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    Clinical Trial Results:
    F1J-MC-HMFN (a) An Open-Label Study of Tolerability, Safety, and Pharmacokinetics of Duloxetine in the Treatment of Children and Adolescents with Major Depressive Disorder

    Summary
    EudraCT number
    		 2017-000211-16
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    22 Sep 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2017
    First version publication date
    16 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F1J-MC-HMFN
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00529789
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial ID: 11664
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877-CTLILLY,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Sep 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Sep 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of your participation in this study is to help answer the following research question, and not to provide you treatment for your condition. Whether duloxetine once daily orally is tolerated and safe, in children (aged 7 through 11 years) and adolescents (aged 12 through 17 years) with Major Depressive Disorder.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 2007
    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
    United States: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    0
    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)
    31
    Adolescents (12-17 years)
    41
    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
    		 Period I was a 2-week Screening/Washout Phase. Period II was a 10-week Dose-Titrating with Pharmacokinetic Sampling Phase. Period III was an 8-week Safety and Tolerability Phase. Period IV was a 3-month Extended Safety and Tolerability Phase. Period V was a 2-week Taper Phase. Results presented are for combined Periods II/III and Period IV.

    Period 1
    Period 1 title
    Study Period II/III
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Duloxetine
    Arm description
    		 20 - 120 milligrams (mg) every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A dose range of 20 - 120 milligrams (mg) Duloxetine every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.

    Number of subjects in period 1
    		Duloxetine
    Started
    72
    Completed
    48
    Not completed
    24
         Parent/Caregiver Decision
    9
         Consent withdrawn by subject
    1
         Physician decision
    3
         Adverse event, non-fatal
    3
         Lost to follow-up
    3
         Lack of efficacy
    2
         Protocol deviation
    3
    Period 2
    Period 2 title
    Study Period IV
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Duloxetine
    Arm description
    		 20 - 120 milligrams (mg) every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A dose range of 20 - 120 milligrams (mg) Duloxetine every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.

    Number of subjects in period 2
    		Duloxetine
    Started
    48
    Completed
    42
    Not completed
    6
         Parent/Caregiver Decision
    1
         Adverse event, non-fatal
    1
         Lost to follow-up
    3
         Lack of efficacy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Duloxetine
    Reporting group description
    		 20 - 120 milligrams (mg) every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.

    Reporting group values
    		 Duloxetine Total
    Number of subjects
    		 72 72
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 31 31
        Adolescents (12-17 years)
    		 41 41
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.5 ( 2.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 35
        Male
    		 37 37
    Region of Enrollment
    Units: Subjects
        United States
    		 72 72
    Race/Ethnicity
    Units: Subjects
        African
    		 17 17
        Caucasian
    		 42 42
        East Asian
    		 1 1
        Hispanic
    		 11 11
        Native American
    		 1 1
    Tobacco Use
    Tobacco use was based on cotinine level.
    Units: Subjects
        No
    		 70 70
        Yes
    		 1 1
        Not Availble
    		 1 1
    Body Mass Index (BMI)
    Body mass index is an estimate of body fat based on body weight divided by height squared.
    Units: Subjects
        arithmetic mean (standard deviation)
    		 23.7 ( 6.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Duloxetine
    Reporting group description
    		 20 - 120 milligrams (mg) every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.
    Reporting group title
    Duloxetine
    Reporting group description
    		 20 - 120 milligrams (mg) every day, once-daily (QD), by mouth (PO) for 30 weeks; If patient is ≤40 kilograms (kg), initial dose is 20 mg, then titrated up. If patient is >40 kg, initial dose is 30 mg, then titrated up.

    Subject analysis set title
    Duloxetine Dose 20mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Summary of observed plasma concentrations of duloxetine 20 mg.

    Subject analysis set title
    Duloxetine Dose 30mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Summary of observed plasma concentrations of duloxetine 30 mg.

    Subject analysis set title
    Duloxetine Dose 60mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Summary of observed plasma concentrations of duloxetine 60 mg.

    Subject analysis set title
    Duloxetine Dose 90mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Summary of observed plasma concentrations of duloxetine 90 mg.

    Subject analysis set title
    Duloxetine Dose 120mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Summary of observed plasma concentrations of duloxetine 120 mg.

