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    Clinical Trial Results:
    A Phase 3, Open-label, Multicentre Study to Provide Access to Guanfacine Hydrochloride Extended-release for European Subjects with Attention-deficit/Hyperactivity Disorder (ADHD) who Participated in Study SPD503-315 or SPD503-316

    Summary
    EudraCT number
    		 2011-004668-31
    Trial protocol
    		 GB   DE   SE   AT   ES   IE   BE   IT   NL   PL  
    Global end of trial date
    15 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD503-318
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01500694
    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
    Study Physician, Shire, +1 866-842-5335,
    Scientific contact
    Study Physician, Shire, +1 866-842-5335,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety and tolerability of SPD503.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) of Good Clinical Practice (GCP), the principles of the Declaration of Helsinki, and other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Mar 2012
    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
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 53
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Ukraine: 41
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    215
    EEA total number of subjects
    174
    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)
    110
    Adolescents (12-17 years)
    100
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 52 sites in 11 countries in Europe: Austria, Belgium, France, Germany, Italy, The Netherlands, Poland, Romania, Spain, Ukraine, and United Kingdom.

    Pre-assignment
    Screening details
    		 Of 218 subjects screened, 215 subjects were enrolled:131 subjects aged 6-12 years and 84 subjects aged 13-18 years. Among them 214 subjects received treatment, of which 133 subjects completed the study. The first subject’s consent was obtained on 20 March 2012 and the last subject assessment took place on 15 September 2015.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SPD503 (6-12 years)
    Arm description
    		 Subjects aged 6-12 years received extended-release guanfacine hydrochloride (SPD503) one tablet (1 x 1 milligram [mg] or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Extended-release guanfacine hydrochloride
    Investigational medicinal product code
    SPD503
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received extended-release guanfacine hydrochloride (SPD503) one tablet (1-4mg) or two tablets (5-7 mg) once daily.

    Arm title
    		 SPD503 (13-18 years)
    Arm description
    		 Subjects aged 13-18 years received extended-release Guanfacine hydrochloride (SPD503) one tablet (1 x 1 mg or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Extended-release guanfacine hydrochloride
    Investigational medicinal product code
    SPD503
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received extended-release guanfacine hydrochloride (SPD503) one tablet (1-4mg) or two tablets (5-7 mg) once daily.

    Number of subjects in period 1 [1]
    		SPD503 (6-12 years) SPD503 (13-18 years)
    Started
    131
    83
    Subjects Received Treatment
    131
    83
    Completed
    79
    54
    Not completed
    52
    29
         Consent withdrawn by subject
    23
    14
         Protocol violation
    -
    1
         Adverse event
    4
    3
         Unspecified
    9
    3
         Lost to follow-up
    2
    3
         Lack of efficacy
    14
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all the subjects reported in the baseline period were treated with the study drug, that is the reason the worldwide number enrolled is not the same as the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SPD503 (6-12 years)
    Reporting group description
    		 Subjects aged 6-12 years received extended-release guanfacine hydrochloride (SPD503) one tablet (1 x 1 milligram [mg] or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.

    Reporting group title
    SPD503 (13-18 years)
    Reporting group description
    		 Subjects aged 13-18 years received extended-release Guanfacine hydrochloride (SPD503) one tablet (1 x 1 mg or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.

    Reporting group values
    		 SPD503 (6-12 years) SPD503 (13-18 years) Total
    Number of subjects
    		 131 83 214
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.8 ± 1.56 14.7 ± 1.49 -
    Gender, Male/Female
    Units: subjects
        Female
    		 26 30 56
        Male
    		 105 53 158

    End points

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    End points reporting groups
    Reporting group title
    SPD503 (6-12 years)
    Reporting group description
    		 Subjects aged 6-12 years received extended-release guanfacine hydrochloride (SPD503) one tablet (1 x 1 milligram [mg] or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.

    Reporting group title
    SPD503 (13-18 years)
    Reporting group description
    		 Subjects aged 13-18 years received extended-release Guanfacine hydrochloride (SPD503) one tablet (1 x 1 mg or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.

