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    Clinical Trial Results:
    A Randomized, Double-blind Comparison of Atomoxetine Hydrochloride and Placebo for Symptoms of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents With Autism Spectrum Disorder

    Summary
    EudraCT number
    		 2006-000304-16
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Oct 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2021
    First version publication date
    22 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B4Z-UT-S017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00380692
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 10483
    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
    01 Oct 2006
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine whether atomoxetine is effective in reducing ADHD (Attention Deficit/Hyperactivity Disorder) symptoms in children and adolescents with ASD (Autism Spectrum 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
    01 Oct 2006
    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
    Netherlands: 97
    Worldwide total number of subjects
    97
    EEA total number of subjects
    97
    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)
    97
    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
    		 -

    Pre-assignment
    Screening details
    		 Not Applicable

    Period 1
    Period 1 title
    Study Period II - Double Blind
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atomoxetine
    Arm description
    		 atomoxetine: 0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atomoxetine
    Investigational medicinal product code
    Other name
    LY139603; Strattera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.

    Arm title
    		 Placebo
    Arm description
    		 placebo: daily (QD), by mouth (PO) for 8 weeks. Then patients can take atomoxetine 0.5-1.2 mg/kg/day QD, PO up to 20 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    placebo: daily (QD), by mouth (PO) for 8 weeks.

    Number of subjects in period 1
    		Atomoxetine Placebo
    Started
    48
    49
    Completed
    43
    46
    Not completed
    5
    3
         Parent/Caregiver Decision
    1
    -
         Physician decision
    -
    1
         Adverse event, non-fatal
    1
    -
         Lack of efficacy
    1
    -
         Protocol deviation
    2
    2
    Period 2
    Period 2 title
    Study Period III - Open Label
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atomoxetine
    Arm description
    		 atomoxetine: 0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atomoxetine
    Investigational medicinal product code
    Other name
    LY139603; Strattera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.

    Arm title
    		 Placebo
    Arm description
    		 placebo: daily (QD), by mouth (PO) for 8 weeks. Then patients can take atomoxetine 0.5-1.2 mg/kg/day QD, PO up to 20 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    placebo: daily (QD), by mouth (PO) for 8 weeks.

    Number of subjects in period 2 [1]
    		Atomoxetine Placebo
    Started
    42
    46
    Completed
    36
    34
    Not completed
    6
    12
         Parent/Caregiver Decision
    1
    1
         Consent withdrawn by subject
    -
    1
         Physician decision
    -
    3
         Adverse event, non-fatal
    5
    3
         Lack of efficacy
    -
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One patient who completed Study Period II did not enter Study Period III.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atomoxetine
    Reporting group description
    		 atomoxetine: 0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 placebo: daily (QD), by mouth (PO) for 8 weeks. Then patients can take atomoxetine 0.5-1.2 mg/kg/day QD, PO up to 20 weeks.

    Reporting group values
    		 Atomoxetine Placebo Total
    Number of subjects
    		 48 49 97
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.9 ( 2.72 ) 10.0 ( 2.90 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 8 14
        Male
    		 42 41 83
    Race/Ethnicity
    Units: Subjects
        Caucasian
    		 48 47 95
        African
    		 0 1 1
        Hispanic
    		 0 1 1
    Region of Enrollment
    Units: Subjects
        Netherlands
    		 48 49 97

    End points

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    End points reporting groups
    Reporting group title
    Atomoxetine
    Reporting group description
    		 atomoxetine: 0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 placebo: daily (QD), by mouth (PO) for 8 weeks. Then patients can take atomoxetine 0.5-1.2 mg/kg/day QD, PO up to 20 weeks.
    Reporting group title
    Atomoxetine
    Reporting group description
    		 atomoxetine: 0.5 mg/kg/day daily (QD), by mouth (PO) for 1 week, atomoxetine 0.8mg/kg/day QD, PO for 1 week, 1.2mg/kg/day QD, PO for 6 weeks then atomoxetine 0.5-1.2 mg/kg/day QD, PO for up to 20 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 placebo: daily (QD), by mouth (PO) for 8 weeks. Then patients can take atomoxetine 0.5-1.2 mg/kg/day QD, PO up to 20 weeks.

