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    Clinical Trial Results:
    A Phase 4, Randomized, Double-blind, Multicenter, Parallel-group, Active-controlled, Forced-dose Titration, Safety and Efficacy Study of SPD489 (VYVANSE®) Compared With OROS-MPH (CONCERTA®) With a Placebo Reference Arm, in Adolescents Aged 13-17 Years With Attention-deficit/Hyperactivity Disorder (ADHD)

    Summary
    EudraCT number
    2011-005452-34
    Trial protocol
    DE   IT   HU   SE  
    Global end of trial date
    22 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Sep 2018
    First version publication date
    20 Mar 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD489-406
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01552902
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    725 Chesterbrook Boulevard, Wayne, Pennsylvania, United States, 19087
    Public contact
    Medical Communications, Shire Pharmaceutical Development Ltd., +44 8000556614, medinfoglobal@shire.com
    Scientific contact
    Medical Communications, Shire Pharmaceutical Development Ltd., +44 8000556614, medinfoglobal@shire.com
    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
    27 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lisdexamfetamine dimesylate 70 milligram (mg) compared with osmotic controlled oral release delivery system-methylphenidate (OROS-MPH) 72 mg in adolescents (13-17 years of age, inclusive) with ADHD.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Apr 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
    United States: 493
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    European Union: 31
    Worldwide total number of subjects
    549
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    549
    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
    The study was conducted at 77 sites in the United States, Canada, and Europe.

    Pre-assignment
    Screening details
    Of the 778 screened subjects, 229 were screen failures and 549 were randomized to treatment. A total of 547 subjects were treated and the reasons for 2 'randomized but not treated' subjects included withdrawal by 1 subject in the Methylphenidate group and 1 subject with a protocol violation in the Lisdexamfetamine group.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    2 placebo over encapsulated capsules once daily orally for 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
    2 placebo over encapsulated capsules once daily orally for 6 weeks.

    Arm title
    Lisdexamfetamine dimesylate
    Arm description
    Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 placebo over encapsulated capsules once daily orally for 6 weeks.

    Investigational medicinal product name
    Lisdexamfetamine dimesylate
    Investigational medicinal product code
    SPD489
    Other name
    Elvanse, Tyvense, Vyvanse, LDX
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).

    Arm title
    Methylphenidate
    Arm description
    Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 placebo over encapsulated capsules once daily orally for 6 weeks.

    Investigational medicinal product name
    Methylphenidate
    Investigational medicinal product code
    Other name
    Concerta, OROS-MPH
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).

    Number of subjects in period 1 [1]
    Placebo Lisdexamfetamine dimesylate Methylphenidate
    Started
    110
    218
    219
    Completed
    97
    181
    186
    Not completed
    13
    37
    33
         Adverse event
    1
    15
    14
         Protocol violation
    3
    3
    3
         Lack of efficacy
    4
    3
    1
         Unspecified
    3
    4
    3
         Consent withdrawn by subject
    1
    9
    6
         Lost to follow-up
    1
    3
    6
    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 enrolled subjects were treated with study drugs. Since baseline period included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    2 placebo over encapsulated capsules once daily orally for 6 weeks.

    Reporting group title
    Lisdexamfetamine dimesylate
    Reporting group description
    Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).

    Reporting group title
    Methylphenidate
    Reporting group description
    Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).

    Reporting group values
    Placebo Lisdexamfetamine dimesylate Methylphenidate Total
    Number of subjects
    110 218 219 547
    Age categorical
    Age was calculated as the difference between date of birth and date of informed consent. The Safety set consisted of all subjects in the Randomized set (all screened subjects for whom a randomization number was generated) who took at least 1 dose of investigational product.
    Units: Subjects
        Less Than or Equal to 18 Years
    110 218 219 547
        Between 18 and 65 Years
    0 0 0 0
        Greater Than or Equal to 65 Years
    0 0 0 0
    Age continuous
    Age was calculated as the difference between date of birth and date of informed consent. Safety set.
    Units: years
        arithmetic mean (standard deviation)
    14.7 ± 1.37 14.6 ± 1.38 14.7 ± 1.42 -
    Gender categorical
    Safety set.
    Units: Subjects
        Female
    34 83 69 186
        Male
    76 135 150 361
    ADHD Subtype
    Safety set.
    Units: Subjects
        Predominantly Inattentive
    40 70 71 181
        Predominantly Hyperactive/Impulsive
    2 2 4 8
        Combined Subtype
    68 146 144 358
    Clinical Global Impressions – Severity of Illness (CGI-S)
    The Clinical Global Impressions Scale permits a global evaluation of the subject’s severity of illness and improvement over time. The scale includes a severity of illness item and a global improvement item. The investigator performed the CGI-S to rate the severity of a 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; or 7=extremely ill). Safety set.
    Units: Subjects
        Borderline mentally ill
    1 0 0 1
        Mildly ill
    2 4 1 7
        Moderately ill
    60 93 115 268
        Markedly ill
    41 106 90 237
        Severely ill
    6 15 13 34
    Attention-deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Total Score
    The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms. Safety set.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    36.1 ± 5.91 37.2 ± 6.46 36.9 ± 6.42 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    2 placebo over encapsulated capsules once daily orally for 6 weeks.

