 )
    2.61 ( 0.11 )
    2.59 ( 0.13 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B

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    End point title
    		 Change From Baseline in Clinical Global Impression - Severity of Illness (CGI-S) Score at Weeks 1, 2, 3, 4, 6, and 8 of Phase B
    End point description
    The CGI-S provides the clinician’s impression of the participant’s current state of mental illness. The clinician uses his or her clinical experience of this participant population to rate the severity of the participant’s current mental illness on a 7-point scale ranging from 1 (normal – not at all ill) to 7 (among the most extremely ill participants). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 1, 2, 3, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    148
    146
    81
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 1 (n=153,148,146,81)
    -0.25 ( 0.07 )
    -0.27 ( 0.07 )
    -0.28 ( 0.07 )
    -0.22 ( 0.08 )
        Change at Week 2 (n=153,146,144,81)
    -0.50 ( 0.08 )
    -0.60 ( 0.08 )
    -0.65 ( 0.08 )
    -0.63 ( 0.10 )
        Change at Week 3 (n=150,145,145,78)
    -0.67 ( 0.08 )
    -0.62 ( 0.08 )
    -0.79 ( 0.08 )
    -0.77 ( 0.10 )
        Change at Week 4 (n=145,137,139,78)
    -0.95 ( 0.09 )
    -1.00 ( 0.09 )
    -1.06 ( 0.09 )
    -1.01 ( 0.12 )
        Change at Week 6 (n=143,136,137,78)
    -1.13 ( 0.10 )
    -1.22 ( 0.10 )
    -1.27 ( 0.10 )
    -1.23 ( 0.12 )
        Change at Week 8 (n=137,132,134,78)
    -1.31 ( 0.10 )
    -1.40 ( 0.11 )
    -1.44 ( 0.11 )
    -1.57 ( 0.13 )
    No statistical analyses for this end point

    Secondary: Clinical Global Impression - Global Improvement (CGI-I) Score

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    End point title
    		 Clinical Global Impression - Global Improvement (CGI-I) Score
    End point description
    The CGI-I provides the clinician’s impression of the participant’s improvement (or worsening). The clinician assesses the participant’s condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    148
    145
    81
    Units: units on a scale
    least squares mean (standard error)
        Week 1 (n = 153, 148, 145, 81)
    3.66 ( 0.07 )
    3.63 ( 0.07 )
    3.60 ( 0.07 )
    3.72 ( 0.08 )
        Week 2 (n = 153, 146, 143, 81)
    3.32 ( 0.08 )
    3.30 ( 0.08 )
    3.19 ( 0.08 )
    3.26 ( 0.10 )
        Week 3 (n = 150, 145, 144, 78)
    3.20 ( 0.08 )
    3.20 ( 0.08 )
    3.14 ( 0.08 )
    3.23 ( 0.10 )
        Week 4 (n = 145, 137, 138, 78)
    2.93 ( 0.09 )
    2.93 ( 0.09 )
    2.82 ( 0.09 )
    2.97 ( 0.11 )
        Week 6 (n = 143, 136, 136, 78)
    2.70 ( 0.09 )
    2.64 ( 0.10 )
    2.65 ( 0.10 )
    2.78 ( 0.12 )
        Week 8 (n = 137, 132, 133, 78)
    2.69 ( 0.10 )
    2.58 ( 0.08 )
    2.60 ( 0.10 )
    2.57 ( 0.12 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With CGI-S Remission

