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    Clinical Trial Results:
    A Phase 3, Double-blind, Randomized, Multi-center, Placebo controlled, Dose-optimization Study Evaluating the Safety, Efficacy, and Tolerability of Once daily Dosing with Extended-release Guanfacine Hydrochloride in Adolescents Aged 13-17 years Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD)

    Summary
    EudraCT number
    		 2011-002221-21
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    16 May 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    25 Nov 2018
    First version publication date
    06 Dec 2014
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update actual start date of recruitment

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD503-312
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01081132
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Blvd., Wayne, United States, 19087
    Public contact
    Study Physician, Shire Development LLC, +1 866-842-5335 ,
    Scientific contact
    Study Physician, Shire Development LLC, +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
    16 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of once daily dosing with optimized SPD503 compared with placebo in the treatment of adolescents aged 13-17 years with a diagnosis of ADHD as measured by the Attention deficit/Hyperactivity Disorder Rating Scale (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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 314
    Worldwide total number of subjects
    314
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    314
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 314
    Number of subjects completed
    		 314

    Period 1
    Period 1 title
    Overall trial (overall period)
    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
    		 Placebo
    Arm description
    		 Orally administered a once-daily dose
    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
    Orally administered a once-daily dose

    Arm title
    		 SPD503
    Arm description
    		 Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Guanfacine Hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).

    Number of subjects in period 1
    		Placebo SPD503
    Started
    157
    157
    Completed
    102
    105
    Not completed
    55
    52
         Patient did not complete wk 14 and 15
    -
    1
         Consent withdrawn by subject
    13
    16
         Missed visits
    1
    1
         Adverse event, non-fatal
    3
    9
         Non-compliance
    4
    3
         Stopped taking meds
    2
    -
         Lost to follow-up
    4
    11
         Declined taper phase
    -
    1
         Lack of efficacy
    25
    9
         Protocol deviation
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Orally administered a once-daily dose

    Reporting group title
    SPD503
    Reporting group description
    		 Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).

    Reporting group values
    		 Placebo SPD503 Total
    Number of subjects
    		 157 157 314
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 157 157 314
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.6 ( 1.44 ) 14.5 ( 1.35 ) -
    Gender categorical
    Units: Subjects
        Female
    		 57 54 111
        Male
    		 100 103 203

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Orally administered a once-daily dose

    Reporting group title
    SPD503
    Reporting group description
    		 Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).

    Primary: Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 13

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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 13
    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. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Primary
    End point timeframe
    Baseline through week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    106
    109
    Units: Units on a scale
        least squares mean (standard error)
    -18.527 ( 1.0841 )
    -24.552 ( 1.0625 )
    Statistical analysis title
    		 Change From Baseline in ADHD-RS-IV Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.865
         upper limit
    		 -3.187

    Secondary: Subjects With an Assessment of Normal/Borderline Mentally Ill on Clinical Global Impression-Severity of Illness (CGI-S) Scale at the Last On-Treatment Assessment

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    End point title
    		 Subjects With an Assessment of Normal/Borderline Mentally Ill on Clinical Global Impression-Severity of Illness (CGI-S) Scale at the Last On-Treatment Assessment
    End point description
    CGI-S assesses the severity of the subject's condition on a 7-point scale: 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely ill). The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline through 13 weeks
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    155
    154
    Units: Subjects
    56
    78
    Statistical analysis title
    		 Clinical Global Impressions - Severity
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

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

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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 Scores at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Learning and School Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    101
    97
    Units: Units on a scale
        least squares mean (standard error)
    -0.457 ( 0.058 )
    -0.572 ( 0.058 )
    Statistical analysis title
    		 WFIRS-P Learning and School Domain
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.104
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.115
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.254
         upper limit
    		 0.024

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

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    End point title
    		 Change From Baseline in the WFIRS-P Family Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Family Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    101
    105
    Units: Units on a scale
        least squares mean (standard error)
    -0.314 ( 0.055 )
    -0.371 ( 0.054 )
    Statistical analysis title
    		 Change From Baseline in the WFIRS-P Family Domain
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.408
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.192
         upper limit
    		 0.078

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

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    End point title
    		 Change From Baseline in the WFIRS-P Behavior in School Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    101
    97
    Units: Units on a scale
        least squares mean (standard error)
    -0.376 ( 0.051 )
    -0.459 ( 0.05 )
    Statistical analysis title
    		 WFIRS-P Behavior in School Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.176
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.203
         upper limit
    		 0.037