    Reporting group title
    Lisdexamfetamine dimesylate
    Reporting group description
    Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).

    Reporting group title
    Methylphenidate
    Reporting group description
    Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS consisted of a total of 532 subjects (106 in placebo, 210 in Lisdexamfetamine dimesylate, and 216 in Methylphenidate) which was defined as all subjects in the Safety set who had at least 1 post-baseline measurement of the ADHD-RS-IV.

    Primary: Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6

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    End point title
    Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6
    End point description
    The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms. FAS.
    End point type
    Primary
    End point timeframe
    Baseline, Week 6
    End point values
    Placebo Lisdexamfetamine dimesylate Methylphenidate
    Number of subjects analysed
    93 [1]
    175 [2]
    181 [3]
    Units: Units on a scale
        least squares mean (standard error)
    -17 ± 1.03
    -25.4 ± 0.74
    -22.1 ± 0.73
    Notes
    [1] - Not all FAS subjects were evaluable for this endpoint.
    [2] - Not all FAS subjects were evaluable for this endpoint.
    [3] - Not all FAS subjects were evaluable for this endpoint.
    Statistical analysis title
    Lisdexamfetamine versus Methylphenidate
    Statistical analysis description
    The least squares mean (LSM), the difference in LSM and its 95% confidence interval (CI), and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on Restricted maximum likelihood (REML) method of estimation and utilized an unstructured covariance.
    Comparison groups
    Lisdexamfetamine dimesylate v Methylphenidate
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0013
    Method
    Mixed models analysis
    Parameter type
    Difference in LSM
    Point estimate
    -3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.4
         upper limit
    -1.3
    Statistical analysis title
    Methylphenidate versus Placebo
    Statistical analysis description
    The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that includes treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.
    Comparison groups
    Methylphenidate v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Difference in LSM
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.6
         upper limit
    -2.6
    Statistical analysis title
    Lisdexamfetamine versus Placebo
    Statistical analysis description
    The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.
    Comparison groups
    Lisdexamfetamine dimesylate v Placebo
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Difference in LSM
    Point estimate
    -8.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11
         upper limit
    -6

    Secondary: Percentage of Subjects With an Improved Measurement in the Clinical Global Impression - Global Improvement (CGI-I) at Week 6

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    End point title
    Percentage of Subjects With an Improved Measurement in the Clinical Global Impression - Global Improvement (CGI-I) at Week 6
    End point description
    The Clinical Global Impressions Scale permits a global evaluation of the subject’s severity of illness and improvement over time. The scale included a severity of illness item and a global improvement item. The investigator performed the CGI-I to rate the improvement of a subject’s ADHD symptoms based on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse.). Percentage of subjects with an improved measurement (response of very much improved and much improved) is reported. FAS.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    Placebo Lisdexamfetamine dimesylate Methylphenidate
    Number of subjects analysed
    106
    210
    216
    Units: Percentage of subjects
        number (not applicable)
    50
    81.4
    71.3
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of double-blind investigational product and up to 3 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety set.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 3 days after last dose (last dose at Week 6)
    End point values
    Placebo Lisdexamfetamine dimesylate Methylphenidate
    Number of subjects analysed
    110
    218
    219
    Units: Subjects
        Subjects with TEAEs
    49
    145
    129
        Subjects with serious TEAEs
    1
    1
    1
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Blood Pressure at Week 6

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    End point title
    Change From Baseline in Blood Pressure at Week 6
    End point description
    Safety set.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 6
    End point values
    Placebo Lisdexamfetamine dimesylate Methylphenidate
    Number of subjects analysed
    93 [4]
    175 [5]
    181 [6]
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Systolic blood pressure
    -1 ± 9.88
    1.5 ± 9.56
    2.4 ± 9.97
        Diastolic blood pressure
    -0.1 ± 8.1
    3.4 ± 8.15
    3.5 ± 8.59
    Notes
    [4] - Not all Safety set subjects were evaluable for this endpoint.
    [5] - Not all Safety set subjects were evaluable for this endpoint.
    [6] - Not all Safety set subjects were evaluable for this endpoint.
    No statistical analyses for this end point

