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    Clinical Trial Results:
    A Randomized, Double-Blind, Crossover Comparison of Atomoxetine and Placebo in Child Outpatients With Attention-Deficit/Hyperactivity Disorder, Reading Disorder, or Comorbid Attention-Deficit/Hyperactivity Disorder and Reading Disorder.

    Summary
    EudraCT number
    		 2006-001866-18
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Dec 2007

    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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B4Z-MC-LYCK
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00191906
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 7955
    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 Apr 2005
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the hypothesis that a 4 week treatment with atomoxetine is more effective than placebo in patients with combined type Attention Deficit/Hyperactivity Disorder (ADHD), patients with only Reading Disorder, and patients with combined type ADHD and Reading 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 Apr 2005
    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
    Belgium: 49
    Country: Number of subjects enrolled
    Netherlands: 72
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    121
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Period I: screening/washout (89 patients screened, 13 screen-failures;45 controls screened). Period II (Visits 2-5): patients received treatment for 4 weeks and then underwent 2-week washout period after which they crossed over to receive the alternate treatment for 4 additional weeks. Period III (Visits 6-12): optional open-label (1 country only).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atomoxetine First, Then Placebo
    Arm description
    		 Atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks, 2 week washout period and then cross-over to placebo, every day, by mouth for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atomoxetine Hydrochloride
    Investigational medicinal product code
    LY139603
    Other name
    Strattera
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atomoxetine, 1.2 mg/kg/day, by mouth (PO).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, every day (QD), by mouth (PO).

    Arm title
    		 Placebo First, Then Atomoxetine
    Arm description
    		 Placebo every day, by mouth for 4 weeks, 2 week washout period and then cross-over to atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, every day (QD), by mouth (PO).

    Investigational medicinal product name
    Atomoxetine Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atomoxetine, 1.2 mg/kg/day, by mouth (PO).

    Arm title
    		 Normal Control
    Arm description
    		 Untreated normal controls were children selected from the general population. The normal control was matched (have same proportion) by sex (male/female) and by age (have same age range) as the study population.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Reading Disordered Control
    Arm description
    		 Untreated reading disordered control group was comprised of children with reading disorder who received standard remedial teaching therapy.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Atomoxetine First, Then Placebo Placebo First, Then Atomoxetine Normal Control Reading Disordered Control
    Started
    39
    37
    27
    18
    Completed
    39
    32
    26
    18
    Not completed
    0
    5
    1
    0
         Parent/Caregiver Decision
    -
    1
    -
    -
         Consent withdrawn by subject
    -
    3
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
         Entry Criteria Exclusion
    -
    -
    1
    -
    Period 2
    Period 2 title
    Study Period III
    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 First, Then Placebo
    Arm description
    		 Atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks, 2 week washout period and then cross-over to placebo, every day, by mouth for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, every day (QD), by mouth (PO).

    Investigational medicinal product name
    Atomoxetine Hydrochloride
    Investigational medicinal product code
    LY139603
    Other name
    Strattera
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atomoxetine, 1.2 mg/kg/day, by mouth (PO).

    Arm title
    		 Placebo First, Then Atomoxetine
    Arm description
    		 Placebo every day, by mouth for 4 weeks, 2 week washout period and then cross-over to atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Atomoxetine Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atomoxetine, 1.2 mg/kg/day, by mouth (PO).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, every day (QD), by mouth (PO).

    Number of subjects in period 2 [1]
    		Atomoxetine First, Then Placebo Placebo First, Then Atomoxetine
    Started
    14
    11
    Completed
    9
    7
    Not completed
    5
    4
         Parent/Caregiver Decision
    1
    -
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    -
    1
         Lack of efficacy
    3
    3
    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: These are patients who continued in optional open-label period (1 country). All received atomoxetine.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atomoxetine First, Then Placebo
    Reporting group description
    		 Atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks, 2 week washout period and then cross-over to placebo, every day, by mouth for 4 weeks.

    Reporting group title
    Placebo First, Then Atomoxetine
    Reporting group description
    		 Placebo every day, by mouth for 4 weeks, 2 week washout period and then cross-over to atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks.