    Primary: Change from Baseline in Mean Systolic Blood Pressure at Final Assessment

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    End point title
    		 Change from Baseline in Mean Systolic Blood Pressure at Final Assessment [1]
    End point description
    Systolic Blood pressure was measured at supine and standing position and mean supine systolic blood pressure was reported here. Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ Early Terminatino [ET]/Day 714). Safety Analysis Set includes all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n = 131, 83)
    107.5 ± 8.73
    113.5 ± 9.23
        Change at Final Assessment (n = 130, 82)
    0.9 ± 9.35
    0.3 ± 9.32
    No statistical analyses for this end point

    Primary: Change From Baseline in Mean Diastolic Blood Pressure at Final Assessment

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    End point title
    		 Change From Baseline in Mean Diastolic Blood Pressure at Final Assessment [2]
    End point description
    Diastolic Blood pressure was measured at supine and standing position and mean supine diastolic blood pressure was reported here. Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Safety Analysis Set includes all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n=131, 83)
    64.3 ± 8.12
    66.8 ± 9.14
        Change at Final Assessment (n = 130, 82)
    0.2 ± 8.96
    0.1 ± 9.55
    No statistical analyses for this end point

    Primary: Change From Baseline in Mean Supine Pulse at Final Assessment

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    End point title
    		 Change From Baseline in Mean Supine Pulse at Final Assessment [3]
    End point description
    Pulse was measured at supine and standing position and mean supine pulse was reported here. Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Safety Analysis Set includes all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: beats per minute(bpm)
    arithmetic mean (standard deviation)
        Baseline (n = 131, 83)
    79.3 ± 11.17
    72.1 ± 9.91
        Change at Final Assessment (n=130, 82)
    -7.1 ± 13.52
    -2.9 ± 11.71
    No statistical analyses for this end point

    Primary: Change From Baseline in Mean Height at Final Assessment

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    End point title
    		 Change From Baseline in Mean Height at Final Assessment [4]
    End point description
    Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Safety Analysis Set included all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: centimeter (cm)
    arithmetic mean (standard deviation)
        Baseline (n = 131, 83)
    142.03 ± 10.916
    166.32 ± 9.274
        Change at Final Assessment (n = 128, 79)
    8.8 ± 5.075
    5.54 ± 5.491
    No statistical analyses for this end point

    Primary: Change From Baseline in Mean Weight at Final Assessment

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    End point title
    		 Change From Baseline in Mean Weight at Final Assessment [5]
    End point description
    Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Safety Analysis Set included all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Baseline (n = 131, 83)
    37.29 ± 9.256
    58.53 ± 11.478
        Change at Final Assessment (n = 128, 79)
    8.96 ± 5.886
    6.74 ± 5.859
    No statistical analyses for this end point

    Primary: Change From Baseline in Electrocardiogram Result (QRS interval) at Final Assessment

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    End point title
    		 Change From Baseline in Electrocardiogram Result (QRS interval) at Final Assessment [6]
    End point description
    Safety Analysis Set included all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories for each arm respectively. Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714).
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: millisecond (ms)
    arithmetic mean (standard deviation)
        Baseline (n=131, 83)
    84.9 ± 7.72
    89.7 ± 6.22
        Change at Final Assessment (n=127, 77)
    1.8 ± 6
    1.8 ± 6.16
    No statistical analyses for this end point

    Primary: Change From Baseline in Electrocardiogram Result (QT interval) at Final Assessment

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    End point title
    		 Change From Baseline in Electrocardiogram Result (QT interval) at Final Assessment [7]
    End point description
    Safety Analysis Set included all enrolled subjects who took at least 1 dose of SPD503. Here, n = number of subjects analysed for the specific categories (Visit 19/ET/Day 714). Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    131
    83
    Units: millisecond (ms)
    arithmetic mean (standard deviation)
        Baseline (n = 131, 83)
    361.4 ± 21.4
    375.9 ± 24.93
        Change at Final Assessment (n = 127, 77)
    16.9 ± 27.87
    9.5 ± 29.93
    No statistical analyses for this end point

