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    Clinical Trial Results:
    A phase 3, randomised, double-blind, multicentre, parallel-group, placebo- and active-reference, dose-optimisation efficacy and safety study of extended-release Guanfacine Hydrochloride in children and adolescents aged 6-17 years with Attention-Deficit/Hyperactivity Disorder

    Summary
    EudraCT number
    2010-018579-12
    Trial protocol
    GB   DE   NL   FR   ES   SE   IE   AT   BG   IT  
    Global end of trial date
    01 May 2013

    Results information
    Results version number
    v1
    This version publication date
    28 Aug 2018
    First version publication date
    01 May 2015
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD503-316
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01244490
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Pharmaceutical Development Ltd.
    Sponsor organisation address
    Hampshire International Business Park, Chineham, Basingstoke, Hampshire, United Kingdom, RG24 8EP
    Public contact
    Shire Development LLC, Study Physician, +1 866 842 5335 ,
    Scientific contact
    Shire Development LLC, Study Physician, +1 866 842 5335 ,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000745-PIP01-09
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 May 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of once daily dosing with optimised SPD503 compared to placebo in the treatment of children and adolescents aged 6-17 years with a diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD) as measured by the ADHD Rating Scale-IV (ADHD-RS-IV).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements. The subject’s informed consent and assent (as applicable) were mandatory for taking part in the study. It was obtained in writing prior to the performance of any study-specific procedures.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jan 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Spain: 51
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 68
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Ukraine: 54
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    United States: 57
    Worldwide total number of subjects
    338
    EEA total number of subjects
    208
    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)
    204
    Adolescents (12-17 years)
    134
    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
    Subjects were recruited to participate at 1 of 58 sites, including 11 sites in the United States (US), 2 sites in Canada, and 45 sites in Europe (Austria, France, Germany, Ireland, Italy, Poland, Romania, Spain, Sweden, Ukraine, and United Kingdom).

    Pre-assignment
    Screening details
    This study consisted of a screening/washout period that lasted for 35 days. Following successful screening, the subject discontinued any current psychoactive medication (if any) for the Washout Period. The washout for all prohibited medications was at least a minimum of 5 times the half-life of the medication.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Capsules were overencapsulated to protect the blind between the active product and the placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects randomized to placebo received SPD503 placebo and STRATTERA placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    SPD503 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were to take 1 matching placebo tablet once daily if optimized to a dose of 1-4mg SPD503 or 2 matching placebo tablets once daily if optimized to a dose of 5-7mg SPD503.

    Investigational medicinal product name
    Strattera Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects optimized to a dose requiring a daily dose higher than 60mg of STRATTERA took 2 matching placebo capsules once daily. Subjects at all other optimized doses (</= 60mg/day) took 1 matching placebo capsule once daily.

    Arm title
    Guanfacine Hydrochloride
    Arm description
    Subjects randomized to guanfacine hydrochloride received active SPD503 and STRATTERA placebo.
    Arm type
    Experimental

    Investigational medicinal product name
    Guanfacine Hydrochloride
    Investigational medicinal product code
    Other name
    SPD503, Intuniv
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A combination of 1, 2, 3, and 4mg tablets for a total dosage of 1mg to 7mg based on age and weight. Subjects were to take either 1 SPD503 tablet once daily if optimized to a dose of 1-4mg or 2 SPD503 tablets once daily if optimized to a dose of 5-7mg.

    Investigational medicinal product name
    Strattera Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects optimized to a dose requiring a daily dose higher than 60mg of STRATTERA took 2 matching placebo capsules once daily. Subjects at all other optimized doses (</= 60mg/day) took 1 matching placebo capsule once daily.

    Arm title
    Atomoxetine Hydrochloride
    Arm description
    Subjects randomized to atomoxetine hydrochloride received active STRATTERA and SPD503 placebo.
    Arm type
    Active comparator

    Investigational medicinal product name
    Atomoxetine Hydrochloride
    Investigational medicinal product code
    Other name
    Strattera
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A combination of 10, 18, 25, 40, or 60mg capsules, once daily, at the optimised dose (10mg to 100mg based on weight). The maximum dose was 4mg/day for children aged 6-12 years and 4-7mg/day for adolescents aged 13-17 years, depending on the subject’s weight. Subjects optimized to a dose requiring a daily dose higher than 60mg took 2 STRATTERA capsules. Subjects at all other optimized doses (</= 60mg/day) took 1 STRATTERA capsule.