    Reporting group title
    Normal Control
    Reporting group description
    		 Untreated normal controls were children selected from the general population. The normal control was matched (have same proportion) by sex (male/female) and by age (have same age range) as the study population.

    Reporting group title
    Reading Disordered Control
    Reporting group description
    		 Untreated reading disordered control group was comprised of children with reading disorder who received standard remedial teaching therapy.

    Reporting group values
    		 Atomoxetine First, Then Placebo Placebo First, Then Atomoxetine Normal Control Reading Disordered Control Total
    Number of subjects
    		 39 37 27 18 121
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.0 ( 1.34 ) 9.9 ( 1.25 ) 9.9 ( 1.01 ) 10.6 ( 0.99 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 10 10 5 38
        Male
    		 26 27 17 13 83
    Region of Enrollment
    Units: Subjects
        Belgium
    		 18 15 0 16 49
        Netherlands
    		 21 22 27 2 72

    End points

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    End points reporting groups
    Reporting group title
    Atomoxetine First, Then Placebo
    Reporting group description
    		 Atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks, 2 week washout period and then cross-over to placebo, every day, by mouth for 4 weeks.

    Reporting group title
    Placebo First, Then Atomoxetine
    Reporting group description
    		 Placebo every day, by mouth for 4 weeks, 2 week washout period and then cross-over to atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks.

    Reporting group title
    Normal Control
    Reporting group description
    		 Untreated normal controls were children selected from the general population. The normal control was matched (have same proportion) by sex (male/female) and by age (have same age range) as the study population.

    Reporting group title
    Reading Disordered Control
    Reporting group description
    		 Untreated reading disordered control group was comprised of children with reading disorder who received standard remedial teaching therapy.
    Reporting group title
    Atomoxetine First, Then Placebo
    Reporting group description
    		 Atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks, 2 week washout period and then cross-over to placebo, every day, by mouth for 4 weeks.

    Reporting group title
    Placebo First, Then Atomoxetine
    Reporting group description
    		 Placebo every day, by mouth for 4 weeks, 2 week washout period and then cross-over to atomoxetine 1.2 mg/kg/day, by mouth for 4 weeks.

    Subject analysis set title
    Atomoxetine
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Atomoxetine, 1.2 mg/kg/day, by mouth for 4 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Placebo, daily, by mouth for 4 weeks.

    Subject analysis set title
    ADHD-Combined Type (ADHD-C)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    atomoxetine-treated Attention-Deficit/Hyperactivity Disorder-Combined Type

    Subject analysis set title
    Reading Disorder
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    atomoxetine-treated Reading Disorder.

    Subject analysis set title
    Reading Disordered Control
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Untreated reading disordered control group was comprised of children with reading disorder who received standard remedial teaching therapy.

    Subject analysis set title
    ADHD-C+RD
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    atomoxetine-treated Comorbid Attention-Deficit/Hyperactivity Disorder-Combined Type + Reading Disorder.

    Primary: Stop Signal Reaction Time (SSRT) as Derived From the Stop Signal Reaction Time Paradigm

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    End point title
    		 Stop Signal Reaction Time (SSRT) as Derived From the Stop Signal Reaction Time Paradigm
    End point description
    SSRT measures response execution (go trials) and response inhibition (stop trials). Go trials consist of stimulus (airplane). Child to press response button corresponding to direction airplane is pointing. Stop trials consist of go trial and audible stop signal. Initial delay between go trial and stop signal = 250 msec. If child succeeded in inhibiting response, delay on next stop trial increased by 50 msec, otherwise, delay decreased by 50 msec. SSRT = subtract mean delay from mean go signal reaction time. Lower scores mean better ability to suppress response when presented with stop signal. Analysis population description (APD): All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    71
    76
    Units: milliseconds (msec)
    least squares mean (standard error)
        ADHD-Combined Type
    299.90 ( 13.29 )
    308.82 ( 14.53 )
        Reading Disorder
    265.61 ( 14.24 )
    260.51 ( 16.02 )
        ADHD-C + Reading Disorder
    277.38 ( 13.80 )
    292.53 ( 15.46 )
        Overall
    280.97 ( 7.96 )
    287.29 ( 8.84 )
    Statistical analysis title
    		 SSRT
    Statistical analysis description
    Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period. Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.504 [1]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [1] - P-value for Overall. No adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Change From Baseline in Mean Stop Signal Reaction Time Comparison of ADHD-C to Normal Control Group in >=10 Year Old Subset