    Secondary: Change From Baseline in the WFIRS-P Global Domain Score at Week 13

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    End point title
    		 Change From Baseline in the WFIRS-P Global Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    105
    108
    Units: Units on a scale
        least squares mean (standard error)
    -0.296 ( 0.036 )
    -0.347 ( 0.035 )
    Statistical analysis title
    		 WFIRS-P Global Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.253
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.136
         upper limit
    		 -0.036

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

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    End point title
    		 Change From Baseline in the WFIRS-P Risk Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Risk Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    105
    107
    Units: Units on a scale
        least squares mean (standard error)
    -0.194 ( 0.027 )
    -0.191 ( 0.026 )
    Statistical analysis title
    		 WFIRS-P Risk Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.912
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.068

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

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    End point title
    		 Change From Baseline in the WFIRS-P Social Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Social Domain consists of 7-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    105
    108
    Units: Units on a scale
        least squares mean (standard error)
    -0.234 ( 0.046 )
    -0.263 ( 0.045 )
    Statistical analysis title
    		 WFIRS-P Social Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.606
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.139
         upper limit
    		 0.081

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

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    End point title
    		 Change From Baseline in the WFIRS-P Child Self-Concept Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Child Self-Concept Domain consists of 3-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    104
    106
    Units: Units on a scale
        least squares mean (standard error)
    -0.376 ( 0.067 )
    -0.275 ( 0.066 )
    Statistical analysis title
    		 WFIRS-P Child Self-Concept Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.228
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.102
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.064
         upper limit
    		 0.268

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

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    End point title
    		 Change From Baseline in the WFIRS-P Life Skills Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). The Life Skills Domain consists of 10-items. Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    105
    107
    Units: Units on a scale
        least squares mean (standard error)
    -0.328 ( 0.046 )
    -0.375 ( 0.045 )
    Statistical analysis title
    		 WFIRS-P Life Skills Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.159
         upper limit
    		 0.065

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

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    End point title
    		 Change From Baseline in the WFIRS-P Academic Performance Domain Score at Week 13
    End point description
    The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    104
    96
    Units: Units on a scale
        least squares mean (standard error)
    -0.632 ( 0.096 )
    -0.841 ( 0.096 )
    Statistical analysis title
    		 WFIRS-P Academic Performance Domain Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.082
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.208
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.443
         upper limit
    		 0.026

    Secondary: Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores at the Last On-Treatment Assessment

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    End point title
    		 Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores at the Last On-Treatment Assessment
    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. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    weeks 1 through 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    155
    154
    Units: Subjects
    71
    104
    Statistical analysis title
    		 Clinical Global Impression-Improvement Scores
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Changes From Baseline in Behavior Rating Inventory of Executive Function (BRIEF) Scores at Week 13

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    End point title
    		 Changes From Baseline in Behavior Rating Inventory of Executive Function (BRIEF) Scores at Week 13
    End point description
    Behavior Rating Inventory of Executive Function (BRIEF) is an 86-item questionnaire composed of three indices (Global Executive Composite, Behavioral Regulation Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). Lower scores reflect better functioning. The Full Analysis Set, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    82
    88
    Units: Units on a scale
    least squares mean (standard error)
        Global Executive Composite
    -10.6 ( 1.23 )
    -12.9 ( 1.19 )
        Behavioral Regulation Index
    -11.5 ( 1.29 )
    -12.4 ( 1.25 )
        Metacognition Index
    -8.9 ( 1.18 )
    -11.6 ( 1.14 )
    Statistical analysis title
    		 Global Executive Composite
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.134
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 0.7
    Statistical analysis title
    		 Behavioral Regulation Index
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.579
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 2.3
    Statistical analysis title
    		 Metacognition Index
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.072
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 0.2

    Secondary: Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Total Score at Week 13

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    End point title
    		 Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Total Score at Week 13
    End point description
    The Pediatric Daytime Sleepiness Scale (PDSS) is an 8 item questionnaire scored on a scale from 0 (never) to 4 (always/very often). Total scores range from 0 to 32, with increasing score reflecting greater sleepiness. The Safety Population, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    105
    108
    Units: Units on a scale
        least squares mean (standard error)
    -3.7 ( 0.52 )
    -4.2 ( 0.51 )
    Statistical analysis title
    		 Pediatric Daytime Sleepiness Scale Total Score
    Comparison groups
    Placebo v SPD503
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.465
    Method
    		 Mixed Models Repeated Measures Analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 0.8