    Primary: ADHD Rating Scale-IV-Parent Version: Investigator Scored - Total Score

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    End point title
    		 ADHD Rating Scale-IV-Parent Version: Investigator Scored - Total Score
    End point description
    Measures the 18 symptoms contained in the Diagnostic and Statistical Manual of Mental Disorders, Version IV (DSM-IV) diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total scores range from 0 to 54.
    End point type
    Primary
    End point timeframe
    Baseline and 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48 [1]
    49 [2]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline Total Score
    40.7 ( 7.47 )
    38.6 ( 8.43 )
        8 Week Endpoint Total Score
    32.3 ( 10.97 )
    37.3 ( 9.57 )
    Notes
    [1] - Baseline Total Score= 48 participants 8 Week Endpoint Total Score= 43 participants
    [2] - Baseline Total Score = 49 Participants 8 Week Endpoint Total Score = 47 Participants
    Statistical analysis title
    		 ADHD Rating Scale-IV-Parent Version
    Comparison groups
    Placebo v Atomoxetine
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 -3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [3] - P-value for treatment group differences over time.

    Secondary: Clinical Global Impressions-ADHD-Improvement (CGI-ADHD - I)

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    End point title
    		 Clinical Global Impressions-ADHD-Improvement (CGI-ADHD - I)
    End point description
    Measures total improvement (or worsening) of a patient's ADHD symptoms from the beginning of treatment (1=very much improved, 7=very much worsened).
    End point type
    Secondary
    End point timeframe
    8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    43
    46
    Units: units on a scale
    geometric mean (standard deviation)
        8 Week Improvement Score
    3.5 ( 1.08 )
    3.9 ( 0.96 )
        28 Week Improvement Score
    2.5 ( 1.14 )
    2.7 ( 1.05 )
    No statistical analyses for this end point

    Secondary: Conners' Teacher Rating Scale - Revised: Short Form (CTRS-R:S)

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    End point title
    		 Conners' Teacher Rating Scale - Revised: Short Form (CTRS-R:S)
    End point description
    A 28-item rating scale (0 [not at all/never] to 3 [very much true/very often]) completed by the teacher to assess problem behaviors related to ADHD. Subscale total scores range from 0 to 15 for Oppositional and Cognitive Problems, 0 to 21 for Hyperactivity, and 0 to 36 for ADHD Index.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    42
    44
    Units: units on a scale
    geometric mean (standard deviation)
        Oppositional: Baseline (n=42, n=44)
    4.1 ( 3.54 )
    3.6 ( 3.53 )
        Oppositional: 8 Week (n=36, n=36)
    3.8 ( 4.43 )
    3.4 ( 3.35 )
        Oppositional: 28 Week (n=26, n= 25)
    2.3 ( 3.33 )
    1.4 ( 1.98 )
        Hyperactivity: Baseline (n=42, n=44)
    8.8 ( 5.50 )
    8.2 ( 5.06 )
        Hyperactivity: 8 Week (n=36, n=36)
    7.6 ( 5.54 )
    8.3 ( 5.63 )
        Hyperactivity: 28 Week (n=26, n=25)
    6.0 ( 4.90 )
    5.2 ( 4.13 )
        Cognitive/Attention: Baseline (n=40, n=44)
    6.8 ( 4.45 )
    4.8 ( 3.68 )
        Cognitive/Attention: 8 Week (n=34, n=36)
    6.1 ( 4.56 )
    4.6 ( 3.53 )
        Cognitive/Attention: 28 Week (n=26, n=25)
    4.7 ( 3.58 )
    4.6 ( 3.85 )
        ADHD: Baseline (n=42, n=44)
    18.5 ( 9.27 )
    18.1 ( 7.49 )
        ADHD: 8 Week (n=36, n=36)
    15.8 ( 9.85 )
    17.2 ( 8.69 )
        ADHD: 28 Week (n=26, n=25)
    13.5 ( 8.61 )
    12.5 ( 5.95 )
    No statistical analyses for this end point

    Secondary: ADHD Rating Scale-IV-Parent Version: Investigator Scored Total Score

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    End point title
    		 ADHD Rating Scale-IV-Parent Version: Investigator Scored Total Score
    End point description
    Measures the 18 symptoms contained in the DSM-IV diagnosis of Attention-Deficit/Hyperactivity Disorder. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often). Total scores range from 0 to 54.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    38
    35
    Units: Units on a Scale
        geometric mean (standard deviation)
    23.6 ( 11.81 )
    25.9 ( 10.58 )
    No statistical analyses for this end point