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    End point title
    		 Change From Baseline in Mean Stop Signal Reaction Time Comparison of ADHD-C to Normal Control Group in >=10 Year Old Subset [2]
    End point description
    SSRT measures response execution (go trials) and response inhibition (stop trials). Go trials consist of stimulus (airplane). Child to press response button corresponding to direction airplane is pointing. Stop trials consist of go trial and audible stop signal. Initial delay between go trial and stop signal = 250 msec. If child succeeded in inhibiting response, delay on next stop trial increased by 50 msec, otherwise, delay decreased by 50 msec. SSRT = subtract mean delay from mean go signal reaction time. Lower scores mean better ability to suppress response when presented with stop signal. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks of therapy
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No inferential statistics were planned or conducted for all baseline period arms.
    End point values
    		 Normal Control ADHD-Combined Type (ADHD-C)
    Number of subjects analysed
    8
    5
    Units: milliseconds
        arithmetic mean (standard deviation)
    11.22 ( 62.77 )
    7.95 ( 48.21 )
    Statistical analysis title
    		 Mean Stop Signal Reaction Time
    Statistical analysis description
    ANCOVA model with baseline value, study arm as covariates for ADHD-C versus Normal controls.
    Comparison groups
    Normal Control v ADHD-Combined Type (ADHD-C)
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Change From Baseline in Mean Stop Signal Reaction Time Comparison of ADHD-C+RD and RD to Reading Disordered Control Group in >=10 Year Old Subset

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    End point title
    		 Change From Baseline in Mean Stop Signal Reaction Time Comparison of ADHD-C+RD and RD to Reading Disordered Control Group in >=10 Year Old Subset
    End point description
    SSRT measures response execution (go trials) and response inhibition (stop trials). Go trials consist of stimulus (airplane). Child to press response button corresponding to direction airplane is pointing. Stop trials consist of go trial and audible stop signal. Initial delay between go trial and stop signal = 250 msec. If child succeeded in inhibiting response, delay on next stop trial increased by 50 msec, otherwise, delay decreased by 50 msec. SSRT = subtract mean delay from mean go signal reaction time. Lower scores mean better ability to suppress response when presented with stop signal. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks of therapy
    End point values
    		 Reading Disorder Reading Disordered Control ADHD-C+RD
    Number of subjects analysed
    13
    14
    16
    Units: milliseconds
        arithmetic mean (standard deviation)
    -34.0 ( 33.91 )
    0.05 ( 24.08 )
    -0.25 ( 53.41 )
    Statistical analysis title
    		 Mean Stop Signal Reaction Time Comparison 1
    Comparison groups
    ADHD-C+RD v Reading Disordered Control
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.579 [5]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [4] - ANCOVA model with baseline value, study arm as covariates for ADHD-C+RD versus RD controls.
    [5] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.
    Statistical analysis title
    		 Mean Stop Signal Reaction Time Comparison 2
    Comparison groups
    Reading Disordered Control v Reading Disorder
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.144 [7]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [6] - ANCOVA model with baseline value, study arm as covariates for RD versus RD controls.
    [7] - There were no adjustments for multiple comparisons - not applicable. All statistical tests are performed using a 0.05 significance level.

    Secondary: Lexical Decision Task Mean Reaction Time: Correct Words

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    End point title
    		 Lexical Decision Task Mean Reaction Time: Correct Words
    End point description
    Measure of reaction time to identify whether a word displayed on a computer is a real or correct word versus a pseudo word. During the performance of the lexical decision task that was presented on a computer, the reaction times and accuracy of responses were measured. Data presented are the mean reaction times over the 4 weeks of each therapy for identifying correct words correctly. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    68
    73
    Units: milliseconds
    least squares mean (standard error)
        ADHD-Combined Type
    1182.9 ( 50.23 )
    1291.9 ( 38.13 )
        Reading Disorder
    1172.4 ( 51.75 )
    1198.6 ( 40.24 )
        ADHD-C + Reading Disorder
    1201.9 ( 51.22 )
    1305.9 ( 39.43 )
        Overall
    1185.7 ( 29.49 )
    1265.5 ( 22.61 )
    Statistical analysis title
    		 Lexical Decision Task Mean Reaction Time
    Statistical analysis description
    Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment by study-arm-interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.005 [9]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [8] - Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period.
    [9] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Lexical Decision Task Mean Reaction Time: Pseudo Words

