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    Clinical Trial Results:
    A Phase III, Double-Blind, Placebo-Controlled, Randomised Withdrawal, Multicentre, Extension, Safety and Efficacy Study of Lisdexamfetamine Dimesylate (LDX) in Children and Adolescents Aged 6-17 with Attention-Deficit/Hyperactivity Disorder (ADHD)

    Summary
    EudraCT number
    		 2008-000720-10
    Trial protocol
    		 DE   FR   NL   SE   BE   GB   IT   HU  
    Global end of trial date
    26 Oct 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jun 2018
    First version publication date
    08 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-326
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00784654
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    Hampshire International Business Park, Chineham, Basingstoke; Hampshire, United Kingdom, RG24 8EP
    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-000553-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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Oct 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2011
    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 maintenance of efficacy of SPD489, using a composite endpoint based on the attention-deficit/hyperactivity disorder (ADHD) Rating Scale – IV (ADHD-RS-IV) and Clinical Global Impression – Severity of Illness (CGI-S) rating scale, via a randomized withdrawal design in children and adolescents diagnosed with moderately symptomatic ADHD. Children and adolescents were treated with SPD489 (30, 50, or 70mg/day) for at least 6 months prior to entering a 6-week double-blind randomized (SPD489 or placebo) withdrawal period.
    Protection of trial subjects
    The subject’s informed consent was mandatory for study participation and was obtained in writing. This study was conducted in accordance with current applicable regulations, International Conference on Harmonisation (ICH) principles of Good Clinical Practice (GCP), and local ethical and legal requirements, and with the principles of the 18th World Medical Assembly (Helsinki 1964) and amendments of the 29th (Tokyo 1975), 35th (Venice 1983), 41st (Hong Kong 1989) and 48th (South Africa 1996) World Medical Assemblies, Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 2009
    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
    Poland: 8
    Country: Number of subjects enrolled
    Sweden: 49
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 95
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    276
    EEA total number of subjects
    236
    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)
    158
    Adolescents (12-17 years)
    118
    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
    		 This study was conducted at 41 investigational sites in the European Union (EU) and the United States (US). The following 8 EU countries participated: Germany (12 sites), Sweden (4 sites), Hungary (4 sites), Poland (4 sites), Great Britain (4 sites), France (3 sites), Italy (3 sites), and Belgium (3 sites). Four sites were located in the US.

    Pre-assignment
    Screening details
    		 Subjects who had been exposed to double-blind test product for a minimum of 4 weeks, reached Visit 4, and completed the 1-week post-treatment washout during Study SPD489-325 were evaluated for study eligibility. US children and adolescents (6-17 years of age inclusive) were also evaluated for direct entry into the study.

    Period 1
    Period 1 title
    Open-label (Non-randomized)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Arm description
    		 Consisted of at least 26 weeks where subjects were titrated to an optimal dose of LDX and then maintained on their optimal dose of open-label LDX.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lisdexamfetamine dimesylate (LDX)
    Investigational medicinal product code
    Other name
    Vyvanse, SPD489
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30, 50, or 70 mg capsule once-daily at approximately 7:00 AM +/- 2 hours

    Number of subjects in period 1
    		Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Started
    276
    Completed
    165
    Not completed
    111
         Home situation intolerable
    1
         'Did not provide end of study page '
    1
         Mother is a drug addict
    1
         Protocol violation
    7
         ADHD-RS score too high for random phase
    1
         Adverse event
    44
         Decision of medical monitor
    1
         Lost to follow-up
    11
         Met stopping criteria for CGI-S score
    1
         Withdrawal by subject
    22
         Lack of efficacy
    21
    Period 2
    Period 2 title
    Randomized Withdrawal
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The test (SPD489) and reference products (placebo) were over-encapsulated and appeared identical

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal)
    Arm description
    		 Subjects were randomized to receive their optimal dose of LDX for up to 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lisdexamfetamine dimesylate (LDX)
    Investigational medicinal product code
    Other name
    Vyvanse, SPD489
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated 30, 50, or 70 mg capsule once-daily at approximately 7:00 AM +/- 2 hours

    Arm title
    		 Placebo (Randomized Withdrawal)
    Arm description
    		 Subjects were randomized to receive placebo for up to 6 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated placebo capsule once-daily at approximately 7:00 AM +/- 2 hours