    Secondary: Sleep Measure Scale

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    End point title
    		 Sleep Measure Scale
    End point description
    10-item parent-based scale assessing sleep problems (6 point Likert scale). Scores: Difficulty falling asleep (1-6); Quality of sleep (3-18); Functional outcome (6-36). Lower scores indicate higher problems with item. Open-ended items: Time to fall asleep (1 [0-15 minutes] to 5 [>1 hour]); Total hours (numbers associated with hours of sleep).
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: Units on a Scale
    geometric mean (standard deviation)
        Time to Fall Asleep: Baseline (n=48, n=49)
    2.9 ( 1.49 )
    2.8 ( 1.41 )
        Time to Fall Asleep: 8 Week (n=43, n=46)
    2.6 ( 1.43 )
    3.0 ( 1.34 )
        Time to Fall Asleep: 28 Week (n=35, n=35)
    3.1 ( 1.49 )
    2.6 ( 1.14 )
        Difficulty Falling Asleep: Baseline (n=48, n=49)
    3.4 ( 1.91 )
    3.3 ( 1.58 )
        Difficulty Falling Asleep: 8 Week (n=43, n=46)
    3.6 ( 1.80 )
    3.3 ( 1.64 )
        Difficulty Falling Asleep: 28 Week (n=38, n=36)
    3.2 ( 1.76 )
    3.7 ( 1.69 )
        Total Hours of Sleep: Baseline (n=48, n=49)
    9.1 ( 1.38 )
    9.3 ( 1.46 )
        Total Hours of Sleep: 8 Weeks (n=42, n=46)
    8.9 ( 1.49 )
    9.1 ( 1.51 )
        Total Hours of Sleep: 28 Week (n=36, n=34)
    8.9 ( 1.61 )
    9.2 ( 1.12 )
        Quality of Sleep: Baseline (n=48, n=49)
    14.1 ( 2.85 )
    14.4 ( 2.84 )
        Quality of Sleep: 8 Week (n=43, n=46)
    14.2 ( 3.08 )
    14.9 ( 2.86 )
        Quality of Sleep: 28 Week (n=38, n=36)
    14.6 ( 2.88 )
    15.0 ( 2.35 )
        Functional Outcome During Day:Baseline (n=48,n=49)
    29.6 ( 4.69 )
    30.0 ( 4.07 )
        Functional Outcome During Day:8 Week (n=43,n=46)
    29.1 ( 5.09 )
    30.0 ( 4.80 )
        Functional Outcome During Day:28Week (n=38,n=36)
    27.8 ( 6.38 )
    29.6 ( 4.76 )
    No statistical analyses for this end point

    Secondary: Aberrant Behavior Checklist (ABC)

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    End point title
    		 Aberrant Behavior Checklist (ABC)
    End point description
    The ABC is a 58-item informant-based scale comprised of five subscales (Irritability [15 items], Lethargy [16], Stereotypic Behaviors [7], Hyperactivity [16], Inappropriate Speech [4]). Individual item scores range from 0 (no problem) to 3 (severe problem). Subscale scores are total of individual item scores in subscale: Irritability (0-45); Lethargy (0-48); Stereotypic (0-21); Hyperactivity (0-48); Inappropriate Speech (0-12).
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: units on a scale
    geometric mean (standard deviation)
        Irritiability: Baseline (n=47, n=49)
    2.9 ( 1.49 )
    2.8 ( 1.41 )
        Irritiability: 8 Week (n=43, n=46)
    2.6 ( 1.43 )
    3.0 ( 1.34 )
        Irritiability: 28 Week (n=38, n=36)
    3.1 ( 1.49 )
    2.6 ( 1.14 )
        Lethargy: Baseline (n=47, n=49)
    3.4 ( 1.91 )
    3.3 ( 1.58 )
        Lethargy: 8 Week (n=43, n=46)
    3.6 ( 1.80 )
    3.3 ( 1.64 )
        Lethargy: 28 Week (n=38 , n=36)
    3.2 ( 1.76 )
    3.7 ( 1.69 )
        Stereotypic: Baseline (n=47, n=49)
    9.1 ( 1.38 )
    9.3 ( 1.46 )
        Stereotypic: 8 Week (n=43, n=46)
    8.9 ( 1.49 )
    9.1 ( 1.51 )
        Stereotypic: 28 Week (n=38, n=36)
    8.9 ( 1.61 )
    9.2 ( 1.12 )
        Hyperactivity: Baseline (n=47, n=49)
    14.1 ( 2.85 )
    14.4 ( 2.84 )
        Hyperactivity: 8 Week (n=43, n=45)
    14.2 ( 3.08 )
    14.9 ( 2.86 )
        Hyperactivity: 28 Week (n=38, n=36)
    14.6 ( 2.88 )
    15.0 ( 2.35 )
        Inappropriate Speech: Baseline (n=47, n=49)
    29.6 ( 4.69 )
    30.0 ( 4.07 )
        Inappropriate Speech: 8 Week (n=43, n=46)
    29.1 ( 5.09 )
    30.0 ( 4.80 )
        Inappropriate Speech: 28 Week (n=38, n=36)
    27.8 ( 6.38 )
    29.6 ( 4.76 )
    No statistical analyses for this end point