    Other pre-specified: Change from Baseline in Pulse Rate at Week 6

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    End point title
    Change from Baseline in Pulse Rate at Week 6
    End point description
    Safety set.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 6
    End point values
    Placebo Lisdexamfetamine dimesylate Methylphenidate
    Number of subjects analysed
    93 [7]
    175 [8]
    181 [9]
    Units: Beats per minute
        arithmetic mean (standard deviation)
    2.4 ± 10.81
    6.7 ± 12.46
    8.2 ± 12.7
    Notes
    [7] - Not all Safety set subjects were evaluable for this endpoint.
    [8] - Not all Safety set subjects were evaluable for this endpoint.
    [9] - Not all Safety set subjects were evaluable for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 3 days after last dose (last dose at Week 6)
    Adverse event reporting additional description
    AEs occurred during the double-blind evaluation phase were considered as TEAEs if AEs had a start date on or after the first dose of double-blind study drug or a start date before the date of the first dose of double-blind study drug, but increased in severity on or after the date of the first dose of double-blind study drug. Safety set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    2 placebo over encapsulated capsules once daily orally for 6 weeks.

    Reporting group title
    Methylphenidate
    Reporting group description
    Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).

    Reporting group title
    Lisdexamfetamine dimesylate
    Reporting group description
    Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).

    Serious adverse events
    Placebo Methylphenidate Lisdexamfetamine dimesylate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 219 (0.46%)
    1 / 218 (0.46%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 219 (0.00%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic episode
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 219 (0.00%)
    0 / 218 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 219 (0.46%)
    0 / 218 (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
    Placebo Methylphenidate Lisdexamfetamine dimesylate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 110 (29.09%)
    99 / 219 (45.21%)
    113 / 218 (51.83%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 110 (0.00%)
    11 / 219 (5.02%)
    23 / 218 (10.55%)
         occurrences all number
    0
    11
    23
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 110 (8.18%)
    35 / 219 (15.98%)
    33 / 218 (15.14%)
         occurrences all number
    13
    40
    45
    Dizziness
         subjects affected / exposed
    0 / 110 (0.00%)
    11 / 219 (5.02%)
    12 / 218 (5.50%)
         occurrences all number
    0
    11
    12
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    7 / 110 (6.36%)
    15 / 219 (6.85%)
    11 / 218 (5.05%)
         occurrences all number
    7
    16
    11
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 110 (0.91%)
    7 / 219 (3.20%)
    16 / 218 (7.34%)
         occurrences all number
    1
    7
    18
    Nausea
         subjects affected / exposed
    3 / 110 (2.73%)
    11 / 219 (5.02%)
    11 / 218 (5.05%)
         occurrences all number
    3
    11
    12
    Abdominal pain upper
         subjects affected / exposed
    2 / 110 (1.82%)
    8 / 219 (3.65%)
    11 / 218 (5.05%)
         occurrences all number
    2
    8
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 110 (2.73%)
    17 / 219 (7.76%)
    17 / 218 (7.80%)
         occurrences all number
    3
    20
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 110 (10.00%)
    51 / 219 (23.29%)
    69 / 218 (31.65%)
         occurrences all number
    11
    52
    74

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2012
    Revision of Inclusion Criterion at the request of the Institutional Review Board to indicate that blood pressure measurements should not exceed the 90th percentile.
    26 Aug 2012
    1. Increased number of sites from 55 to approximately 65 to support study recruitment 2. Replaced World Health Organization body mass index (BMI) values with Centers for Disease Control and Prevention (CDC) BMI values 3. Revision of reporting instructions for the treatment assignment to be unblinded as soon as possible after the investigator was unblinded 4. Changed the start of the screening and washout phase from 7-28 days to 3-28 days prior to the baseline visit (Visit 0) to address day of enrolment for subjects who did not require a medication washout 5. Clarification that the washout telephone call was applicable to all subjects. Modified washout telephone call procedures 6. Modification that subjects accepted to participate in the pharmacogenomic substudy signed the pharmacogenomic informed consent and assent 7. Revision to include provision for additional care of subjects after the study.
    04 Jan 2013
    1. Addition of Europe and Canada to support study recruitment 2. Addition of text indicating randomization would be stratified by geographic region 3. Revision of text regarding Shire’s serious adverse event (SAE) reporting information 4. Clarification that timeframe for reporting SAEs was 24 hours (rather than 1 business day) to comply with Medicines and Healthcare Products Regulatory Agency (United Kingdom) 5. Addition of Inclusion Criterion to allow subjects not completely satisfied with aspects of their current ADHD therapy to participate in the study 6. Removal of Exclusion Criterion that disqualified subjects who were well-controlled on their current ADHD medication with acceptable tolerability 7. Increased the number of sites from 65 to approximately 80 to account for the addition of Europe and Canada 8. Inclusion of updated information regarding the definition, period of observation, and recording of AEs 9. Addition of text to indicate that a change in a vital sign or ECG value could represent an AE if clinically relevant 10. Specification of information related to inpatient hospitalization or prolongation of existing hospitalization for SAEs.

    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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