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    Clinical Trial Results:
    A Phase 3, Double-Blind, Placebo-Controlled, Multicentre, Randomised-Withdrawal, Long-Term Maintenance of Efficacy and Safety Study of Extended-Release Guanfacine Hydrochloride in Children and Adolescents Aged 6-17 with Attention-deficit/Hyperactivity Disorder

    Summary
    EudraCT number
    2009-018161-12
    Trial protocol
    GB   DE   NL   ES   SE   BE   IT  
    Global end of trial date
    09 Jul 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Sep 2018
    First version publication date
    07 Dec 2014
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Need to correct PIP information.

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD503-315
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01081145
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, 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
    11 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the long-term maintenance of efficacy of SPD503 in children and adolescents (6-17 years) with attention-deficit/hyperactivity disorder (ADHD) who respond to an initial open label, short-term treatment with SPD503.
    Protection of trial subjects
    The role of the DMC was to protect the interests of subjects in the study and of potential subjects, by review of accumulating safety and tolerability data as it was generated. This study was conducted in accordance with International Conference on Harmonisation of good clinical practice (GCP), 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
    11 May 2010
    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
    Netherlands: 29
    Country: Number of subjects enrolled
    Spain: 68
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    United States: 280
    Worldwide total number of subjects
    528
    EEA total number of subjects
    218
    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)
    334
    Adolescents (12-17 years)
    194
    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
    Participants took part in the study at 67 investigative sites in Belgium, Canada, France, Italy, Germany, the Netherlands, Spain, Sweden, the United Kingdom, and the United States from 11 May 2010 to 9 July 2013.

    Pre-assignment
    Screening details
    Children and adolescents aged 6-17 with attention-deficit/hyperactivity disorder were enrolled in 1 of 2 [guanfacine hydrochloride 1-7 mg once daily (QD); placebo QD] treatment groups.

    Period 1
    Period 1 title
    Open-Label Phase
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Guanfacine Hydrochloride
    Arm description
    -
    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
    Administered as a once-daily oral dose between 1-7mg/day depending on age and weight

    Number of subjects in period 1
    Guanfacine Hydrochloride
    Started
    528
    Completed
    316
    Not completed
    212
         Protocol deviation
    4
         Adverse event
    42
         Lack of efficacy
    56
         Withdrawal by subject
    41
         Not specified
    12
         Response criteria not met
    46
         Lost to follow-up
    11
    Period 2
    Period 2 title
    Double-Blind Randomized-Withdrawal Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The actual treatment given to individual subjects during the Double-Blind Randomized-Withdrawal Phase was determined by a randomization schedule. The associated treatment assignments giving details of individual subject treatment were automatically assigned by the interactive response technology (IRT).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Guanfacine Hydrochloride
    Arm description
    -
    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
    Administered as a once-daily oral dose between 1-7mg/day depending on age and weight

    Arm title
    Placebo
    Arm description
    -
    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
    Administered as a once-daily oral dose

    Number of subjects in period 2
    Guanfacine Hydrochloride Placebo
    Started
    157
    159
    Completed
    76
    53
    Not completed
    81
    106
         Protocol deviation
    1
    -
         Adverse event
    3
    2
         Lack of efficacy
    13
    20
         Withdrawal by subject
    10
    8
         Not specified
    4
    3
         Treatment failure criteria met
    47
    71
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-Label Phase
    Reporting group description
    -

    Reporting group values
    Open-Label Phase Total
    Number of subjects
    528 528
    Age categorical
    Units: Subjects
        6-12 years
    393 393
        13-17 years
    135 135
    Gender categorical
    Units: Subjects
        Female
    131 131
        Male
    397 397
    Region of enrollment
    Units: Subjects
        Belgium
    19 19
        Canada
    30 30
        France
    14 14
        Germany
    27 27
        Italy
    31 31
        Netherlands
    29 29
        Spain
    68 68
        Sweden
    5 5
        United Kingdom
    25 25
        United States
    280 280

    End points

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    End points reporting groups
    Reporting group title
    Guanfacine Hydrochloride
    Reporting group description
    -
    Reporting group title
    Guanfacine Hydrochloride
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Percentage of Subjects With Treatment Failures During the Double-Blind Randomized-Withdrawal Phase