    Investigational medicinal product name
    SPD503 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were to take 1 matching placebo tablet once daily if optimized to a dose of 1-4mg SPD503 or 2 matching placebo tablets once daily if optimized to a dose of 5-7mg SPD503.

    Number of subjects in period 1
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Started
    111
    115
    112
    Completed
    92
    91
    89
    Not completed
    19
    24
    23
         Adverse event
    1
    9
    5
         Lack of efficacy
    14
    5
    5
         Withdrawal by subject
    4
    4
    9
         Not specified
    -
    -
    1
         Lost to follow-up
    -
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to placebo received SPD503 placebo and STRATTERA placebo.

    Reporting group title
    Guanfacine Hydrochloride
    Reporting group description
    Subjects randomized to guanfacine hydrochloride received active SPD503 and STRATTERA placebo.

    Reporting group title
    Atomoxetine Hydrochloride
    Reporting group description
    Subjects randomized to atomoxetine hydrochloride received active STRATTERA and SPD503 placebo.

    Reporting group values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride Total
    Number of subjects
    111 115 112 338
    Age categorical
    Units: Subjects
        6-12 years
    79 81 82 242
        13-17 years
    32 34 30 96
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11 ± 2.76 10.9 ± 2.78 10.5 ± 2.81 -
    Gender categorical
    Units: Subjects
        Female
    25 38 25 88
        Male
    86 77 87 250
    Region of enrollment
    Units: Subjects
        Austria
    2 4 5 11
        Canada
    6 7 6 19
        France
    2 2 2 6
        Germany
    23 23 22 68
        Ireland
    0 1 1 2
        Italy
    5 4 4 13
        Poland
    11 14 12 37
        Romania
    5 3 6 14
        Spain
    16 18 17 51
        Sweden
    1 1 2 4
        Ukraine
    21 18 15 54
        United Kingdom
    1 0 1 2
        United States
    18 20 19 57

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to placebo received SPD503 placebo and STRATTERA placebo.

    Reporting group title
    Guanfacine Hydrochloride
    Reporting group description
    Subjects randomized to guanfacine hydrochloride received active SPD503 and STRATTERA placebo.

    Reporting group title
    Atomoxetine Hydrochloride
    Reporting group description
    Subjects randomized to atomoxetine hydrochloride received active STRATTERA and SPD503 placebo.

    Primary: Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 10/13 - Last Observation Carried Forward (LOCF)

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    End point title
    Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 10/13 - Last Observation Carried Forward (LOCF)
    End point description
    The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 20% of the items used for summing a score were missing, the score was set to missing.
    End point type
    Primary
    End point timeframe
    Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    111
    112
    112
    Units: units on a scale
        least squares mean (standard error)
    -15 ± 1.1612
    -23.9 ± 1.1531
    -18.8 ± 1.1549
    Statistical analysis title
    Analysis of ADHD-RS-IV total score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -8.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.9
         upper limit
    -5.8
    Statistical analysis title
    Analysis of ADHD-RS-IV total score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    -0.7

    Secondary: Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Score

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    End point title
    Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Score
    End point description
    Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. Not all subjects in the FAS population had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    111
    112
    112
    Units: percent of subjects
        number (not applicable)
    44.1
    67.9
    56.3
    Statistical analysis title
    Analysis of CGI-I score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in percentage improvement
    Point estimate
    23.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.1
         upper limit
    36.4
    Statistical analysis title
    Analysis of CGI-I score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.024
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in percentage improvement
    Point estimate
    12.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    25.1

    Secondary: Change From Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Learning and School Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Learning and School Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Learning in School Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    100
    103
    100
    Units: units on a scale
        least squares mean (standard error)
    -0.419 ± 0.0537
    -0.636 ± 0.0527
    -0.581 ± 0.0534
    Statistical analysis title
    Analysis of WFIRS-P learning domain score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.217
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.358
         upper limit
    -0.076
    Statistical analysis title
    Analysis of WFIRS-P learning domain score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.026
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.162
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.305
         upper limit
    -0.019

    Secondary: Change From Baseline in the WFIRS-P Family Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Family Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Family Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    106
    109
    105
    Units: units on a scale
        least squares mean (standard error)
    -0.409 ± 0.0568
    -0.617 ± 0.0558
    -0.499 ± 0.0566
    Statistical analysis title
    Analysis of WFIRS-P family domain score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.209
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.358
         upper limit
    -0.059
    Statistical analysis title
    Analysis of WFIRS-P family domain score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.242
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.241
         upper limit
    -0.061