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    End point title
    		 Lexical Decision Task Mean Reaction Time: Pseudo Words
    End point description
    Measure of reaction time to identify whether a word displayed on a computer is a pseudo word versus a real or correct word. During the performance of the lexical decision task that was presented on a computer, the reaction times and accuracy of responses were measured. Data presented are the mean reaction times over the 4 weeks of each therapy for identifying pseudo words correctly. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    68
    73
    Units: milliseconds
    least squares mean (standard error)
        ADHD-Combined Type
    1403.0 ( 63.72 )
    1475.4 ( 50.08 )
        Reading Disorder
    1365.0 ( 65.62 )
    1412.2 ( 52.90 )
        ADHD-C + Reading Disorder
    1426.1 ( 64.83 )
    1487.0 ( 51.73 )
        Overall
    1398.0 ( 37.33 )
    1458.2 ( 29.63 )
    Statistical analysis title
    		 Lexical Decision Task Mean Reaction Time
    Statistical analysis description
    Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period. Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Placebo v Atomoxetine
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097 [10]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [10] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Working Memory by Corsi Block Tapping Test (CBTT)

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    End point title
    		 Working Memory by Corsi Block Tapping Test (CBTT)
    End point description
    Measures the visuo-spatial working memory span, and corresponds to the longest sequence of blocks that has been reproduced correctly at least once. Scores can range from 3 to 8, with the higher score indicating better function. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    69
    73
    Units: blocks correctly sequenced
    least squares mean (standard error)
        ADHD-Combined Type
    5.29 ( 0.22 )
    4.98 ( 0.21 )
        Reading Disorder
    5.50 ( 0.23 )
    5.14 ( 0.23 )
        ADHD-C + Reading Disorder
    5.92 ( 0.23 )
    5.29 ( 0.23 )
        Overall
    5.57 ( 0.13 )
    5.14 ( 0.13 )
    Statistical analysis title
    		 CBTT
    Statistical analysis description
    Repeated measures model including terms for study arm, treatment sequence, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.003 [12]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [11] - Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period.
    [12] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Total Score

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    End point title
    		 Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and 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 score is the sum of the scores on the 18 items and range from 0 to 54. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    46
    47
    Units: units on a scale
    least squares mean (standard error)
        ADHD-Combined Type
    30.86 ( 2.14 )
    35.20 ( 1.78 )
        ADHD-Combined Type + Reading Disorder
    22.44 ( 2.38 )
    35.17 ( 2.07 )
        Overall
    26.65 ( 1.60 )
    35.18 ( 1.34 )
    Statistical analysis title
    		 Attention-Deficit/Hyperactivity Disorder
    Comparison groups
    Placebo v Atomoxetine
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001 [14]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [13] - Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period. Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    [14] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Inattention Subscale

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    End point title
    		 Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Inattention Subscale
    End point description
    Measures the degree of inattention symptoms based on answers to 9 items. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often), for a total Inattention Subscale score range of 0 to 27. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    46
    47
    Units: units on a scale
    least squares mean (standard error)
        ADHD-Combined Type
    15.27 ( 1.09 )
    17.82 ( 0.93 )
        ADHD-Combined Type + Reading Disorder
    12.25 ( 1.22 )
    18.28 ( 1.09 )
        Overall
    13.76 ( 0.82 )
    18.05 ( 0.70 )
    Statistical analysis title
    		 Attention-Deficit/Hyperactivity Disorder
    Statistical analysis description
    Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period. Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [15]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [15] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Hyperactivity-Impulsivity Subscale