    Number of subjects in period 2 [1]
    		Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Started
    78
    79
    Completed
    60
    16
    Not completed
    18
    63
         Protocol violation
    2
    1
         Did not complete a visit
    1
    -
         Adverse event
    1
    1
         'Met relapse criteria per investigator '
    8
    35
         Family reasons
    -
    1
         Lack of efficacy
    5
    18
         Withdrawal by subject
    1
    7
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Eight subjects completed the original protocol design/Open-label period but were not randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label (Non-randomized)
    Reporting group description
    		 All enrolled subjects

    Reporting group values
    		 Open-label (Non-randomized) Total
    Number of subjects
    		 276 276
    Age categorical
    Units: Subjects
        6-12 years
    		 191 191
        13-17 years
    		 85 85
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.9 ± 2.82 -
    Gender categorical
    Units: Subjects
        Female
    		 64 64
        Male
    		 212 212
    Region of enrollment
    Units: Subjects
        United States
    		 40 40
        Italy
    		 20 20
        United Kingdom
    		 16 16
        France
    		 11 11
        Hungary
    		 28 28
        Belgium
    		 9 9
        Poland
    		 8 8
        Germany
    		 95 95
        Sweden
    		 49 49

    End points

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    End points reporting groups
    Reporting group title
    Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Reporting group description
    		 Consisted of at least 26 weeks where subjects were titrated to an optimal dose of LDX and then maintained on their optimal dose of open-label LDX.
    Reporting group title
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal)
    Reporting group description
    		 Subjects were randomized to receive their optimal dose of LDX for up to 6 weeks.

    Reporting group title
    Placebo (Randomized Withdrawal)
    Reporting group description
    		 Subjects were randomized to receive placebo for up to 6 weeks.

    Primary: Percent of Participants With Treatment Failures at End of the Randomized Withdrawal Period

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    End point title
    		 Percent of Participants With Treatment Failures at End of the Randomized Withdrawal Period
    End point description
    Treatment failure was defined as a 50% increase (worsening) in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) total score and >= 2 point increase (worsening) in the Clinical Global Impression-Severity of Illness (CGI-S) score observed at any visit during the randomized withdrawal period compared to the respective scores at baseline of the randomized withdrawal period. This end point was analysed using the Randomized Full Analysis Set (Randomized FAS), which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period. Subjects without an endpoint value were classed as treatment failures.
    End point type
    Primary
    End point timeframe
    Baseline of the randomized withdrawal period and its relevant endpoint
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    76
    77
    Units: treatment failure subjects-percent
        number (not applicable)
    15.8
    67.5
    Statistical analysis title
    		 Treatment Failures at Endpoint
    Comparison groups
    Placebo (Randomized Withdrawal) v Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal)
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change From Open-label Baseline in the Attention Deficit Hyperactivity Disorder Rating Scale-Fourth Edition (ADHD-RS-IV) Total Score at Endpoint (Week-26) of the Open-label Period

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    End point title
    		 Change From Open-label Baseline in the Attention Deficit Hyperactivity Disorder Rating Scale-Fourth Edition (ADHD-RS-IV) Total Score at Endpoint (Week-26) of the Open-label Period
    End point description
    ADHD-RS-IV consists of 18 items scored on a 4-point scale from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. A decrease in score indicates an improvement in ADHD symptomology. This end point was analysed using the Open-label Full Analysis set (Open-label FAS), which included all subjects who received at least 1 dose of investigational product during the open-label period.
    End point type
    Secondary
    End point timeframe
    Open-label baseline and Endpoint (Week-26)
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    257
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -26.6 ± 11.39
    No statistical analyses for this end point

    Secondary: Change From Randomized Withdrawal Baseline in the ADHD-RS-IV Total Score at Endpoint of the Randomized Withdrawal Period

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    End point title
    		 Change From Randomized Withdrawal Baseline in the ADHD-RS-IV Total Score at Endpoint of the Randomized Withdrawal Period
    End point description
    ADHD-RS-IV consists of 18 items scored on a 4-point scale from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. A decrease in score indicates an improvement in ADHD symptomology. This end point was analysed using the Randomized FAS, which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period.
    End point type
    Secondary
    End point timeframe
    Baseline of the randomized withdrawal period and its relevant endpoint
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    73
    73
    Units: scores on a scale
        least squares mean (standard error)
    1.2 ± 1.09
    13.8 ± 1.06
    Statistical analysis title
    		 Change From Baseline in ADHD-RS-IV Total Score
    Comparison groups
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) v Placebo (Randomized Withdrawal)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.4
         upper limit
    		 -9.8