    Secondary: Children's Social Behavior Questionnaire (CSBQ) Total Score

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    End point title
    		 Children's Social Behavior Questionnaire (CSBQ) Total Score
    End point description
    CSBQ is filled out by parents and consists of 49 items. Items are rated in an ordinal rather than a discrete fashion in order to establish the extent to which problems are present. The CSBQ consists of six subscales. Individual item scores range from 0=does not apply to 2=applies clearly. Total score ranges from 0 to 98.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: units on a scale
    geometric mean (standard deviation)
        Baseline (n=48, n=49)
    53.6 ( 14.81 )
    52.4 ( 15.97 )
        8 Week (n=43, n=46)
    46.1 ( 15.88 )
    50.2 ( 14.62 )
        28 Week (n=38, n=35)
    40.4 ( 19.55 )
    43.6 ( 17.26 )
    No statistical analyses for this end point

    Secondary: General Health Questionnaire (GHQ) Total Score

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    End point title
    		 General Health Questionnaire (GHQ) Total Score
    End point description
    Parental distress is measured with the GHQ. The raw total score (based on 0-0-1-1 scoring system) can be used as an overall index of psychological distress, ranging from 0 to 12 with higher scores indicating more distress. APD: Randomized participants with value at timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=48, n=49)
    2.9 ( 3.45 )
    4.0 ( 3.79 )
        8 Week (n=43, n=46)
    2.3 ( 3.35 )
    3.1 ( 3.31 )
        28 Week (n=38, n=36)
    1.7 ( 2.61 )
    2.3 ( 2.70 )
    No statistical analyses for this end point

    Secondary: Nijmeegse Ouderlijke Stress Index (NOSI) Total Score

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    End point title
    		 Nijmeegse Ouderlijke Stress Index (NOSI) Total Score
    End point description
    The NOSI contains 123 items to be completed by the primary caregiver. Individual item scores range from 1 (completely agree) to 6 (completely disagree). Total scores range from 123 to 738.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks, 28 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: units on a scale
    geometric mean (standard deviation)
        Baseline (n=42, n=44)
    368.6 ( 79.22 )
    379.5 ( 78.74 )
        8 Week (n=38, n=39)
    350.0 ( 75.07 )
    368.8 ( 81.83 )
        28 Week (n=35, n=34)
    325.2 ( 85.76 )
    328.4 ( 89.23 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Error Rates

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Error Rates
    End point description
    Focused attention assessed distractibility. Child needs to identify a specific target (eg, Cherry); non-target is any other fruit. Child presses "yes" when target occurs in relevant position (eg, one of vertical positions on diamond). Child presses "no" when target is absent, or when target appears on horizontal position (irrelevant target). Error rates are percentage of missing relevant targets and percentage of false alarms in response to (irr)relevant (non)targets based on number of errors/total number of trials X 100. APD: Number of participants with baseline and a non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 Weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: error rate (percentage)
    arithmetic mean (standard deviation)
        Irrelevant Targets Baseline (n=35, n=44)
    12.3 ( 13.95 )
    11.8 ( 16.06 )
        Irrelevant Targets 8 Week (n=35, n=44)
    10.0 ( 16.09 )
    13.3 ( 14.36 )
        Relevant Nontargets Baseline (n=35, n=44)
    5.7 ( 8.15 )
    2.9 ( 5.97 )
        Relevant Nontargets 8 Week (n=35, n=44)
    5.1 ( 9.48 )
    3.3 ( 7.04 )
        Relevant Targets Baseline (n=35, n=44)
    4.8 ( 5.49 )
    6.9 ( 9.04 )
        Relevant Targets 8 Week (n=35, n=44)
    7.3 ( 9.42 )
    7.2 ( 14.47 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Reaction Times for Hits and Correct Rejections