    Secondary: Clinical Global Impression-Severity of Illness (CGI-S) - LOCF

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    End point title
    Clinical Global Impression-Severity of Illness (CGI-S) - LOCF
    End point description
    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. Not all subjects in the FAS population had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    111
    112
    112
    Units: percent of subjects
    number (not applicable)
        1 (Normal, not at all ill)
    9.9
    14.3
    6.3
        2 (Borderline mentally ill)
    15.3
    23.2
    19.6
        3 (Mildly ill)
    20.7
    31.3
    32.1
        4 (Moderately ill)
    20.7
    22.3
    19.6
        5 (Markedly ill)
    25.2
    5.4
    13.4
        6 (Severely ill)
    6.3
    3.6
    7.1
        7 (Among the most extremely ill)
    1.8
    0
    1.8
    Statistical analysis title
    Analysis of CGI-S
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of CGI-S #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.196 [2]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Nominal p-value uncorrected for multiplicity.

    Secondary: Health Utilities Index-2/3 (HUI 2/3) Scores - LOCF

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    End point title
    Health Utilities Index-2/3 (HUI 2/3) Scores - LOCF
    End point description
    HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. Not all subjects in the FAS population had data for this outcome.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    106
    110
    106
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.927 ± 0.095
    0.922 ± 0.0908
    0.913 ± 0.1052
    No statistical analyses for this end point

    Secondary: Change From Baseline in the WFIRS-P Global Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Global Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Global Score is the mean of 50 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Baseline and Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    104
    110
    104
    Units: units on a scale
        least squares mean (standard error)
    -0.321 ± 0.0387
    -0.487 ± 0.0374
    -0.425 ± 0.0384
    Statistical analysis title
    Analysis of WFIRS-P global score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [3]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.165
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.266
         upper limit
    -0.064
    Notes
    [3] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P global score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.048 [4]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.104
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.207
         upper limit
    -0.001
    Notes
    [4] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Academic Performance Domain is the mean of 4 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    96
    103
    101
    Units: units on a scale
        least squares mean (standard error)
    -0.555 ± 0.0784
    -0.766 ± 0.0757
    -0.681 ± 0.0759
    Statistical analysis title
    Analysis of WFIRS-P academic performance score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.043 [5]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.211
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.416
         upper limit
    -0.007
    Notes
    [5] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P academic performance score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.231 [6]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.125
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.331
         upper limit
    0.08
    Notes
    [6] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Behavior in School Domain is the mean of 6 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    100
    103
    100
    Units: units on a scale
        least squares mean (standard error)
    -0.363 ± 0.0512
    -0.592 ± 0.0502
    -0.544 ± 0.0509
    Statistical analysis title
    Analysis of WFIRS-P school behavior score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [7]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.229
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.364
         upper limit
    -0.094
    Notes
    [7] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P school behavior score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009 [8]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.181
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.317
         upper limit
    -0.045
    Notes
    [8] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Life Skills Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    105
    110
    104
    Units: units on a scale
        least squares mean (standard error)
    -0.383 ± 0.0422
    -0.477 ± 0.0411
    -0.45 ± 0.0422
    Statistical analysis title
    Analysis of WFIRS-P life skills domain score
    Comparison groups
    Guanfacine Hydrochloride v Placebo
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.096 [9]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.094
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.204
         upper limit
    0.017
    Notes
    [9] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P life skills domain score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.242 [10]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.18
         upper limit
    0.046
    Notes
    [10] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Child Self-Concept Domain is the mean of 3 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    101
    108
    103
    Units: units on a scale
        least squares mean (standard error)
    -0.312 ± 0.0544
    -0.361 ± 0.0528
    -0.39 ± 0.0536
    Statistical analysis title
    Analysis of WFIRS-P self-concept domain score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5 [11]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.049
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.191
         upper limit
    0.094
    Notes
    [11] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P self-concept domain score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.288 [12]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.078
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.222
         upper limit
    0.066
    Notes
    [12] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in the WFIRS-P Social Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Social Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Social Domain is the mean of 7 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    104
    110
    104
    Units: units on a scale
        least squares mean (standard error)
    -0.322 ± 0.0537
    -0.555 ± 0.0519
    -0.434 ± 0.0532
    Statistical analysis title
    Analysis of WFIRS-P social domain score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [13]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.233
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.374
         upper limit
    -0.092
    Notes
    [13] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P social domain score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.124 [14]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.253
         upper limit
    0.031
    Notes
    [14] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in the WFIRS-P Risk Domain Score at Week 10/13 - LOCF