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    End point title
    Percentage of Subjects With Treatment Failures During the Double-Blind Randomized-Withdrawal Phase
    End point description
    Treatment failure was defined as >= 50% increase (worsening) in ADHD-RS-IV total score and a >= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-Blind Randomized-Withdrawal Baseline Visit at 2 consecutive Double-Blind Randomized-Withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.
    End point type
    Primary
    End point timeframe
    26 weeks
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    150
    151
    Units: percentage of treatment failures
        number (confidence interval 95%)
    49.3 (41.3 to 57.3)
    64.9 (57.3 to 72.5)
    Statistical analysis title
    Treatment Failures
    Comparison groups
    Guanfacine Hydrochloride v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Treatment Failures
    Point estimate
    -15.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.6
         upper limit
    -4.5

    Secondary: Time to Treatment Failure During the Double-Blind Randomized-Withdrawal Phase

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    End point title
    Time to Treatment Failure During the Double-Blind Randomized-Withdrawal Phase
    End point description
    Treatment failure was defined as >= 50% increase (worsening) in ADHD-RS-IV total score and a >= 2 point increase (worsening) in CGI-S score compared with the respective scores at the Double-Blind Randomized-Withdrawal Baseline Visit at 2 consecutive Double-Blind Randomized-Withdrawal Phase visits. Subjects meeting these criteria were regarded as treatment failures regardless of whether or not they were withdrawn. All subjects who discontinued the study for any reason were regarded as treatment failures for the primary analysis.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    150
    151
    Units: Days
    218
    56
    Statistical analysis title
    Time to Treatment Failure
    Comparison groups
    Placebo v Guanfacine Hydrochloride
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Logrank
    Confidence interval

    Secondary: Change From Double-Blind Randomized-Withdrawal Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - Last Observation Carried Forward (LOCF)

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    End point title
    Change From Double-Blind Randomized-Withdrawal Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - 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.
    End point type
    Secondary
    End point timeframe
    Baseline and week 26
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    150
    151
    Units: units on a scale
        least squares mean (standard error)
    9.64 ± 1.21
    15.89 ± 1.225
    Statistical analysis title
    Change From Baseline in ADHD-RS-IV Score Week 26
    Comparison groups
    Guanfacine Hydrochloride v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    ANCOVA
    Parameter type
    Difference in Least Squares Mean
    Point estimate
    -6.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.01
         upper limit
    -3.48
    Notes
    [1] - Nominal p-value uncorrected for multiplicity.

    Secondary: Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on the Clinical Global Impression-Severity of Illness (CGI-S) Scale During the Double-Blind Randomized-Withdrawal Phase - LOCF

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    End point title
    Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on the Clinical Global Impression-Severity of Illness (CGI-S) Scale During the Double-Blind Randomized-Withdrawal Phase - LOCF
    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)
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    150
    151
    Units: percentage of subjects
        number (not applicable)
    50
    32.5
    Statistical analysis title
    Clinical Global Impressions - Severity
    Comparison groups
    Guanfacine Hydrochloride v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Percent of Subjects
    Point estimate
    17.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    28.5
    Notes
    [2] - Nominal p-value uncorrected for multiplicity.

    Secondary: Change From Double-Blind Randomized-Withdrawal Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - LOCF

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    End point title
    Change From Double-Blind Randomized-Withdrawal Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Week 26 of the Double-Blind Randomized-Withdrawal Phase - LOCF
    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.
    End point type
    Secondary
    End point timeframe
    Baseline and week 26
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    150
    151
    Units: units on a scale
        least squares mean (standard error)
    0.16 ± 0.035
    0.23 ± 0.036
    Statistical analysis title
    Change from Baseline WFIRS-P Global Score Week 26
    Comparison groups
    Guanfacine Hydrochloride v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.118 [3]
    Method
    ANCOVA
    Parameter type
    Difference in Least Squares Mean
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.02
    Notes
    [3] - Nominal p-value uncorrected for multiplicity.

    Secondary: Health Utilities Index-2/3 (HUI 2/3) Scores During the Double-Blind Randomized-Withdrawal Phase - LOCF

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    End point title
    Health Utilities Index-2/3 (HUI 2/3) Scores During the Double-Blind Randomized-Withdrawal Phase - 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.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    138
    142
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.9 ± 0.1229
    0.899 ± 0.1272
    No statistical analyses for this end point

    Secondary: Columbia-Suicide Severity Rating Scale During the Double-Blind Randomized-Withdrawal Phase

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    End point title
    Columbia-Suicide Severity Rating Scale During the Double-Blind Randomized-Withdrawal Phase
    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.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    Guanfacine Hydrochloride Placebo
    Number of subjects analysed
    157
    158
    Units: subjects
        Suicidal Ideation
    2
    2
        Suicidal Behavior
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Open-Label Baseline in ADHD-RS-IV Total Score at Week 13 of the Open-Label Phase - LOCF