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Reaction Times for Hits and Correct Rejections
    End point description
    Task is the same as described in Outcome Measure #10. Reaction times (RT) for hits are mean RTs of correct responses to relevant targets. RTs for correct rejections are mean RTs for correct rejections are mean RTs for correct no responses to irrelevant targets and relevant nontargets. APD: Number of participants with baseline and a non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 Weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: milliseconds
    arithmetic mean (standard deviation)
        Irrelevant Target Baseline (n=34, n=42)
    1260.1 ( 413.09 )
    1217.3 ( 533.92 )
        Irrelevant Target 8 Week (n=32, n=43)
    1167.8 ( 493.57 )
    1206.0 ( 547.64 )
        Relevant Nontarget Baseline (n=34, n=43)
    1208.4 ( 509.62 )
    1220.9 ( 550.25 )
        Relevant Nontarget 8 Week (n=33, n=43)
    1165.4 ( 570.35 )
    1168.9 ( 569.16 )
        Mean Reaction Time Hits Baseline (n=34, n=42)
    1045.6 ( 411.14 )
    1084.4 ( 518.50 )
        Mean Reaction Time Hits 8 Week (n=33, n=43)
    1013.0 ( 505.52 )
    1017.7 ( 475.82 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Standard Deviation of Reaction Times for Hits and Correct Rejections

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Focused Attention Task - Standard Deviation of Reaction Times for Hits and Correct Rejections
    End point description
    Task is the same as described in Outcome Measure #10. Standard deviations of reaction times (RT) assess intraindividual variability in RT and refer to the same conditions as those for mean reaction times described in Outcome Measure #11.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 Weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: milliseconds
    arithmetic mean (standard deviation)
        Irrelevant Target Baseline (n=33, n=39)
    421.0 ( 263.84 )
    429.4 ( 382.61 )
        Irrelevant Target 8 Week (n=29, n=41)
    341.0 ( 259.84 )
    431.7 ( 363.62 )
        Relevant Nontarget Baseline (n=33, n=40)
    442.2 ( 374.99 )
    565.6 ( 455.54 )
        Relevant Nontarget 8 Week (n=30, n=41)
    442.6 ( 413.74 )
    455.6 ( 376.87 )
        Standard Deviation Hits Baseline (n=33, n=39)
    434.3 ( 302.61 )
    497.9 ( 365.48 )
        Standard Deviation Hits 8 Week (n=30, n=41)
    381.5 ( 286.96 )
    393.9 ( 299.08 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Error Rates

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Error Rates
    End point description
    The memory search task aims at measuring serial search processes to be carried out in working memory. There are 2 blocks (loads) with 40 trials each. Load 1 has 1 target to identify (e.g., an animal). A "yes" is required whenever the target is part of the displayed set of four stimuli (all animals). Load 2 has 2 targets. Whenever 1 of the targets appears in the successively displayed sets of four animals, a "yes" is required. Targets are present in 50% of trials. Error rates are the percentages of errors made in each task condition, based on the number of errors/total number of trials X 100. APD: Number of participants with baseline and a non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 Weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: error rate (percentage)
    arithmetic mean (standard deviation)
        Absent Targets Load 2 Baseline (n=33, n=35)
    2.0 ( 3.52 )
    4.4 ( 9.61 )
        Absent Targets Load 2 8 Week (n=34, n=35)
    4.0 ( 6.83 )
    4.3 ( 6.20 )
        Absent Targets Load 1 Baseline (n=34, n=35)
    5.9 ( 14.06 )
    5.1 ( 5.49 )
        Absent Targets Load 1 8 Week (n=34, n=35)
    5.3 ( 6.96 )
    7.6 ( 13.25 )
        Present Targets Load 1 Baseline (n=34, n=35)
    6.5 ( 9.66 )
    6.6 ( 6.84 )
        Present Targets Load 1 8 Week (34, n=35)
    7.6 ( 9.07 )
    7.9 ( 10.93 )
        Present Targets Load 2 Baseline (n=33, n=35)
    9.5 ( 9.38 )
    9.7 ( 10.07 )
        Present Targets Load 2 8 Week (n=34, n=35)
    8.7 ( 10.10 )
    10.1 ( 9.51 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Reaction Times for Hits and Correct Rejections