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    End point title
    		 Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Hyperactivity-Impulsivity Subscale
    End point description
    Measures the degree of hyperactivity-impulsivity symptoms, based on answers to 9 items. Individual item scores range from 0 (none/never or rarely) to 3 (severe/very often) for a total Hyperactivity-Impulsivity Subscale score of 0 to 27. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    46
    47
    Units: units on a scale
    least squares mean (standard error)
        ADHD-Combined Type
    15.51 ( 1.14 )
    17.24 ( 0.96 )
        ADHD-Combined Type + Reading Disorder
    10.32 ( 1.27 )
    17.03 ( 1.12 )
        Overall
    12.91 ( 0.85 )
    17.13 ( 0.73 )
    Statistical analysis title
    		 Attention-Deficit/Hyperactivity Disorder
    Statistical analysis description
    Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period. Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [16]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [16] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Total T-Score

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    End point title
    		 Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored - Total T-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 score is computed as the sum of the scores on each of the 18 items. Total score is the sum of the scores on the 18 items and range from 0 to 54. Total T-score = (Total Score - 50)/10. Total T-score ranges from -5 (low severity) to 0.4 (high severity). APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of initial therapy and Week 4 of crossover therapy
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    46
    47
    Units: T-Score of units on a scale
    least squares mean (standard error)
        ADHD-Combined Type
    -1.91 ( 0.21 )
    -1.48 ( 0.18 )
        ADHD-Combined Type + Reading Disorder
    -2.76 ( 0.24 )
    -1.48 ( 0.21 )
        Overall
    -2.34 ( 0.16 )
    -1.48 ( 0.13 )
    Statistical analysis title
    		 Attention-Deficit/Hyperactivity Disorder
    Statistical analysis description
    Least Squares Mean (LSMean) values were calculated from the measurements taken at baseline and at the end of each 4 week therapy period. Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [17]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [17] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Clinical Global Impression-Attention Deficit Hyperactivity Disorder-Improvement Scale

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    End point title
    		 Clinical Global Impression-Attention Deficit Hyperactivity Disorder-Improvement Scale
    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). APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    4 week therapy endpoint
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    47
    52
    Units: units on a scale
    least squares mean (standard error)
        ADHD-Combined Type
    3.69 ( 0.24 )
    3.70 ( 0.23 )
        ADHD-Combined Type + Reading Disorder
    2.98 ( 0.24 )
    3.76 ( 0.24 )
        Overall
    3.34 ( 0.17 )
    3.73 ( 0.16 )
    Statistical analysis title
    		 Clinical Global Impression-Attention
    Statistical analysis description
    Repeated measures model including terms for study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094 [18]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [18] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Clinical Global Impression-Attention Deficit Hyperactivity Disorder-Severity Scale

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    End point title
    		 Clinical Global Impression-Attention Deficit Hyperactivity Disorder-Severity Scale
    End point description
    Measures severity of the patient's overall severity of ADHD symptoms (1=normal, not at all ill; 7=among the most extremely ill patients). APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    4 week therapy endpoint
    End point values
    		 Atomoxetine Placebo
    Number of subjects analysed
    47
    52
    Units: units on a scale
    least squares mean (standard error)
        ADHD-Combined Type
    4.05 ( 0.21 )
    3.73 ( 0.19 )
        ADHD-Combined Type + Reading Disorder
    3.65 ( 0.21 )
    4.34 ( 0.20 )
        Overall
    3.85 ( 0.14 )
    4.04 ( 0.13 )
    Statistical analysis title
    		 Clinical Global Impression-Attention Deficit
    Statistical analysis description
    Repeated measures model including terms for baseline, study arm, treatment sequence, visit, treatment, and treatment-by-study-arm interaction.
    Comparison groups
    Atomoxetine v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.312 [19]
    Method
    		 Repeated Measures
    Confidence interval
    Notes
    [19] - P-value for Overall. There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C to Normal Control Group in >=10 Year Old Subset: Pseudohomophones