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    End point title
    		 Percentage of Participants With CGI-S Remission
    End point description
    CGI-S remission was defined as a CGI-S score of 1 or 2. The CGI-S provides the clinician’s impression of the participant’s current state of mental illness. The clinician uses his or her clinical experience of this participant population to rate the severity of the participant’s current mental illness on a 7-point scale ranging from 1 (normal – not at all ill) to 7 (among the most extremely ill participants). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 6, and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    153
    148
    148
    81
    Units: percentage of participants
    number (not applicable)
        Week 1 (n = 153, 148, 146, 81)
    0
    0.7
    0
    0
        Week 2 (n = 153, 148, 147, 81)
    0.7
    3.4
    1.4
    3.7
        Week 3 (n = 153, 148, 148, 81)
    3.3
    4.1
    4.7
    7.4
        Week 4 (n = 153, 148, 148, 81)
    8.5
    8.1
    12.8
    12.3
        Week 6 (n = 153, 148, 148, 81)
    14.4
    16.2
    16.2
    14.8
        Week 8 (n = 153, 148, 148, 81)
    22.9
    22.3
    20.9
    29.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Children's Global Assessment Scale (CGAS) Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in Children's Global Assessment Scale (CGAS) Score at Weeks 4 and 8 of Phase B
    End point description
    The CGAS is a clinician-rated global scale to measure the lowest level of functioning for a child (4 to 16 years) during a specified time period. The CGAS contains behaviourally-oriented descriptors at each anchor point that depict behaviours and life situations applicable to a child. The score ranges from 1 (most functionally impaired child) to 100 (the healthiest). A score greater than 70 indicates normal function. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    146
    139
    142
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=146,139,142,79)
    8.93 ( 1.23 )
    9.84 ( 1.25 )
    8.73 ( 1.26 )
    10.54 ( 1.39 )
        Change at Week 8 (n=136,132,134,78)
    12.71 ( 1.31 )
    12.98 ( 1.33 )
    13.22 ( 1.34 )
    16.35 ( 1.51 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Visual Analogue Scales (VAS): Afraid or Scared (Anxiety) Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Visual Analogue Scales (VAS): Afraid or Scared (Anxiety) Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -0.48 ( 0.27 )
    -0.51 ( 0.27 )
    -0.48 ( 0.27 )
    -0.41 ( 0.31 )
        Change at Week 8 (n=136,130,134,78)
    -0.73 ( 0.26 )
    -1.07 ( 0.27 )
    -1.01 ( 0.27 )
    -1.08 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL VAS: Sad or Blue (Sadness) Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL VAS: Sad or Blue (Sadness) Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -1.20 ( 0.31 )
    -1.65 ( 0.31 )
    -1.78 ( 0.31 )
    -1.42 ( 0.35 )
        Change at Week 8 (n=136,130,134,78)
    -1.72 ( 0.32 )
    -2.23 ( 0.32 )
    -2.05 ( 0.32 )
    -2.31 ( 0.36 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL VAS: Angry Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL VAS: Angry Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    144
    139
    140
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=144,139,140,79)
    -0.98 ( 0.30 )
    -1.36 ( 0.31 )
    -1.33 ( 0.31 )
    -1.22 ( 0.35 )
        Change at Week 8 (n=136,130,133,78)
    -1.24 ( 0.31 )
    -1.98 ( 0.32 )
    -1.36 ( 0.32 )
    -1.67 ( 0.36 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL VAS: Worry Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL VAS: Worry Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -0.63 ( 0.31 )
    -1.48 ( 0.32 )
    -1.21 ( 0.32 )
    -1.27 ( 0.36 )
        Change at Week 8 (n=136,130,134,78)
    -1.08 ( 0.32 )
    -1.82 ( 0.33 )
    -1.45 ( 0.33 )
    -1.41 ( 0.36 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL VAS: Tired (Fatigue) Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL VAS: Tired (Fatigue) Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -1.22 ( 0.34 )
    -1.19 ( 0.35 )
    -1.63 ( 0.35 )
    -0.94 ( 0.39 )
        Change at Week 8 (n=136,130,134,78)
    -1.39 ( 0.36 )
    -1.32 ( 0.37 )
    -1.74 ( 0.37 )
    -1.73 ( 0.41 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL VAS: Pain or Hurt Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL VAS: Pain or Hurt Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -0.22 ( 0.28 )
    -0.81 ( 0.28 )
    -0.45 ( 0.28 )
    -0.50 ( 0.32 )
        Change at Week 8 (n=136,130,134,78)
    -0.70 ( 0.28 )
    -0.79 ( 0.28 )
    -1.02 ( 0.28 )
    -0.69 ( 0.32 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL VAS Total Average Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL VAS Total Average Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL™ VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue, and pain using visual analogue scales. The functionality for each domain is measured on a 10cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. The total score is the average of all 6 items. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -0.81 ( 0.19 )
    -1.19 ( 0.19 )
    -1.17 ( 0.20 )
    -1.01 ( 0.22 )
        Change at Week 8 (n=136,130,134,78)
    -1.17 ( 0.20 )
    -1.55 ( 0.20 )
    -1.47 ( 0.20 )
    -1.54 ( 0.23 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL Emotional Distress Summary Average Score at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PedsQL Emotional Distress Summary Average Score at Weeks 4 and 8 of Phase B
    End point description
    The PedsQL™ VAS is designed to measure at-that-moment functioning in children and adolescents. The PedsQL VAS consists of 6 domains: anxiety, sadness, anger, worry, fatigue and pain using visual analogue scales. The functionality for each domain is measured on a 10 cm line with a happy face at one end and a sad face at the other (0-10 points). The participants are asked to mark on the line how they feel. The average emotional distress summary score is the mean of the anxiety, sadness, anger, and worry items. A lower value represents a better outcome. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    141
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,141,79)
    -0.84 ( 0.21 )
    -1.28 ( 0.21 )
    -1.22 ( 0.22 )
    -1.13 ( 0.24 )
        Change at Week 8 (n=136,130,134,78)
    -1.22 ( 0.22 )
    -1.80 ( 0.22 )
    -1.51 ( 0.22 )
    -1.66 ( 0.25 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Score (Items 1 to 14) at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Score (Items 1 to 14) at Weeks 4 and 8 of Phase B
    End point description
    The PQ-LES-Q is a patient-rated scale designed to assess satisfaction with life. The PQ-LES-Q consist of 15 items, item 1 to 14 assess the degree of satisfaction experienced by participants in various areas of daily functioning, and item 15 allows subjects to summarise their experience in a global rating. Each item is rated on a 5-point scale from 1 (very poor) to 5 (very good). The total score range of item 1 to 14 is 14 to 70, with higher scores indicating greater satisfaction. FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    140
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,140,79)
    3.94 ( 0.95 )
    4.90 ( 0.96 )
    4.90 ( 0.97 )
    4.36 ( 1.09 )
        Change at Week 8 (n=136,132,134,78)
    6.22 ( 0.98 )
    7.08 ( 0.99 )
    7.14 ( 1.00 )
    6.79 ( 1.12 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PQ-LES-Q Overall Evaluation Score (Item 15) at Weeks 4 and 8 of Phase B