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Memory Search Task - Reaction Times for Hits and Correct Rejections
    End point description
    Memory search task aims at measuring serial search processes to be carried out in working memory. There are 2 blocks (loads) with 40 trials each. Load 1 has 1 target to remember (one animal). A "yes" is required whenever the target is part of displayed set of 4 animals. Load 2 has 2 animals. A "yes" is required whenever one of the animals appears in successively displayed sets of 4 animals. Targets are present in 50% of the trials. Reaction time (RT) for hits is mean RT of correct "yes" responses to targets. RT correct rejections are mean RTs of correct "no" responses when target was missing. APD: Number of participants with baseline and a non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 Weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: milliseconds
    arithmetic mean (standard deviation)
        Load 1 Baseline (n=33, n=35)
    1051.9 ( 338.41 )
    1010.4 ( 382.92 )
        Load 1 8 Week (n=34, n=34)
    1014.8 ( 394.58 )
    928.7 ( 301.04 )
        Load 2 Baseline (n=32, n=34)
    1411.0 ( 357.50 )
    1387.2 ( 595.37 )
        Load 2 8 Week (n=34, n=34)
    1130.4 ( 460.66 )
    1294.2 ( 552.25 )
        Reaction Time Hits Load 1 Baseline (n=33, n=35)
    932.7 ( 295.14 )
    881.7 ( 304.42 )
        Reaction Time Hits Load 1 8 Week (n=34, n=34)
    882.4 ( 327.30 )
    786.8 ( 257.19 )
        Reaction Time Hits Load 2 Baseline (n=32, n=34)
    1131.5 ( 293.84 )
    1111.8 ( 442.97 )
        Reaction Time Hits Load 2 8 Week (n=34, n=34)
    1060.0 ( 343.53 )
    1110.8 ( 445.61 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Pursuit Motor Control Task - Accuracy

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Pursuit Motor Control Task - Accuracy
    End point description
    A complex visuo-motor flexibility task that aims at measuring eye-hand co-ordination and fine motor control. By moving mouse cursor, the child is required to follow as closely as possible a target that randomly moves across the PC-screen. Accuracy is the mean distance between the mouse cursor and the moving target. APD: Number of participants with baseline and non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: millimeters
    arithmetic mean (standard deviation)
        Baseline (n=30,n=33)
    7.8 ( 5.62 )
    8.1 ( 5.49 )
        8 Week (n=31,n=33)
    8.2 ( 6.88 )
    10.1 ( 11.92 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Pursuit Motor Control Task - Stability of Movement

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Pursuit Motor Control Task - Stability of Movement
    End point description
    A complex visuo-motor flexibility task that measures eye-hand co-ordination and fine motor control. By moving mouse cursor, the child is required to follow as closely as possible a target that randomly moves across the PC-screen. Stability is within subject variability of mean distance between cursor and target. APD: Number of participants with baseline and non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    31
    33
    Units: millimeters
    arithmetic mean (standard deviation)
        Baseline (n=30,n=33)
    7.6 ( 8.24 )
    8.2 ( 7.90 )
        8 Week (n=31,n=33)
    8.2 ( 8.61 )
    9.4 ( 9.24 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Go/No-Go Response Inhibition Task - Error Rates

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Go/No-Go Response Inhibition Task - Error Rates
    End point description
    Measures inhibition of pre-potent responses. 24 Go signals (open squares) are presented, randomly mixed with 24 No-Go signals (closed squares). Subjects are required to press a key if a Go signal (target) appears on the screen but to withhold a response if they see a No-Go signal. Error rate is the percentage of key presses to No-Go signals/total number of trials X 100. APD: Number of participants with baseline and a non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    37
    45
    Units: error rate (percentage)
    arithmetic mean (standard deviation)
        Absent Target Baseline
    8.0 ( 16.30 )
    6.8 ( 8.49 )
        Absent Target 8 Week
    4.5 ( 4.75 )
    9.0 ( 15.07 )
        Present Target Baseline
    2.0 ( 5.25 )
    2.9 ( 6.14 )
        Present Target 8 Week
    3.7 ( 10.01 )
    1.9 ( 5.15 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Flanker Interference Task - Error Rates