    Primary: Number of Participants with Emergence of Suicidal Ideation During Period II/III

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    End point title
    		 Number of Participants with Emergence of Suicidal Ideation During Period II/III [1]
    End point description
    Emergence of Any Suicidal Ideation: Item 13 of Children's Depression Rating Scale-Revised (CDRS-R) has possible scores of 1 (no thoughts of suicide) to 7 (contemplation of suicide). Emergence of suicidal ideation was defined as an increase in severity of suicidal ideation for those patients who did not have suicidal ideation at baseline (Week 0).
    End point type
    Primary
    End point timeframe
    Baseline to 18 weeks
    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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    72
    Units: participants
        number (not applicable)
    2
    No statistical analyses for this end point

    Primary: Number of Participants with Emergence of Suicidal Ideation During Period IV

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    End point title
    		 Number of Participants with Emergence of Suicidal Ideation During Period IV [2]
    End point description
    Emergence of Any Suicidal Ideation: Item 13 of Children's Depression Rating Scale-Revised (CDRS-R) has possible scores of 1 (no thoughts of suicide) to 7 (contemplation of suicide). Emergence of suicidal ideation was defined as an increase in severity of suicidal ideation for those patients who did not have suicidal ideation at baseline (Week 0).
    End point type
    Primary
    End point timeframe
    Week 0 and Between 18 and 30 Weeks
    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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    48
    Units: participants
        number (not applicable)
    0
    No statistical analyses for this end point

    Primary: Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) During Period II/III

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    End point title
    		 Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) During Period II/III [3]
    End point description
    The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. Some questions are yes/no and some are on a scale of 1 (low severity) to 5 (high severity). Completed suicide and non-fatal suicide events are yes/no questions and results presented are the number of participants with these events. Worsening of suicidal ideation was an increase in severity of suicidal ideation from baseline.
    End point type
    Primary
    End point timeframe
    Baseline to 18 Weeks
    Notes
    [3] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    72
    Units: participants
    number (not applicable)
        Completed Suicide
    0
        Non-fatal Suicide Event
    1
        Worsening of Suicidal Ideation
    1
    No statistical analyses for this end point

    Primary: Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) During Period IV

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    End point title
    		 Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) During Period IV [4]
    End point description
    The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. Some questions are yes/no and some are on a scale of 1 (low severity) to 5 (high severity). Completed suicide and non-fatal suicide events are yes/no questions and results presented are the number of participants with these events. Worsening of suicidal ideation was an increase in severity of suicidal ideation from baseline.
    End point type
    Primary
    End point timeframe
    Between 18 and 30 Weeks
    Notes
    [4] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    45 [5]
    Units: participants
    number (not applicable)
        Completed suicide
    0
        Non-fatal suicide event
    0
        Worsening of Suicidal Ideation
    1
    Notes
    [5] - Number of enrolled patients with baseline and post-baseline values in Period IV.
    No statistical analyses for this end point

    Primary: Number of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values at Any Time During Period II/III

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    End point title
    		 Number of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values at Any Time During Period II/III [6]
    End point description
    Total number of patients with any abnormal post-baseline value, based on all values at scheduled and unscheduled visits. Criteria: High Diastolic Blood Pressure = increase of at least 5 mmHg to a value above the 95th percentile; High Systolic Blood Pressure = increase of at least 5 mmHg to a value above the 95th percentile; High Pulse = increase of at least 25 to a value of at least 110.
    End point type
    Primary
    End point timeframe
    Baseline to 18 Weeks
    Notes
    [6] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    72
    Units: participants
    number (not applicable)
        High Diastolic Blood Pressure
    22
        High Systolic Blood Pressure
    25
        High Pulse
    2
    No statistical analyses for this end point

    Primary: Number of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values at Any Time During Period IV

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    End point title
    		 Number of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values at Any Time During Period IV [7]
    End point description
    Total number of patients with any abnormal post-baseline value, based on all values at scheduled and unscheduled visits. Criteria: High Diastolic Blood Pressure = increase of at least 5 mmHg to a value above the 95th percentile; High Systolic Blood Pressure = increase of at least 5 mmHg to a value above the 95th percentile; High Pulse = increase of at least 25 to a value of at least 110.
    End point type
    Primary
    End point timeframe
    Between 18 and 30 Weeks
    Notes
    [7] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    45
    Units: participants
    number (not applicable)
        High Diastolic Blood Pressure
    3
        High Systolic Blood Pressure
    1
        High Pulse
    0
    No statistical analyses for this end point