    Secondary: Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Last On-Treatment Assessment

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    End point title
    		 Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Last On-Treatment Assessment
    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. The Safety Population, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    151
    151
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -7 ( 9.85 )
    -9.1 ( 8.11 )
    No statistical analyses for this end point

    Secondary: Structure Side-Effect Questionnaire (SSEQ)

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    End point title
    		 Structure Side-Effect Questionnaire (SSEQ)
    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’ or ‘no’ on the checklist for each of the events listed. The Safety Population, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Through week 16
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    155
    157
    Units: Subjects
        Nausea
    33
    37
        Vomiting
    17
    18
        Diarrhea
    24
    29
        Abdominal pain
    28
    30
        Decreased Appetite
    42
    48
        Increased Appetite
    47
    42
        Headache
    53
    76
        Dizziness
    31
    49
        Fatigue
    43
    65
        Nervousness/anxiety
    23
    30
        Insomnia
    25
    28
        Somnolence
    26
    41
        Depression
    17
    14
        Itching
    9
    11
        Rash
    7
    6
        Missed menses
    1
    4
    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. The Safety Population, which consisted of all randomized subjects who took at least 1 dose of investigational product, was used for this end point.
    End point type
    Secondary
    End point timeframe
    Through week 16
    End point values
    		 Placebo SPD503
    Number of subjects analysed
    155
    154
    Units: Subjects
        Suicidal ideation
    4
    5
        Suicidal behavior
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 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
    		 Orally administered a once-daily dose

    Reporting group title
    SPD503
    Reporting group description
    		 Orally administered a once-daily optimal dose between 0.05 mg/kg/day - 0.12 mg/kg/day (up to 7 mg/day depending on weight).

    Serious adverse events
    		 Placebo SPD503
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 155 (1.29%)
    4 / 157 (2.55%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Withdrawal hypertension
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Homicidal ideation
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo SPD503
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 155 (77.42%)
    147 / 157 (93.63%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 155 (10.32%)
    25 / 157 (15.92%)
         occurrences all number
    17
    32
    Dizziness postural
         subjects affected / exposed
    3 / 155 (1.94%)
    8 / 157 (5.10%)
         occurrences all number
    3
    8
    Headache
         subjects affected / exposed
    28 / 155 (18.06%)
    42 / 157 (26.75%)
         occurrences all number
    43
    64
    Sedation
         subjects affected / exposed
    3 / 155 (1.94%)
    18 / 157 (11.46%)
         occurrences all number
    3
    21
    Somnolence
         subjects affected / exposed
    33 / 155 (21.29%)
    69 / 157 (43.95%)
         occurrences all number
    39
    102
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 155 (12.26%)
    35 / 157 (22.29%)
         occurrences all number
    21
    41
    Irritability
         subjects affected / exposed
    6 / 155 (3.87%)
    11 / 157 (7.01%)
         occurrences all number
    6
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 155 (3.87%)
    9 / 157 (5.73%)
         occurrences all number
    7
    10
    Abdominal pain upper
         subjects affected / exposed
    7 / 155 (4.52%)
    10 / 157 (6.37%)
         occurrences all number
    7
    11
    Diarrhoea
         subjects affected / exposed
    13 / 155 (8.39%)
    12 / 157 (7.64%)
         occurrences all number
    15
    17
    Dry mouth
         subjects affected / exposed
    0 / 155 (0.00%)
    12 / 157 (7.64%)
         occurrences all number
    0
    12
    Nausea
         subjects affected / exposed
    21 / 155 (13.55%)
    19 / 157 (12.10%)
         occurrences all number
    22
    22
    Vomiting
         subjects affected / exposed
    10 / 155 (6.45%)
    9 / 157 (5.73%)
         occurrences all number
    12
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 155 (5.16%)
    3 / 157 (1.91%)
         occurrences all number
    8
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 155 (3.87%)
    14 / 157 (8.92%)
         occurrences all number
    7
    16
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 155 (5.81%)
    18 / 157 (11.46%)
         occurrences all number
    9
    20
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 155 (7.74%)
    14 / 157 (8.92%)
         occurrences all number
    14
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 155 (13.55%)
    23 / 157 (14.65%)
         occurrences all number
    24
    27
    Increased appetite
         subjects affected / exposed
    13 / 155 (8.39%)
    14 / 157 (8.92%)
         occurrences all number
    15
    15

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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