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Flanker Interference Task - Error Rates
    End point description
    Measures ability to neglect stimuli interfering with predefined stimulus-response coupling. Child presented with displays of 9 colored squares. Child responds to color of central square by pressing left mouse key when blue, and right mouse key when yellow. Part 1 (40 trials), surrounding squares may be same color (compatible) or different (neutral). Part 2 (80 trials), in 50% of trials, surrounding squares have color corresponding to predefined key press for other hand (incompatible). Error rates are percentages of errors in response to compatible and incompatible signals, respectively. APD: Number of participants with baseline and one non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    33
    35
    Units: error rate (percentages)
    arithmetic mean (standard deviation)
        Compatible Signals Baseline (n=32, n=35)
    7.7 ( 9.80 )
    8.5 ( 10.06 )
        Compatible Signals 8 Week (n=33, n=35)
    -2.1 ( 8.92 )
    -1.8 ( 11.43 )
        Incompatible Signals Baseline (n=32, n=35)
    8.4 ( 10.33 )
    9.1 ( 6.62 )
        Incompatible Signals 8 Week (n=32, n=35)
    -0.4 ( 11.11 )
    0.1 ( 8.19 )
    No statistical analyses for this end point

    Secondary: Amsterdam Neuropsychological Tasks (ANT): Flanker Interference Task - Reaction Times

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    End point title
    		 Amsterdam Neuropsychological Tasks (ANT): Flanker Interference Task - Reaction Times
    End point description
    Task is the same as described in Outcome Measure #19. Mean reaction times (RTs) are computed for correct responses to compatible and incompatible flankers, respectively. APD: Number of participants with baseline and non-missing postbaseline value at visit.
    End point type
    Secondary
    End point timeframe
    Baseline, 8 weeks
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    33
    35
    Units: milliseconds
    arithmetic mean (standard deviation)
        Compatible Flankers Part 2 Baseline (n=31,n=34)
    863.1 ( 234.70 )
    925.4 ( 384.55 )
        Compatible Flankers Part 2 8 Week (n=33,n=35)
    901.1 ( 350.27 )
    897.7 ( 376.63 )
        Incompatible Flankers Part 2 Baseline (n=31,n=35)
    959.4 ( 295.32 )
    976.5 ( 412.76 )
        Incompatible Flankers Part 2 8 Week (n=33,n=35)
    931.9 ( 347.99 )
    946.2 ( 419.63 )
    No statistical analyses for this end point

    Secondary: Cytochrome P450 2D6 Genotype

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    End point title
    		 Cytochrome P450 2D6 Genotype
    End point description
    Genotype characterization was used to determine participants' metabolic status. APD: All randomized participants.
    End point type
    Secondary
    End point timeframe
    baseline
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    48
    49
    Units: participants
    number (not applicable)
        Extensive Metabolizer
    28
    28
        Intermediate Metabolizer
    13
    15
        Poor Metabolizer
    6
    6
        Missing
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Core Study
    Adverse event reporting additional description
    B4Z-UT-S017(b)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Atomoxetine
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Atomoxetine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Atomoxetine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 49 (65.31%)
    39 / 48 (81.25%)
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    1
    3
    headache
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    9 / 49 (18.37%)
    12 / 48 (25.00%)
         occurrences all number
    13
    17
    psychomotor hyperactivity
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 48 (2.08%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 49 (8.16%)
    11 / 48 (22.92%)
         occurrences all number
    4
    12
    pyrexia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 48 (8.33%)
         occurrences all number
    4
    5
    abdominal pain upper
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 49 (6.12%)
    9 / 48 (18.75%)
         occurrences all number
    3
    9
    diarrhoea
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    nausea
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    4 / 49 (8.16%)
    14 / 48 (29.17%)
         occurrences all number
    5
    15
    vomiting
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    5 / 49 (10.20%)
    7 / 48 (14.58%)
         occurrences all number
    6
    10
    Psychiatric disorders
    aggression
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 48 (4.17%)
         occurrences all number
    3
    2
    early morning awakening
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 49 (0.00%)
    5 / 48 (10.42%)
         occurrences all number
    0
    5
    initial insomnia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 48 (6.25%)
         occurrences all number
    5
    3
    Musculoskeletal and connective tissue disorders
    myalgia
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Infections and infestations
    influenza
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 11.0
         subjects affected / exposed
    3 / 49 (6.12%)
    13 / 48 (27.08%)
         occurrences all number
    3
    13

    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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