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    End point title
    Change From Open-Label Baseline in ADHD-RS-IV Total Score at Week 13 of the Open-Label Phase - 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.
    End point type
    Secondary
    End point timeframe
    Baseline and 13 weeks
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    497
    Units: units on a scale
        arithmetic mean (standard deviation)
    -25.2 ± 11.97
    No statistical analyses for this end point

    Secondary: Percentage of Responders in the Open-Label Phase - LOCF

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    End point title
    Percentage of Responders in the Open-Label Phase - LOCF
    End point description
    Response is defined as a percentage decrease (improvement) from Baseline in the ADHD-RS-IV total score of >=30% and a CGI-S score of 1 or 2.
    End point type
    Secondary
    End point timeframe
    13 Weeks
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    497
    Units: percentage of participants
        number (not applicable)
    68.6
    No statistical analyses for this end point

    Secondary: Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores During the Open-Label Phase - LOCF

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    End point title
    Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores During the Open-Label Phase - LOCF
    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.
    End point type
    Secondary
    End point timeframe
    13 Weeks
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    497
    Units: percentage of participants
        number (not applicable)
    76.1
    No statistical analyses for this end point

    Secondary: Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on the CGI-S Scale During the Open-Label Phase - LOCF

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    End point title
    Percent of Subjects With an Assessment of Normal/Borderline Mentally Ill on the CGI-S Scale During the Open-Label Phase - LOCF
    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).
    End point type
    Secondary
    End point timeframe
    13 Weeks
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    503
    Units: percentage of participants
        number (not applicable)
    68.9
    No statistical analyses for this end point

    Secondary: Change From Open-Label Baseline in the WFIRS-P Global Score at Week 13 of the Open-Label Phase - LOCF

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    End point title
    Change From Open-Label Baseline in the WFIRS-P Global Score at Week 13 of the Open-Label Phase - LOCF
    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.
    End point type
    Secondary
    End point timeframe
    Baseline and week 13
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    405
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.35 ± 0.414
    No statistical analyses for this end point

    Secondary: HUI 2/3 Scores During the Open-Label Phase - LOCF

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    End point title
    HUI 2/3 Scores During the Open-Label Phase - 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.
    End point type
    Secondary
    End point timeframe
    13 weeks
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    417
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.892 ± 0.123
    No statistical analyses for this end point

    Secondary: Columbia-Suicide Severity Rating Scale During the Open-Label Phase

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    End point title
    Columbia-Suicide Severity Rating Scale During the Open-Label Phase
    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.
    End point type
    Secondary
    End point timeframe
    13 weeks
    End point values
    Guanfacine Hydrochloride
    Number of subjects analysed
    526
    Units: subjects
        Suicidal Ideation
    1
        Suicidal Behavior
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    42 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Guanfacine Hydrochloride (Open-Label Phase)
    Reporting group description
    -

    Reporting group title
    Placebo (Randomized-Withdrawal Phase)
    Reporting group description
    -

    Reporting group title
    Guanfacine Hydrochloride (Randomized-Withdrawal Phase)
    Reporting group description
    -