    Secondary: Percent of Participants With Clinical Global Impression - Severity of Illness (CGI-S) at Endpoint (Week-26) of the Open-label Period

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    End point title
    		 Percent of Participants With Clinical Global Impression - Severity of Illness (CGI-S) at Endpoint (Week-26) of the Open-label Period
    End point description
    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). This end point was analysed using the Open-label FAS, which included all subjects who received at least 1 dose of investigational product during the open-label period.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    198
    Units: percentage of subjects
    number (not applicable)
        Normal, not at all ill
    39.9
        Borderline mentally ill
    46.5
        Mildly ill
    1.5
        Moderately ill
    6.6
        Markedly ill
    4.5
        Severely ill
    0.5
        Among the most extremely ill
    0.5
    No statistical analyses for this end point

    Secondary: Percent of Participants With CGI-S at Endpoint of the Randomized Withdrawal Period, LOCF

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    End point title
    		 Percent of Participants With CGI-S at Endpoint of the Randomized Withdrawal Period, LOCF
    End point description
    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). This end point was analysed using the Randomized FAS, which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period.
    End point type
    Secondary
    End point timeframe
    At endpoint of the randomized withdrawal period
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    75
    73
    Units: percentage of subjects
    number (not applicable)
        Normal, not at all ill
    40
    8.2
        Borderline mentally ill
    41.3
    19.2
        Mildly ill
    8
    11
        Moderately ill
    10.7
    39.7
        Markedly ill
    0
    15.1
        Severely ill
    0
    6.8
        Among the most extremely ill
    0
    0
    Statistical analysis title
    		 CGI-S at Endpoint of The Period
    Comparison groups
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) v Placebo (Randomized Withdrawal)
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percent of Participants With Improvement on Clinical Global Impression - Improvement (CGI-I) at Endpoint (Week-26) of the Open-label Period

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    End point title
    		 Percent of Participants With Improvement on Clinical Global Impression - Improvement (CGI-I) at Endpoint (Week-26) of the Open-label Period
    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. This end point was analysed using the Open-label FAS, which included all subjects who received at least 1 dose of investigational product during the open-label period. Improvement includes CGI-I categories of very much improved and much improved. No improvement includes all other assessed categories.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    257
    Units: percentage of improved subjects
        number (not applicable)
    79.8
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline in the Health Utilities Index-2 (HUI-2) Scores at Endpoint (Week-26) of the Open-label Period, LOCF

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    End point title
    		 Change From Open-label Baseline in the Health Utilities Index-2 (HUI-2) Scores at Endpoint (Week-26) of the Open-label Period, 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. This end point was analysed using the Open-label FAS, which included all subjects who received at least 1 dose of investigational product during the open-label period.
    End point type
    Secondary
    End point timeframe
    At open-label baseline and endpoint (Week-26) of the open-label period
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    223
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.087 ± 0.1307
    No statistical analyses for this end point

    Secondary: Change From Randomized Withdrawal Baseline in the HUI-2 Scores at Endpoint of the Randomized Withdrawal Period

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    End point title
    		 Change From Randomized Withdrawal Baseline in the HUI-2 Scores at Endpoint of the Randomized Withdrawal Period
    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. This end point was analysed using the Randomized FAS, which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period.
    End point type
    Secondary
    End point timeframe
    Baseline of the randomized withdrawal period and its relevant endpoint
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    59
    62
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.005 ± 0.0772
    -0.046 ± 0.1098
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline in the Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF) Global T-score at Endpoint (Week-26) of the Open-label Period

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    End point title
    		 Change From Open-label Baseline in the Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF) Global T-score at Endpoint (Week-26) of the Open-label Period
    End point description
    The CHIP-CE:PRF evaluates health-related quality of life. It is composed of 5 domains (satisfaction, comfort, resilience, avoidance, and achievement) consisting of a total of 76 items. The global score is an average of the scores for the 5 domains. The majority of items assess frequency of events using a 5-point response format. There is no range for a total score. Raw scale scores were used to generate T-scores. Higher scores indicate better health. This end point was analysed using the Open-label FAS, which included all subjects who received at least 1 dose of investigational product during the open-label period.
    End point type
    Secondary
    End point timeframe
    At open-label baseline and endpoint (Week -26) of the open-label period
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    207
    Units: T-scores
        arithmetic mean (standard deviation)
    10.2 ± 10.71
    No statistical analyses for this end point