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    End point title
    		 Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C to Normal Control Group in >=10 Year Old Subset: Pseudohomophones [20]
    End point description
    Measure of reaction time in determining whether the stimulus sounds like a real word ('yes' response) or not ('no' response) using pseudohomophones and pseudo words. Data presented here are for reaction time to identifying psuedohomophones correctly. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks of therapy
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No inferential statistics were planned or conducted for all baseline period arms.
    End point values
    		 Normal Control ADHD-Combined Type (ADHD-C)
    Number of subjects analysed
    6
    5
    Units: milliseconds
        arithmetic mean (standard deviation)
    -339.17 ( 176.32 )
    -230.40 ( 239.43 )
    Statistical analysis title
    		 Phonological Task Mean Reaction Time
    Statistical analysis description
    ANCOVA model with baseline value, study arm as covariates for ADHD-C versus normal controls.
    Comparison groups
    Normal Control v ADHD-Combined Type (ADHD-C)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.508 [21]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [21] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C to Normal Control Group in >=10 Year Old Subset: Pseudo Words

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    End point title
    		 Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C to Normal Control Group in >=10 Year Old Subset: Pseudo Words [22]
    End point description
    Measure of reaction time in determining whether the stimulus sounds like a real word ('yes' response) or not ('no' response) using pseudo homophones and pseudo words. Data presented here are for reaction time to identifying pseudo words correctly. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks of therapy
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No inferential statistics were planned or conducted for all baseline period arms.
    End point values
    		 Normal Control ADHD-Combined Type (ADHD-C)
    Number of subjects analysed
    6
    5
    Units: milliseconds
        arithmetic mean (standard deviation)
    -536.00 ( 303.27 )
    -523.20 ( 524.36 )
    Statistical analysis title
    		 Phonological Task Mean Reaction Time
    Statistical analysis description
    ANCOVA model with baseline value, study arm as covariate for ADHD-C versus normal controls.
    Comparison groups
    Normal Control v ADHD-Combined Type (ADHD-C)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.769 [23]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [23] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C+RD and RD to Reading Disordered Control Group in >=10 Year Old Subset: Pseudohomophones

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    End point title
    		 Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C+RD and RD to Reading Disordered Control Group in >=10 Year Old Subset: Pseudohomophones
    End point description
    Measure of reaction time in determining whether the stimulus sounds like a real word ('yes' response) or not ('no' response) using pseudo homophones and pseudo words. Data presented here are for reaction time to identifying psuedohomophones correctly. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks of therapy
    End point values
    		 Reading Disorder Reading Disordered Control ADHD-C+RD
    Number of subjects analysed
    13
    14
    16
    Units: milliseconds
        arithmetic mean (standard deviation)
    -241.00 ( 317.47 )
    -254.86 ( 266.46 )
    -170.81 ( 243.33 )
    Statistical analysis title
    		 Phonological Task Mean Reaction Time Comparison 2
    Statistical analysis description
    ANCOVA model with baseline value, study arm as covariate for RD versus RD controls.
    Comparison groups
    Reading Disorder v Reading Disordered Control
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.663 [24]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [24] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.
    Statistical analysis title
    		 Phonological Task Mean Reaction Time Comparison 1
    Statistical analysis description
    ANCOVA model with baseline value, study arm as covariates for ADHD-C+RD versus RD controls.
    Comparison groups
    Reading Disordered Control v ADHD-C+RD
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.302 [25]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [25] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Secondary: Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C+RD and RD to Reading Disordered Control Group in >=10 Year Old Subset: Pseudo Words

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    End point title
    		 Change From Baseline in Phonological Task Mean Reaction Time Comparison of ADHD-C+RD and RD to Reading Disordered Control Group in >=10 Year Old Subset: Pseudo Words
    End point description
    Measure of reaction time in determining whether the stimulus sounds like a real word ('yes' response) or not ('no' response) using pseudo homophones and pseudo words. Data presented here are for reaction time to indentifying pseudo words correctly. APD: All efficacy information is summarized and/or presented in data listings based on the Safety sample: Includes all patients who were randomized to double-blind treatment and received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks of therapy
    End point values
    		 Reading Disorder Reading Disordered Control ADHD-C+RD
    Number of subjects analysed
    13
    14
    16
    Units: milliseconds
        arithmetic mean (standard deviation)
    -213.00 ( 512.33 )
    -368.14 ( 422.42 )
    -113.06 ( 432.68 )
    Statistical analysis title
    		 Phonological Task Mean Reaction Time Comparison 2
    Comparison groups
    Reading Disorder v Reading Disordered Control
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.179 [27]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [26] - ANCOVA model with baseline value, study arm as covariate for RD versus RD controls.
    [27] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.
    Statistical analysis title
    		 Phonological Task Mean Reaction Time Comparison 1
    Statistical analysis description
    ANCOVA model with baseline value, study arm as covariate for ADHD-C+RD versus RD controls.
    Comparison groups
    Reading Disordered Control v ADHD-C+RD
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07 [28]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [28] - There were no adjustments for multiple comparisons - not applicable. All statistical tests were performed using a 0.05 significance level.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    All patients who were randomized to double-blind treatment and received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, daily, by mouth for 4 weeks.