    Serious adverse events
    Guanfacine Hydrochloride (Open-Label Phase) Placebo (Randomized-Withdrawal Phase) Guanfacine Hydrochloride (Randomized-Withdrawal Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 526 (0.95%)
    4 / 158 (2.53%)
    2 / 157 (1.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 158 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Family stress
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 158 (0.63%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Grand mal convulsion
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 158 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 158 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 526 (0.38%)
    1 / 158 (0.63%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 526 (0.19%)
    1 / 158 (0.63%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conduct disorder
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 158 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 158 (0.63%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 158 (0.63%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Guanfacine Hydrochloride (Open-Label Phase) Placebo (Randomized-Withdrawal Phase) Guanfacine Hydrochloride (Randomized-Withdrawal Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    423 / 526 (80.42%)
    51 / 158 (32.28%)
    65 / 157 (41.40%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    29 / 526 (5.51%)
    0 / 158 (0.00%)
    1 / 157 (0.64%)
         occurrences all number
    32
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 526 (2.66%)
    9 / 158 (5.70%)
    5 / 157 (3.18%)
         occurrences all number
    14
    11
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    50 / 526 (9.51%)
    2 / 158 (1.27%)
    3 / 157 (1.91%)
         occurrences all number
    62
    2
    3
    Headache
         subjects affected / exposed
    144 / 526 (27.38%)
    18 / 158 (11.39%)
    25 / 157 (15.92%)
         occurrences all number
    242
    24
    34
    Sedation
         subjects affected / exposed
    47 / 526 (8.94%)
    0 / 158 (0.00%)
    2 / 157 (1.27%)
         occurrences all number
    61
    0
    2
    Somnolence
         subjects affected / exposed
    254 / 526 (48.29%)
    0 / 158 (0.00%)
    19 / 157 (12.10%)
         occurrences all number
    386
    0
    27
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    130 / 526 (24.71%)
    2 / 158 (1.27%)
    8 / 157 (5.10%)
         occurrences all number
    186
    2
    11
    Irritability
         subjects affected / exposed
    37 / 526 (7.03%)
    3 / 158 (1.90%)
    2 / 157 (1.27%)
         occurrences all number
    41
    3
    2
    Pyrexia
         subjects affected / exposed
    22 / 526 (4.18%)
    5 / 158 (3.16%)
    10 / 157 (6.37%)
         occurrences all number
    28
    5
    10
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    60 / 526 (11.41%)
    8 / 158 (5.06%)
    3 / 157 (1.91%)
         occurrences all number
    70
    10
    4
    Constipation
         subjects affected / exposed
    31 / 526 (5.89%)
    3 / 158 (1.90%)
    5 / 157 (3.18%)
         occurrences all number
    38
    3
    5
    Diarrhoea
         subjects affected / exposed
    37 / 526 (7.03%)
    3 / 158 (1.90%)
    4 / 157 (2.55%)
         occurrences all number
    46
    4
    5
    Nausea
         subjects affected / exposed
    33 / 526 (6.27%)
    4 / 158 (2.53%)
    5 / 157 (3.18%)
         occurrences all number
    42
    4
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    30 / 526 (5.70%)
    0 / 158 (0.00%)
    0 / 157 (0.00%)
         occurrences all number
    32
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 526 (6.84%)
    13 / 158 (8.23%)
    11 / 157 (7.01%)
         occurrences all number
    39
    14
    14
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 526 (5.89%)
    10 / 158 (6.33%)
    8 / 157 (5.10%)
         occurrences all number
    33
    10
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2010
    *The maximum dose allowed was reduced from 8mg to 7mg. Text relating to dose titration in certain adolescent weight groups was updated to remove the 2mg starting dose and to reflect the reduced maximum dose. *Inclusion Criterion #10 was added to exclude subjects with a supine and standing blood pressure measurement within the 95th percentile for age, gender, and height. *Instructions to assess the suitability of subjects to remain in the study were added.
    17 Jun 2010
    *Inclusion Criterion #3 was updated to allow for inclusion of inattentive subtype of ADHD. *Exclusion Criterion #5 wording was updated for clarification that only clinically significant electrocardiograms were exclusionary. *Exclusion Criterion #15 wording was changed to specifically exclude past or present active suicidal ideation and to clarify that intermittent passive suicidal ideation was not necessarily exclusionary. *Exclusion Criterion #17 wording was updated to exclude those with a presence of a serious tic disorder. *Exclusion Criterion #18 was added to exclude subjects if another member of the same household was currently participating in the study. *Body mass index was deleted from Visits 13 and 23. *Follow-up contact was changed to follow-up visit. *Added that the subject’s lifetime non-pharmacological interventions (behavioral therapy) for ADHD were to be collected. *Added that a subject could have continued participation in behavioral therapy, provided they had been receiving the therapy for at least 1 month at the time of Enrollment/Visit 2/Week 0 and that the behavioral therapy must have remained stable throughout the study. *The fasting requirement was removed for biochemistry samples and it was clarified that samples could have been drawn with the subject in a fasting or non-fasting state. *The Prior Psychoactive Medication Questionnaire and the Oppositional subscale of the CPRS-R:L were added and study assessments and statistical methods sections were updated accordingly.
    01 Mar 2011
    Following responses from the Ethics Committees in Spain, Germany, and The Netherlands, Exclusion Criterion #2 was added to exclude subjects who were well-controlled on their current ADHD medication with acceptable tolerability and the parent/caregiver did not object to the current ADHD medication.
    27 Nov 2012
    *Time to treatment failure was added as a key secondary endpoint. Statistical methods sections were updated accordingly. Time to treatment failure is the key secondary objective as defined in the final SAP (Version 3.0 dated 23 May 2013). *“Temperature” or “oral temperature” was changed to “temperature (oral or tympanic)” to clarify that a subject’s temperature could have been obtained via oral or tympanic readings. *The sentence “Medical history will be summarized by treatment group using the number of observations and percentages of subjects reporting each category” was deleted, as medical history was not being coded.

    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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