    Secondary: Change From Randomized Withdrawal Baseline in the CHIP-CE:PRF Global T-score at Endpoint of the Randomized Withdrawal Period

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    End point title
    		 Change From Randomized Withdrawal Baseline in the CHIP-CE:PRF Global T-score at Endpoint of the Randomized Withdrawal Period
    End point description
    The CHIP-CE:PRF evaluates health-related quality of life. It is composed of 5 domains (satisfaction, comfort, resilience, avoidance, and achievement) consisting of a total of 76 items. The global score is an average of the scores for the 5 domains. The majority of items assess frequency of events using a 5-point response format. There is no range for a total score. Raw scale scores were used to generate T-scores. Higher scores indicate better health. This end point was analysed using the Randomized FAS, which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period.
    End point type
    Secondary
    End point timeframe
    Baseline of the randomized withdrawal period and its relevant endpoint
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    52
    60
    Units: T-scores
        least squares mean (standard error)
    1.1 ± 1.17
    -5.4 ± 1.1
    Statistical analysis title
    		 Change From Baseline in CHIP-CE:PRF Global T-score
    Comparison groups
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) v Placebo (Randomized Withdrawal)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.5
         upper limit
    		 9.5

    Secondary: Change From Open-label Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Endpoint (Week-26) of the Open-label Period

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    End point title
    		 Change From Open-label Baseline in the Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Endpoint (Week-26) of the Open-label Period
    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. This end point was analysed using the Open-label FAS, which included all subjects who received at least 1 dose of investigational product during the open-label period.
    End point type
    Secondary
    End point timeframe
    At open-label baseline and endpoint (Week-26) of the open-label period
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    223
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.43 ± 0.42
    No statistical analyses for this end point

    Secondary: Change From Randomized Withdrawal Baseline in the WFIRS-P Global Score at Endpoint of the Randomized Withdrawal Period

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    End point title
    		 Change From Randomized Withdrawal Baseline in the WFIRS-P Global Score at Endpoint of the Randomized Withdrawal Period
    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. This end point was analysed using the Randomized FAS, which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period.
    End point type
    Secondary
    End point timeframe
    Baseline of the randomized withdrawal period and its relevant endpoint
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    58
    61
    Units: scores on a scale
        least squares mean (standard error)
    0.01 ± 0.03
    0.2 ± 0.03
    Statistical analysis title
    		 Change From Baseline in the WFIRS-P Global Score
    Comparison groups
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) v Placebo (Randomized Withdrawal)
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.11

    Secondary: Change From Open-label Baseline in the Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Endpoint (Week-26) of the Open-label Period

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    End point title
    		 Change From Open-label Baseline in the Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Endpoint (Week-26) of the Open-label Period
    End point description
    The BPRS-C characterizes psychopathology. A total of 21 items were 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 end point was analysed using the Open-label Safety Population, which included all subjects who received at least 1 dose of investigational product in the open-label period.
    End point type
    Secondary
    End point timeframe
    At open-label baseline and endpoint (Week-26) of the open-label period
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    84
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -13.9 ± 12.58
    No statistical analyses for this end point

    Secondary: Change From Randomized Withdrawal Baseline in the BPRS-C Total Score at Endpoint of the Randomized Withdrawal Period

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    End point title
    		 Change From Randomized Withdrawal Baseline in the BPRS-C Total Score at Endpoint of the Randomized Withdrawal Period
    End point description
    The BPRS-C characterizes psychopathology. A total of 21 items were 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. This end point was analysed using the Randomized Safety Population, which included all subjects who received at least 1 dose of any investigational product during the randomized withdrawal period.
    End point type
    Secondary
    End point timeframe
    Baseline of the randomized withdrawal period and its relevant endpoint
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    23
    27
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -17.1 ± 11.17
    -9.1 ± 11.26
    No statistical analyses for this end point

    Other pre-specified: Percent of Participants With CGI-S at Open-label Baseline

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    End point title
    		 Percent of Participants With CGI-S at Open-label Baseline
    End point description
    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). This end point was analyzed using the Open-label FAS, which included all subjects who received at least 1 dose of investigational product during the open-label period.
    End point type
    Other pre-specified
    End point timeframe
    Open-label baseline
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    261
    Units: percentage of subjects
    number (not applicable)
        Normal, not at all ill
    0
        Borderline mentally ill
    0
        Mildly ill
    1.5
        Moderately ill
    27.2
        Markedly ill
    50.2
        Severely ill
    17.6
        Among the most extremely ill
    3.4
    No statistical analyses for this end point