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

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    End point title
    		 Columbia-Suicide Severity Rating Scale (C-SSRS) [8]
    End point description
    C-SSRS is a semi-structured interview that captures the occurrence, severity and frequency of suicide-related thoughts and behaviours during the assessment period.There is a maximum of 19 items to be completed: 7 that are required, 10 potential additional items if there is a positive response to a required item and 2 items for suicide/suicide behaviour present during the interview. Final Assessment is last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Safety Analysis Set included all enrolled subjects who took at least 1 dose of SPD503 with number of subjects evaluable for this end point only. One subject aged 6-12 years responded "yes" to the suicidal ideation category of "wish to be dead" while not on treatment (at the end of treatment visit, after his last dose).
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis were performed, inferential statistics were not performed.
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    130
    82
    Units: subjects
    number (not applicable)
        Suicidal Ideation: Wish to Dead
    2
    1
        Suicidal Ideation: Non-specific Suicidal Thoughts
    2
    0
        Suicidal Behaviour: Non-suicidal Self-injurious
    0
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Attention deficit and Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV)- Total Score at Final Assessment

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    End point title
    		 Change From Baseline in Attention deficit and Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV)- Total Score at Final Assessment
    End point description
    ADHD-RS-IV was developed to measure the behaviours of children with ADHD with 18 items. Each item is scored from a range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54. The 18 items may be grouped into 2 sub-scales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17) with possible score range from 0 (no symptoms) to 27 (most severe symptoms). The ADHD-RS-IV possible total scores range from 0 (no symptoms) to 54 (most severe symptoms). Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Full Analysis Set included enrolled subjects who took at least 1 dose of SPD503, excluding subjects from site 403. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    128
    81
    Units: units on a scale
    arithmetic mean (standard error)
        Baseline (n = 127, 81)
    40 ± 0.78
    31.2 ± 1.19
        Change at Final Assessment (n = 126, 80)
    -20.2 ± 1.1
    -19.3 ± 1.31
    No statistical analyses for this end point

    Secondary: Number of subjects assessed with Clinical Global Impression - Severity of Illness (CGI-S) Scale

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    End point title
    		 Number of subjects assessed with Clinical Global Impression - Severity of Illness (CGI-S) Scale
    End point description
    The CGI-S evaluate each subject's severity and improvement over time. The severity of a subject’s condition is rated on a 7-point scale ranging from 1 to 7. The scale measures 0= Not assessed, 1 = Normal, not at all ill, 2 = Borderline mentally ill (BL-MI), 3 = Mildly ill, 4 = Moderately ill, 5 = Markedly ill, 6 = Severely ill, 7 = Among the most extremely ill subjects. Final Assessment is the last valid assessment obtained after Baseline (Visit 2/Day 0) whilst on investigational product and before first dose taper medication (Visit 19/ET/Day 714). Full Analysis Set included enrolled subjects who took at least 1 dose of SPD503, excluding subjects from site 403. Here, n = number of subjects analysed for the specific categories for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Final Assessment (last non missing data/up to Day 714)
    End point values
    		 SPD503 (6-12 years) SPD503 (13-18 years)
    Number of subjects analysed
    128
    81
    Units: subjects
    number (not applicable)
        Baseline: Normal/BL-MI (n=127, 81)
    0
    2
        Baseline: Mildly ill or greater (n=127, 81)
    127
    79
        Final assessment:Normal/BL-MI(n=127,80)
    45
    51
        Final Asesment:Mildly ill or greater(n=127,80)
    82
    29
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of the study drug administration up to 10 days after the last dose of study drug administration
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    SPD503 (6-12 years )
    Reporting group description
    		 Subjects aged 6-12 years received extended-release guanfacine hydrochloride (SPD503) one tablet (1 x 1 mg or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.

    Reporting group title
    SPD503 (13-18 years )
    Reporting group description
    		 Subjects aged 13-18 years received extended-release guanfacine hydrochloride (SPD503) one tablet (1 x 1 mg or 2 mg or 3 mg or 4mg) or two tablets (1 x 2+3 mg or 1 x 2+4 mg, 1 x 3+4 mg) once daily for up to 2 years.