    Reporting group title
    Atomoxetine
    Reporting group description
    		 Atomoxetine, 1.2 mg/kg/day, by mouth for 4 weeks.

    Serious adverse events
    		 Placebo Atomoxetine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 74 (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: 0%
    Non-serious adverse events
    		 Placebo Atomoxetine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 76 (35.53%)
    35 / 74 (47.30%)
    Vascular disorders
    pallor
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    raynaud's phenomenon
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    tooth extraction
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    9 / 74 (12.16%)
         occurrences all number
    1
    9
    feeling abnormal
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    irritability
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 74 (4.05%)
         occurrences all number
    1
    3
    malaise
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    peripheral coldness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    pyrexia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Social circumstances
    job dissatisfaction
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 74 (4.05%)
         occurrences all number
    2
    3
    dyspnoea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    epistaxis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    pharyngolaryngeal pain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    rhinalgia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    rhinorrhoea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Psychiatric disorders
    apathy
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    eating disorder
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    emotional disorder
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    fear
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    initial insomnia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    insomnia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    middle insomnia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    negativism
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    nightmare
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    sleep disorder
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    Investigations
    weight increased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Injury, poisoning and procedural complications
    joint sprain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    upper limb fracture
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    wound
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Nervous system disorders
    disturbance in attention
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    dizziness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    headache
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    10 / 76 (13.16%)
    11 / 74 (14.86%)
         occurrences all number
    10
    11
    poor quality sleep
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    somnolence
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 74 (2.70%)
         occurrences all number
    1
    2
    syncope
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    ear pain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Eye disorders
    eyelid oedema
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    mydriasis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    visual disturbance
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    6 / 74 (8.11%)
         occurrences all number
    2
    6
    abdominal pain upper
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    5 / 74 (6.76%)
         occurrences all number
    2
    5
    diarrhoea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 74 (5.41%)
         occurrences all number
    1
    4
    dysphagia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    nausea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    8 / 74 (10.81%)
         occurrences all number
    1
    8
    tooth disorder
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    vomiting
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    0
    5
    Skin and subcutaneous tissue disorders
    erythema
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    rash erythematous
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    rash pruritic
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    skin discolouration
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    swelling face
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    enuresis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    muscle spasms
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    pain in extremity
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    gastroenteritis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    0
    3
    gastroenteritis viral
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    influenza
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    nasopharyngitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    pharyngitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    tonsillitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    urinary tract infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    anorexia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    decreased appetite
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 76 (2.63%)
    6 / 74 (8.11%)
         occurrences all number
    2
    6
    oral intake reduced
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2004
    - The open-label extension (Study Period III) has been removed; - Secondary objectives were modified; - Inclusion and exclusion criteria's were revised; - The 2.5 mg and 25 mg capsules were removed from the list of study materials as the capsules will not be available in blister packs during the double-blind crossover phase; - The final visit was changed throughout the protocol from Visit 10 to Visit 5, due to the deletion of Study Period III; - The Study Schedule has been modified to remove the open-label extension, revise the end-of-study procedures.
    07 Mar 2005
    - The word “clinical” has been replaced with the word “subclinical” to more accurately describe the norms for the Disruptive Behaviour Disorder Rating Scale (DBD); - Slight clarifications were made to inclusion and exclusion criteria; - Study schedule was revised to reflect the change in visit intervals, the deletion of the thyroid stimulating hormone (TSH) test; - Clarifications made on Disease Diagnostic Criteria
    09 Feb 2006
    - Screening procedure, Inclusion and Exclusion criteria was revised; - criteria for diagnosing Reading Disorder was clarified.

    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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