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    End point title
    		 Change From Baseline in PQ-LES-Q Overall Evaluation Score (Item 15) at Weeks 4 and 8 of Phase B
    End point description
    The PQ-LES-Q is a patient-rated scale designed to assess satisfaction with life. It is an adaptation of the Quality of Life Enjoyment and Satisfaction Questionnaire, which is used to measure quality of life in adults. The PQ-LES-Q consist of 15 items, item 1 to 14 assess the degree of satisfaction experienced by participants in various areas of daily functioning, and item 15 allows subjects to summarize their experience in a global rating. Item 15 is rated on a 5-point scale from 1 (very poor) to 5 (very good). FAS included all participants randomized to the DB, 8-week treatment period (Phase B) who took at least 1 dose of DB study drug and who had a valid baseline (Week 4 of Phase A) assessment and at least 1 valid post-baseline assessment of the CDRS-R total score. Overall number of participants analyzed = participants evaluated for this outcome measure. n = participants evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 4 of Phase A), Weeks 4 and 8 of Phase B
    End point values
    		 Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Number of subjects analysed
    145
    139
    140
    79
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 4 (n=145,139,140,79)
    0.28 ( 0.09 )
    0.37 ( 0.09 )
    0.43 ( 0.09 )
    0.24 ( 0.11 )
        Change at Week 8 (n=136,132,134,78)
    0.41 ( 0.09 )
    0.49 ( 0.09 )
    0.52 ( 0.09 )
    0.45 ( 0.11 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 16
    Adverse event reporting additional description
    All-patients-treated set Phase A (APTS_A) included all participants enrolled to the 4-week Single-blind period (Phase A) who received at least 1 dose of study drug. All-patients-treated set Phase B (APTS) included all participants randomized to the double-blind, 8-week treatment period (Phase B) who took at least 1 dose of double-blind study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Single-Blind: Placebo
    Reporting group description
    		 Participants received BPI (3 sessions) and placebo capsules orally once daily for 4 weeks.

    Reporting group title
    Double-Blind: Placebo
    Reporting group description
    		 Participants received placebo capsules orally once daily for 8 weeks. Participants received 2 sessions of BPI also.

    Reporting group title
    Double-Blind: Vortioxetine 10 mg
    Reporting group description
    		 Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days and thereafter they received 10 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.

    Reporting group title
    Double-Blind: Vortioxetine 20 mg
    Reporting group description
    		 Participants initiated treatment with vortioxetine capsules 5 mg/day orally for 2 days followed by 10 mg/day for 2 days and 15 mg/day for 2 days, and thereafter they received vortioxetine 20 mg/day for up to Week 8. Based on the tolerability, vortioxetine dose could be reduced by 5 mg/day at Week 4. Participants received 2 sessions of BPI also.

    Reporting group title
    Double-Blind: Fluoxetine 20 mg
    Reporting group description
    		 Participants initiated treatment with fluoxetine 10 mg/day orally for 6 days and thereafter they received 20 mg/day. for up to Week 8. Based on the tolerability, fluoxetine dose could be reduced by 10 mg/day at Week 4. Participants received 2 sessions of BPI also.