    Other pre-specified: Percent of Participants With CGI-S at Randomized Withdrawal Baseline

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    End point title
    		 Percent of Participants With CGI-S at Randomized Withdrawal Baseline
    End point description
    CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). This end point was analysed using the Randomized FAS, which included all subjects who were randomized and received at least 1 dose of investigational product during the randomized withdrawal period.
    End point type
    Other pre-specified
    End point timeframe
    Randomized withdrawal baseline
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    74
    77
    Units: percentage of subjects
    number (not applicable)
        Normal, not at all ill
    50
    46.8
        Borderline mentally ill
    50
    53.2
        Mildly ill
    0
    0
        Moderately ill
    0
    0
        Markedly ill
    0
    0
        Severely ill
    0
    0
        Among the most extremely ill
    0
    0
    Statistical analysis title
    		 CGI-S at Randomized Withdrawal Baseline
    Comparison groups
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) v Placebo (Randomized Withdrawal)
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.726
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Other pre-specified: Columbia-Suicide Severity Rating Scale (C-SSRS) During the Open-label Period

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    End point title
    		 Columbia-Suicide Severity Rating Scale (C-SSRS) During the Open-label Period
    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. 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. This endpoint was analysed using the Open-label Safety Population, which included all subjects who received at least 1 dose of investigational product in the open-label period.
    End point type
    Other pre-specified
    End point timeframe
    From open-label baseline to Week-26
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Number of subjects analysed
    118
    Units: subjects
        Suicidal ideation
    1
        Suicidal behaviour
    0
    No statistical analyses for this end point

    Other pre-specified: C-SSRS During the Randomized Withdrawal Period

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    End point title
    		 C-SSRS During the Randomized Withdrawal Period
    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. 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. This end point was analysed using the Randomized Safety Population, which included all subjects who received at least 1 dose of any investigational product during the randomized withdrawal period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline of the randomized withdrawal period to end of the study
    End point values
    		 Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Number of subjects analysed
    45
    41
    Units: subjects
        Suicidal ideation
    0
    0
        Suicidal behaviour
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    33 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Lisdexamfetamine Dimesylate (LDX)(Open-label)
    Reporting group description
    		 Consisted of at least 26 weeks where subjects were titrated to an optimal dose of LDX (30, 50 or 70 mg once-daily orally at approximately 7:00 AM +/- 2 hours) and then maintained on their optimal dose of LDX (30, 50 or 70 mg once-daily orally at approximately 7:00 AM +/- 2 hours).

    Reporting group title
    Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal)
    Reporting group description
    		 Subjects were randomized to receive their optimal dose of LDX at 30, 50, or 70 mg once-daily orally at approximately 7:00 AM +/- 2 hours for up to 6 weeks.

    Reporting group title
    Placebo (Randomized Withdrawal)
    Reporting group description
    		 Subjects were randomized to receive placebo once-daily orally at approximately 7:00 AM +/- 2 hours for up to 6 weeks.