    Serious adverse events
    		 SPD503 (6-12 years ) SPD503 (13-18 years )
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 131 (6.11%)
    2 / 83 (2.41%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    2 / 131 (1.53%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SPD503 (6-12 years ) SPD503 (13-18 years )
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 131 (77.86%)
    55 / 83 (66.27%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 131 (9.16%)
    9 / 83 (10.84%)
         occurrences all number
    16
    10
    Headache
         subjects affected / exposed
    38 / 131 (29.01%)
    23 / 83 (27.71%)
         occurrences all number
    91
    43
    Somnolence
         subjects affected / exposed
    50 / 131 (38.17%)
    27 / 83 (32.53%)
         occurrences all number
    81
    37
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 131 (22.90%)
    13 / 83 (15.66%)
         occurrences all number
    43
    15
    Pyrexia
         subjects affected / exposed
    8 / 131 (6.11%)
    2 / 83 (2.41%)
         occurrences all number
    9
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 131 (6.87%)
    4 / 83 (4.82%)
         occurrences all number
    11
    4
    Abdominal pain upper
         subjects affected / exposed
    8 / 131 (6.11%)
    2 / 83 (2.41%)
         occurrences all number
    11
    2
    Diarrhoea
         subjects affected / exposed
    7 / 131 (5.34%)
    3 / 83 (3.61%)
         occurrences all number
    8
    3
    Nausea
         subjects affected / exposed
    12 / 131 (9.16%)
    2 / 83 (2.41%)
         occurrences all number
    15
    2
    Vomiting
         subjects affected / exposed
    8 / 131 (6.11%)
    3 / 83 (3.61%)
         occurrences all number
    12
    4
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    7 / 131 (5.34%)
    4 / 83 (4.82%)
         occurrences all number
    8
    5
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    7 / 131 (5.34%)
    2 / 83 (2.41%)
         occurrences all number
    7
    2
    Insomnia
         subjects affected / exposed
    10 / 131 (7.63%)
    6 / 83 (7.23%)
         occurrences all number
    10
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 131 (5.34%)
    18 / 83 (21.69%)
         occurrences all number
    14
    24
    Rhinitis
         subjects affected / exposed
    8 / 131 (6.11%)
    3 / 83 (3.61%)
         occurrences all number
    11
    3
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 131 (6.87%)
    4 / 83 (4.82%)
         occurrences all number
    16
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2011
    -It was clarified that adolescent subjects aged greater than equal (>=) 13 years enrolling from Study SPD503-316 (2010-018579-12) must have completed 13 weeks of double-blind treatment in study SPD503-316 (2010-018579-12). -Sentences that limited dose reduction to only 1 reduction during the study were removed.
    10 Jan 2012
    -The primary and secondary objectives were revised. -The rationale and study design were clarified to align with the revised primary and secondary objectives. -Text was added to clarify visit windows for Visits 18 and 19 (Schedule of Assessments). -The number of days between Visit 18 and Visit 19 was revised to 98 days to be consistent with the 14 weeks between these visits. -The total days listed for Visits 20 and 21 was revised. -Urine pregnancy test for all female subjects of childbearing potential at Visit 6 and Visits 10-18 was added. -Bands were removed from hematology assessments. -The days provided in Table 6 (dose tapering schedule) were revised from Days 700-714 to Days 714-728.
    29 Jan 2013
    -Serious adverse events (SAE), pregnancy, and product quality complaint reporting language was updated. -The number of expected sites was updated. -It was clarified when the screening visit for this study could occur in relation to the antecedent study. -Inclusion criteria were revised for subjects enrolling from antecedent study SPD503-315 (2009-018161-12) and SPD503-316 (2010-018579-12). -Wash period of 30 days was deleted from Investigational compounds. -A minimum washout” was deleted from Investigational compounds to be consistent with the rest of the table. -With the exception of investigational product taken in Study SPD503-315 (2009-018161-12) which only required a 7-day washout prior to the baseline visit (Visit 2)” was deleted from alpha (α) 2-adrenergic agonists. -Electrocardiogram (ECGs) was deleted from screening visit. -Information on the planned data cut for regulatory authority submission purposes was added.

    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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