    Serious adverse events
    		 Single-Blind: Placebo Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 677 (0.89%)
    3 / 153 (1.96%)
    1 / 151 (0.66%)
    2 / 153 (1.31%)
    1 / 83 (1.20%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 677 (0.00%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 677 (0.15%)
    1 / 153 (0.65%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 677 (0.00%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    1 / 153 (0.65%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 677 (0.00%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    1 / 153 (0.65%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 677 (0.00%)
    1 / 153 (0.65%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 677 (0.00%)
    1 / 153 (0.65%)
    0 / 151 (0.00%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 677 (0.00%)
    0 / 153 (0.00%)
    1 / 151 (0.66%)
    0 / 153 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Single-Blind: Placebo Double-Blind: Placebo Double-Blind: Vortioxetine 10 mg Double-Blind: Vortioxetine 20 mg Double-Blind: Fluoxetine 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 677 (15.66%)
    45 / 153 (29.41%)
    55 / 151 (36.42%)
    42 / 153 (27.45%)
    27 / 83 (32.53%)
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 677 (0.15%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    1 / 153 (0.65%)
    2 / 83 (2.41%)
         occurrences all number
    1
    0
    0
    1
    2
    Weight increased
         subjects affected / exposed
    1 / 677 (0.15%)
    4 / 153 (2.61%)
    1 / 151 (0.66%)
    3 / 153 (1.96%)
    2 / 83 (2.41%)
         occurrences all number
    1
    4
    1
    3
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    39 / 677 (5.76%)
    17 / 153 (11.11%)
    14 / 151 (9.27%)
    14 / 153 (9.15%)
    4 / 83 (4.82%)
         occurrences all number
    54
    23
    19
    16
    5
    Dizziness
         subjects affected / exposed
    9 / 677 (1.33%)
    5 / 153 (3.27%)
    7 / 151 (4.64%)
    5 / 153 (3.27%)
    3 / 83 (3.61%)
         occurrences all number
    10
    5
    7
    5
    4
    General disorders and administration site conditions
    Illness
         subjects affected / exposed
    0 / 677 (0.00%)
    0 / 153 (0.00%)
    0 / 151 (0.00%)
    5 / 153 (3.27%)
    0 / 83 (0.00%)
         occurrences all number
    0
    0
    0
    8
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    15 / 677 (2.22%)
    4 / 153 (2.61%)
    4 / 151 (2.65%)
    3 / 153 (1.96%)
    3 / 83 (3.61%)
         occurrences all number
    16
    4
    6
    4
    3
    Nausea
         subjects affected / exposed
    23 / 677 (3.40%)
    7 / 153 (4.58%)
    19 / 151 (12.58%)
    17 / 153 (11.11%)
    5 / 83 (6.02%)
         occurrences all number
    23
    7
    22
    25
    6
    Abdominal pain
         subjects affected / exposed
    9 / 677 (1.33%)
    2 / 153 (1.31%)
    9 / 151 (5.96%)
    6 / 153 (3.92%)
    2 / 83 (2.41%)
         occurrences all number
    9
    2
    11
    8
    2
    Diarrhoea
         subjects affected / exposed
    9 / 677 (1.33%)
    4 / 153 (2.61%)
    5 / 151 (3.31%)
    1 / 153 (0.65%)
    3 / 83 (3.61%)
         occurrences all number
    9
    5
    5
    1
    6
    Dry mouth
         subjects affected / exposed
    5 / 677 (0.74%)
    4 / 153 (2.61%)
    4 / 151 (2.65%)
    1 / 153 (0.65%)
    0 / 83 (0.00%)
         occurrences all number
    5
    4
    4
    1
    0
    Vomiting
         subjects affected / exposed
    13 / 677 (1.92%)
    3 / 153 (1.96%)
    14 / 151 (9.27%)
    10 / 153 (6.54%)
    3 / 83 (3.61%)
         occurrences all number
    13
    3
    20
    16
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 677 (0.30%)
    0 / 153 (0.00%)
    1 / 151 (0.66%)
    0 / 153 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    2
    0
    1
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 677 (1.92%)
    5 / 153 (3.27%)
    6 / 151 (3.97%)
    4 / 153 (2.61%)
    3 / 83 (3.61%)
         occurrences all number
    13
    8
    8
    4
    3
    Viral infection
         subjects affected / exposed
    3 / 677 (0.44%)
    0 / 153 (0.00%)
    1 / 151 (0.66%)
    0 / 153 (0.00%)
    2 / 83 (2.41%)
         occurrences all number
    3
    0
    1
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 677 (0.00%)
    2 / 153 (1.31%)
    1 / 151 (0.66%)
    2 / 153 (1.31%)
    3 / 83 (3.61%)
         occurrences all number
    0
    2
    2
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2018
    Due to recruitment difficulties modified the study design to include an interim analysis to potentially stop the study early for either efficacy or futility. The interim analysis was performed when at least 240 randomized participants had either completed or been withdrawn from the study. If it was planned to continue the study after the interim analysis, the study would include only 3 arms.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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