    Primary: Number of Participants Meeting Criteria for Potentially Clinically Significant (PCS) Laboratory Analyte Values at Any Time During Period II/III

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    End point title
    		 Number of Participants Meeting Criteria for Potentially Clinically Significant (PCS) Laboratory Analyte Values at Any Time During Period II/III [8]
    End point description
    The results shown are for all laboratory analytes where PCS criteria were met, based on criteria used for adult studies. Criteria: High Alanine transaminase (>165 Units/Liter [U/L]); High Creatine Phosphokinase (females: >507 U/L; males:>594 U/L); Low Glucose (<2.498 millimoles/L); Low Hematocrit (females: <0.32; males <0.37); Low Hemoglobin (females <5.896 millimoles/L [mmol/L] iron; males <7.137 mmol/L iron); High Inorganic Phosphorus (>1.776 millimoles/L); Low Leukocyte Count (<2.8 X10^9/L). Number of patients with baseline (and none abnormal) and post-baseline values, based on all values at scheduled and unscheduled visits
    End point type
    Primary
    End point timeframe
    Baseline to 18 Weeks
    Notes
    [8] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    72
    Units: participants
    number (not applicable)
        High Alanine Transaminase (N=69)
    1
        High Creatine Phosphokinase (N=69)
    6
        Low Glucose (N=69)
    1
        Low Hematocrit (N=60)
    8
        Low Hemoglobin (N=67)
    1
        High Inorganic Phosphorus (N=62)
    16
        Low Leukocyte Count (N=68)
    1
    No statistical analyses for this end point

    Primary: Number of Participants Meeting Criteria for Potentially Clinically Significant (PCS) Laboratory Analyte Values at Any Time During Period IV

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    End point title
    		 Number of Participants Meeting Criteria for Potentially Clinically Significant (PCS) Laboratory Analyte Values at Any Time During Period IV [9]
    End point description
    The results shown are for all laboratory analytes where PCS criteria were met, based on criteria used for adult studies. Criteria: High Alkaline Phosphatase (>420 Units/Liter [U/L]); Low Hematocrit (females <0.32; males <0.37); High Inorganic Phosphorus (>1.776 millimoles/L). Total number of patients with baseline (and none abnormal) and post-baseline values in Period IV, based on all values at scheduled and unscheduled visits.
    End point type
    Primary
    End point timeframe
    Between 18 and 30 Weeks
    Notes
    [9] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    48
    Units: participants
    number (not applicable)
        High Alkaline Phosphatase (N=42)
    1
        Low Hematocrit (N=39)
    1
        High Inorganic Phosphorus (N=39)
    3
    No statistical analyses for this end point

    Primary: Number of Participants Meeting Criteria for Potentially Clinically Significant Electrocardiograms at Any Time in Period II/III

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    End point title
    		 Number of Participants Meeting Criteria for Potentially Clinically Significant Electrocardiograms at Any Time in Period II/III [10]
    End point description
    Total number of patients with any abnormal post-baseline values, based on all values at scheduled and unscheduled visits. Criteria: High QRS Interval = ≥100 milliseconds (msec); High QTc Bazette's or Fredericia's correction - Female = ≥470 msec; High QTc Bazette's or Fredericia's correction - Male = ≥450 msec. Number of patients with baseline (and none abnormal) and post-baseline values, based on all values at scheduled and unscheduled visits
    End point type
    Primary
    End point timeframe
    Baseline to 18 Weeks
    Notes
    [10] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    72
    Units: participants
    number (not applicable)
        High QRS Interval (N=63)
    1
        High QTc Bazette's Correction (N=64)
    2
        High QTc Fredericia's Correction (N=65)
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Potentially Clinically Significant Electrocardiograms at Any Time in Period IV