    Serious adverse events
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label) Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 276 (4.35%)
    0 / 78 (0.00%)
    1 / 79 (1.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 276 (0.72%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Treatment noncompliance
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    2 / 276 (0.72%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anger
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oppositional defiant disorder
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 78 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric infection
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Lisdexamfetamine Dimesylate (LDX)(Open-label) Lisdexamfetamine Dimesylate (LDX)(Randomized Withdrawal) Placebo (Randomized Withdrawal)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    227 / 276 (82.25%)
    31 / 78 (39.74%)
    20 / 79 (25.32%)
    Investigations
    Weight decreased
         subjects affected / exposed
    46 / 276 (16.67%)
    2 / 78 (2.56%)
    1 / 79 (1.27%)
         occurrences all number
    60
    2
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    3 / 276 (1.09%)
    2 / 78 (2.56%)
    0 / 79 (0.00%)
         occurrences all number
    3
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 276 (2.90%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    8
    0
    0
    Headache
         subjects affected / exposed
    58 / 276 (21.01%)
    6 / 78 (7.69%)
    5 / 79 (6.33%)
         occurrences all number
    80
    6
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 276 (6.52%)
    1 / 78 (1.28%)
    0 / 79 (0.00%)
         occurrences all number
    22
    1
    0
    Irritability
         subjects affected / exposed
    13 / 276 (4.71%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    17
    0
    0
    Pyrexia
         subjects affected / exposed
    18 / 276 (6.52%)
    1 / 78 (1.28%)
    1 / 79 (1.27%)
         occurrences all number
    25
    1
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    6 / 276 (2.17%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    6
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 276 (7.25%)
    2 / 78 (2.56%)
    0 / 79 (0.00%)
         occurrences all number
    25
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    23 / 276 (8.33%)
    4 / 78 (5.13%)
    2 / 79 (2.53%)
         occurrences all number
    25
    4
    2
    Diarrhoea
         subjects affected / exposed
    12 / 276 (4.35%)
    1 / 78 (1.28%)
    0 / 79 (0.00%)
         occurrences all number
    12
    1
    0
    Nausea
         subjects affected / exposed
    27 / 276 (9.78%)
    2 / 78 (2.56%)
    0 / 79 (0.00%)
         occurrences all number
    36
    2
    0
    Vomiting
         subjects affected / exposed
    32 / 276 (11.59%)
    2 / 78 (2.56%)
    1 / 79 (1.27%)
         occurrences all number
    43
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 276 (6.88%)
    2 / 78 (2.56%)
    0 / 79 (0.00%)
         occurrences all number
    25
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    15 / 276 (5.43%)
    3 / 78 (3.85%)
    4 / 79 (5.06%)
         occurrences all number
    18
    3
    4
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    7 / 276 (2.54%)
    2 / 78 (2.56%)
    0 / 79 (0.00%)
         occurrences all number
    7
    2
    0
    Anxiety
         subjects affected / exposed
    9 / 276 (3.26%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    9
    0
    0
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    2 / 276 (0.72%)
    0 / 78 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    2
    0
    2
    Depressed mood
         subjects affected / exposed
    11 / 276 (3.99%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    16
    0
    0
    Initial insomnia
         subjects affected / exposed
    20 / 276 (7.25%)
    1 / 78 (1.28%)
    0 / 79 (0.00%)
         occurrences all number
    22
    1
    0
    Insomnia
         subjects affected / exposed
    39 / 276 (14.13%)
    1 / 78 (1.28%)
    1 / 79 (1.27%)
         occurrences all number
    44
    1
    1
    Tic
         subjects affected / exposed
    8 / 276 (2.90%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    11
    0
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    9 / 276 (3.26%)
    1 / 78 (1.28%)
    2 / 79 (2.53%)
         occurrences all number
    11
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    43 / 276 (15.58%)
    7 / 78 (8.97%)
    3 / 79 (3.80%)
         occurrences all number
    64
    7
    3
    Rhinitis
         subjects affected / exposed
    1 / 276 (0.36%)
    2 / 78 (2.56%)
    0 / 79 (0.00%)
         occurrences all number
    2
    2
    0
    Sinusitis
         subjects affected / exposed
    7 / 276 (2.54%)
    1 / 78 (1.28%)
    1 / 79 (1.27%)
         occurrences all number
    7
    1
    1
    Tonsillitis
         subjects affected / exposed
    6 / 276 (2.17%)
    1 / 78 (1.28%)
    0 / 79 (0.00%)
         occurrences all number
    6
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 276 (5.07%)
    1 / 78 (1.28%)
    1 / 79 (1.27%)
         occurrences all number
    21
    1
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    41 / 276 (14.86%)
    0 / 78 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    48
    0
    0
    Decreased appetite
         subjects affected / exposed
    76 / 276 (27.54%)
    3 / 78 (3.85%)
    0 / 79 (0.00%)
         occurrences all number
    91
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2009
    Primarily incorporated revisions associated with the change in the primary objective of the study from long-term safety to long-term maintenance of efficacy. The Fixed Dose and Randomized Withdrawal Periods were added to the study.
    17 Dec 2009
    Added the Brief Psychiatric Rating Scale for Children (BPRS-C) and Columbia-Suicide Severity Rating Scale (C-SSRS) assessments. This Amendment also referenced the inclusion of subjects from the United States (US), where necessary.
    21 May 2010
    Changed the safety follow-up assessment from a telephone call to a site visit as required by the European Medicines Agency Paediatric Committee, 19 Feb 2010.
    29 Mar 2011
    Primarily clarified the statistical analysis of the separate components of the primary efficacy measure.

    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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