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    End point title
    Change From Baseline in the WFIRS-P Risk Domain Score at Week 10/13 - LOCF
    End point description
    The WFIRS-P Risk Domain is the mean of 10 items, ranging from 0 (never/not at all) to 3 (very often/very much). Higher scores indicate greater functional impairment. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized subjects who took at least 1 dose of investigational product. If more than 30% of items used to derive the score were missing, the corresponding score was considered as missing.
    End point type
    Secondary
    End point timeframe
    Up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    99
    105
    97
    Units: units on a scale
        least squares mean (standard error)
    -0.134 ± 0.0284
    -0.19 ± 0.0275
    -0.173 ± 0.0285
    Statistical analysis title
    Analysis of WFIRS-P risk domain score
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.139 [15]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.131
         upper limit
    0.018
    Notes
    [15] - Nominal p-value uncorrected for multiplicity.
    Statistical analysis title
    Analysis of WFIRS-P risk domain score #2
    Comparison groups
    Placebo v Atomoxetine Hydrochloride
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.315 [16]
    Method
    ANCOVA
    Parameter type
    Difference in least squares mean
    Point estimate
    -0.039
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.115
         upper limit
    0.037
    Notes
    [16] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Weeks 10/13 - LOCF

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    End point title
    Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Weeks 10/13 - LOCF
    End point description
    The BPRS-C characterizes childhood behavioral and emotional symptomatology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology. Outcome measure is at 10 weeks for ages 6-12 years and at 13 weeks for ages 13-17 years. This endpoint analyzed the Safety Population, defined as of randomized subjects who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 10 weeks for children aged 6-12 years and up to 13 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    102
    101
    99
    Units: units on a scale
        arithmetic mean (standard deviation)
    -5.6 ± 8.82
    -8.3 ± 8.4
    -6.5 ± 9.23
    No statistical analyses for this end point

    Secondary: Structure Side-Effect Questionnaire

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    End point title
    Structure Side-Effect Questionnaire
    End point description
    The Structured Side-effect Questionnaire is a simple checklist of 17 side effects. The subject indicates whether a side effect has occurred since the last visit by marking 'yes' on the checklist for each of the events listed. Outcome measure is at 12 weeks for ages 6-12 years and at 15 weeks for ages 13-17 years. This endpoint analyzed the Safety Population, defined as of randomized subjects who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks for children aged 6-12 years and up to 15 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    111
    112
    112
    Units: participants
        Nausea
    19
    30
    39
        Vomiting
    11
    7
    25
        Diarrhea
    15
    18
    8
        Abdominal Pain
    26
    45
    42
        Decreased Appetite
    25
    31
    48
        Increased Appetite
    30
    40
    25
        Headache
    35
    52
    34
        Dizziness
    16
    28
    23
        Fatigue
    30
    55
    35
        Nervousness/Anxiety
    25
    37
    34
        Insomnia
    19
    32
    24
        Somnolence
    26
    57
    38
        Depression
    7
    7
    9
        Itching
    7
    13
    10
        Rash
    4
    9
    8
        Missed Menses
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-SSRS is a semi-structured interview that captures the occurence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale. Outcome measure is at 12 weeks for ages 6-12 years and at 15 weeks for ages 13-17 years. This endpoint analyzed the Safety Population, defined as of randomized subjects who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks for children aged 6-12 years and up to 15 weeks for adolescents aged 13-17 years
    End point values
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Number of subjects analysed
    111
    112
    112
    Units: participants
        Suicidal Ideation
    2
    3
    5
        Suicidal Behaviour
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    13 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to placebo received SPD503 placebo and STRATTERA placebo.

    Reporting group title
    Guanfacine Hydrochloride
    Reporting group description
    Subjects randomized to guanfacine hydrochloride received active SPD503 and STRATTERA placebo.

    Reporting group title
    Atomoxetine Hydrochloride
    Reporting group description
    Subjects randomized to atomoxetine hydrochloride received active STRATTERA and SPD503 placebo.