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    End point title
    		 Number of Participants with Potentially Clinically Significant Electrocardiograms at Any Time in Period IV [11]
    End point description
    Total number of patients with any abnormal post-baseline values, based on all values at scheduled and unscheduled visits. Criteria: High QRS Interval = ≥100 milliseconds (msec); High QTc Bazette's or Fredericia's correction - Female = ≥470 msec; High QTc Bazette's or Fredericia's correction - Male = ≥450 msec. Number of patients with baseline (and none abnormal) and post-baseline values, based on all values at scheduled and unscheduled visits.
    End point type
    Primary
    End point timeframe
    Between 18 and 30 Weeks
    Notes
    [11] - 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: The primary objective of this study was to assess the safety and tolerability of duloxetine in children and adolescents. This was an open-label, single arm study with no comparison groups and statistical analyses were not conducted.
    End point values
    		 Duloxetine
    Number of subjects analysed
    48
    Units: participants
    number (not applicable)
        High QRS Interval (N=39)
    1
        High QTc Bazette's Correction (N=41)
    1
        High QTc Fredericia's Correction (N=41)
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Summary of Observed Duloxetine Plasma Concentrations Stratified by Duloxetine Dose

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    End point title
    		 Pharmacokinetics: Summary of Observed Duloxetine Plasma Concentrations Stratified by Duloxetine Dose
    End point description
    Plasma samples were obtained at steady state, and approximately 95% of duloxetine concentrations were within the 24 hour dosing interval.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 6, 8, 10, 14, 18
    End point values
    		 Duloxetine Dose 20mg Duloxetine Dose 30mg Duloxetine Dose 60mg Duloxetine Dose 90mg Duloxetine Dose 120mg
    Number of subjects analysed
    14
    53
    41
    33
    19
    Units: nanograms per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    15.2 ( 12 )
    20.8 ( 21.2 )
    41.1 ( 34.7 )
    57.6 ( 43.2 )
    77.6 ( 54.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to 18 Weeks and 30 Weeks in Clinical Global Impressions of Severity Scale (CGI-S)

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    End point title
    		 Change from Baseline to 18 Weeks and 30 Weeks in Clinical Global Impressions of Severity Scale (CGI-S)
    End point description
    Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Baseline is the same timepoint (Week 0) for both comparisons, but due to differences in number of patients in both periods (II/III vs IV), the baseline values may be slightly different. 18 Week results are for all enrolled patients with a baseline and at least one non-missing post-baseline value; 30 Week results are for the enrolled patients with a baseline and at least one non-missing post-baseline value in Period IV. Last observation carried forward.
    End point type
    Secondary
    End point timeframe
    Week 0 (Baseline), 18 Weeks, 30 Weeks
    End point values
    		 Duloxetine Duloxetine
    Number of subjects analysed
    72 [12]
    45 [13]
    Units: units on a scale
    arithmetic mean (standard deviation)
        18 Week Baseline
    4.5 ( 0.58 )
    0 ( 0 )
        18 Week Change from Baseline
    -2.11 ( 1.17 )
    0 ( 0 )
        30 Week Baseline
    0 ( 0 )
    4.5 ( 0.59 )
        30 Week Change from Baseline
    0 ( 0 )
    -2.7 ( 1.07 )
    Notes
    [12] - All enrolled patients with a baseline and at least 1 non-missing post-baseline value at 18 Weeks.
    [13] - All enrolled patients with a baseline and at least 1 non-missing post-baseline value at 30 Weeks.
    No statistical analyses for this end point

    Secondary: Change from Baseline to 18 Weeks and 30 Weeks in Children's Depression Rating Scale-Revised (CDRS-R) Total Score

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    End point title
    		 Change from Baseline to 18 Weeks and 30 Weeks in Children's Depression Rating Scale-Revised (CDRS-R) Total Score
    End point description
    Measures presence and severity of depression. Consists of 17 items scored on a 1-5 or 1-7 scale. A rating of 1 indicates normal, thus the minimum score is 17. The maximum score is 113. In general, scores below 20 indicate an absence of depression; scores of 20 or 30 indicate borderline depression; scores of 40 to 60 indicate moderate depression. Baseline is the same timepoint (Week 0) for both comparisons, but due to differences in number of patients in both periods (II/III vs IV), the baseline values may be slightly different. 18 Week results are for all enrolled patients with a baseline and at least one non-missing post-baseline value; 30 Week results are for the enrolled patients with a baseline and at least one non-missing post-baseline value in Period IV. Last observation carried forward.
    End point type
    Secondary
    End point timeframe
    Week 0 (Baseline), 18 Weeks, 30 Weeks
    End point values
    		 Duloxetine Duloxetine
    Number of subjects analysed
    72 [14]
    45 [15]
    Units: units on a scale
    arithmetic mean (standard deviation)
        18 Week Baseline
    61.69 ( 8.98 )
    0 ( 0 )
        18 Week Change from Baseline
    -32.11 ( 12.92 )
    0 ( 0 )
        30 Week Baseline
    0 ( 0 )
    61.8 ( 9.28 )
        30 Week Change from Baseline
    0 ( 0 )
    -38.8 ( 11.14 )
    Notes
    [14] - All enrolled patients with a baseline and at least one post-baseline value at 18 Weeks.
    [15] - All enrolled patients with a baseline and at least one post-baseline value at 30 Weeks.
    No statistical analyses for this end point