    Serious adverse events
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Guanfacine Hydrochloride Atomoxetine Hydrochloride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 111 (55.86%)
    79 / 114 (69.30%)
    67 / 112 (59.82%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 111 (8.11%)
    14 / 114 (12.28%)
    17 / 112 (15.18%)
         occurrences all number
    9
    18
    24
    Headache
         subjects affected / exposed
    27 / 111 (24.32%)
    30 / 114 (26.32%)
    22 / 112 (19.64%)
         occurrences all number
    46
    51
    36
    Somnolence
         subjects affected / exposed
    16 / 111 (14.41%)
    50 / 114 (43.86%)
    20 / 112 (17.86%)
         occurrences all number
    18
    94
    32
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 111 (18.02%)
    29 / 114 (25.44%)
    24 / 112 (21.43%)
         occurrences all number
    22
    45
    32
    Pyrexia
         subjects affected / exposed
    4 / 111 (3.60%)
    7 / 114 (6.14%)
    3 / 112 (2.68%)
         occurrences all number
    4
    9
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 111 (7.21%)
    9 / 114 (7.89%)
    7 / 112 (6.25%)
         occurrences all number
    15
    16
    18
    Insomnia
         subjects affected / exposed
    7 / 111 (6.31%)
    13 / 114 (11.40%)
    8 / 112 (7.14%)
         occurrences all number
    7
    21
    10
    Nervousness
         subjects affected / exposed
    6 / 111 (5.41%)
    6 / 114 (5.26%)
    6 / 112 (5.36%)
         occurrences all number
    7
    7
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 111 (18.02%)
    19 / 114 (16.67%)
    19 / 112 (16.96%)
         occurrences all number
    32
    29
    31
    Abdominal pain upper
         subjects affected / exposed
    6 / 111 (5.41%)
    7 / 114 (6.14%)
    2 / 112 (1.79%)
         occurrences all number
    6
    7
    3
    Diarrhoea
         subjects affected / exposed
    15 / 111 (13.51%)
    10 / 114 (8.77%)
    2 / 112 (1.79%)
         occurrences all number
    18
    16
    3
    Nausea
         subjects affected / exposed
    11 / 111 (9.91%)
    18 / 114 (15.79%)
    30 / 112 (26.79%)
         occurrences all number
    13
    19
    54
    Vomiting
         subjects affected / exposed
    8 / 111 (7.21%)
    6 / 114 (5.26%)
    18 / 112 (16.07%)
         occurrences all number
    9
    8
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 111 (10.81%)
    15 / 114 (13.16%)
    31 / 112 (27.68%)
         occurrences all number
    23
    20
    44
    Increased appetite
         subjects affected / exposed
    9 / 111 (8.11%)
    12 / 114 (10.53%)
    4 / 112 (3.57%)
         occurrences all number
    11
    15
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 111 (5.41%)
    6 / 114 (5.26%)
    3 / 112 (2.68%)
         occurrences all number
    7
    7
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2011
    The following changes to study inclusion criteria and procedures were made based on communications with country-specific Ethics Committees: *Following responses from the Ethics Committees in Spain, Germany, and The Netherlands, an Exclusion Criterion (#2) was added: “Subject is well-controlled on their current ADHD medication, with acceptable tolerability and the parent/caregiver does not object to the current medication.” *Following a request from the French Ethics Committee, all CYP2D6 inhibitors were prohibited from use during the study, without exception and Exclusion Criterion (#10) that details use of prohibited medications was modified to include CYP2D6 inhibitors. In addition, the washout schedule for CYP2D6 inhibitors was modified such that all CYP2D6 inhibitors were required to have a 30-day washout period prior to the Baseline Visit (Visit 2/Week 0). Additional text was inserted as a prompt that these medications may have signaled the presence of an exclusionary diagnosis (Exclusion Criterion #10). Other changes included: *Neutrophil band analysis was removed. *Screening for methylphenidate was removed from drug and alcohol screen. * Appendix 2.5 presenting stature-for-age percentiles was inserted.
    15 Feb 2012
    In the context of the challenges with recruitment and enrollment in the study, the statistical power of the study was decreased to 80% and the numbers of subjects required was decreased accordingly. Approximately 333 subjects (111 per treatment arm) was changed to approximately 252 subjects (84 per treatment arm). The number of subjects assessed for the primary efficacy was decreased according to the decreased power of the study. Approximately 210 subjects (105 subjects in each of the SPD503 and placebo groups) was changed to approximately 158 subjects (79 subjects in each of the SPD503 and placebo groups).
    24 Jul 2012
    The approximate number of subjects to be randomized was increased back to the original target number (ie, 333). The increase was in response to a higher than anticipated recruitment rate. Approximately 252 subjects (84 per treatment arm) was changed to approximately 333 subjects (111 per treatment arm). The numbers of subject assessed for primary efficacy was increased as enrollment rates had improved and the statistical power of the study was increased from 80% (as per Amendment 3) to the original 90%.

    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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