    Other pre-specified: Adverse Events Leading to Discontinuation

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    End point title
    		 Adverse Events Leading to Discontinuation
    End point description
    A listing of adverse events leading to discontinuation from the study. Abbreviation in data table: ADHD = Attention-Deficit/Hyperactivity Disorder.
    End point type
    Other pre-specified
    End point timeframe
    Week 0 (Baseline) to 30 Weeks
    End point values
    		 Duloxetine Duloxetine
    Number of subjects analysed
    72
    48
    Units: participants
    number (not applicable)
        Nausea
    1
    0
        Worsening of ADHD
    1
    0
        Rash
    1
    0
        Irritability
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    F1J-MC-HMFN
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Duloxetine-SPII-III
    Reporting group description
    		 -

    Reporting group title
    Duloxetine-SPIV
    Reporting group description
    		 -

    Serious adverse events
    		 Duloxetine-SPII-III Duloxetine-SPIV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oppositional defiant disorder
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    self injurious behaviour
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    suicidal ideation
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    gastroenteritis viral
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Duloxetine-SPII-III Duloxetine-SPIV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 72 (79.17%)
    21 / 48 (43.75%)
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 48 (4.17%)
         occurrences all number
    5
    2
    irritability
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 48 (2.08%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    menstruation delayed
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    ovarian cyst
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    asthma exercise induced
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    cough
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    pharyngolaryngeal pain
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    respiratory tract congestion
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    rhinorrhoea
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 48 (2.08%)
         occurrences all number
    5
    1
    Psychiatric disorders
    aggression
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    anxiety
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    bruxism
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    insomnia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    libido increased
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    oppositional defiant disorder
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    restlessness
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 48 (2.08%)
         occurrences all number
    2
    1
    suicidal ideation
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Investigations
    white blood cell count decreased
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    excoriation
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 48 (2.08%)
         occurrences all number
    2
    1
    skin laceration
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    Cardiac disorders
    palpitations
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    7 / 72 (9.72%)
    0 / 48 (0.00%)
         occurrences all number
    7
    0
    headache
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    10 / 72 (13.89%)
    0 / 48 (0.00%)
         occurrences all number
    13
    0
    migraine
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    sedation
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    7 / 72 (9.72%)
    1 / 48 (2.08%)
         occurrences all number
    7
    1
    somnolence
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    7 / 72 (9.72%)
    2 / 48 (4.17%)
         occurrences all number
    8
    2
    tremor
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Eye disorders
    myopia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    abdominal pain upper
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    6 / 72 (8.33%)
    0 / 48 (0.00%)
         occurrences all number
    8
    0
    constipation
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    diarrhoea
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    dry mouth
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    flatulence
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    nausea
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    18 / 72 (25.00%)
    1 / 48 (2.08%)
         occurrences all number
    20
    1
    vomiting
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    10 / 72 (13.89%)
    1 / 48 (2.08%)
         occurrences all number
    13
    1
    Skin and subcutaneous tissue disorders
    hyperhidrosis
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Infections and infestations
    ear infection
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    gastroenteritis viral
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    influenza
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 72 (4.17%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    9 / 72 (12.50%)
    0 / 48 (0.00%)
         occurrences all number
    9
    0
    pharyngitis streptococcal
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    sinusitis
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 48 (2.08%)
         occurrences all number
    2
    1
    upper respiratory tract infection
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 48 (2.08%)
         occurrences all number
    4
    1
    obesity
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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