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    Clinical Trial Results:
    A phase III, randomized, double blind, multicenter, parallel group, placebo and active controlled, dose optimization safety and efficacy study of Lisdexamfetamine Dimesylate (LDX) in children and adolescent aged 6-17 with attention-deficit/hyperactivity disorder (ADHD)

    Summary
    EudraCT number
    		 2008-000679-90
    Trial protocol
    		 GB   DE   FR   ES   NL   SE   BE   IT   HU  
    Global end of trial date
    16 Mar 2011

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SPD489-325
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00763971
    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
    16 Mar 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 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 efficacy of SPD489 administered as a daily morning dose (30, 50, and 70mg/day) compared to placebo over the course of 7 weeks. This study enrolled children and adolescents (6-17 years of age, inclusive) diagnosed with moderately symptomatic ADHD. The primary measure of efficacy was the clinician-administered ADHD Rating Scale-IV (ADHD-RS-IV).
    Protection of trial subjects
    It was the responsibility of the Investigator to obtain written Informed Consent and assent, where applicable, from study subjects. The subject’s informed consent was mandatory for study participation and was obtained in writing.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Nov 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Sweden: 52
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 107
    Country: Number of subjects enrolled
    Hungary: 32
    Country: Number of subjects enrolled
    Italy: 25
    Worldwide total number of subjects
    336
    EEA total number of subjects
    336
    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)
    197
    Adolescents (12-17 years)
    139
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited to participate at 48 sites in the European Union.

    Pre-assignment
    Screening details
    		 Subjects were screened for eligibility over a period of 42 days.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The test product, reference product, and placebo were overencapsulated and appeared identical.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lisdexamfetamine Dimesylate
    Arm description
    		 Lisdexamfetamine Dimesylate was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lisdexamfetamine Dimesylate
    Investigational medicinal product code
    Other name
    LDX, Vyvanse, SPD489
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One 30, 50, or 70mg capsule orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Arm title
    		 Methylphenidate Hydrochloride
    Arm description
    		 Methylphenidate Hydrochloride was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylphenidate Hydrochloride
    Investigational medicinal product code
    Other name
    Concerta, OROS MPH
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 18, 36, or 54mg tablet orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period); 54mg is the maximum approved dose of CONCERTA in Europe.

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered orally once-daily at approximately 7:00AM for 7 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
    Placebo was administered orally once-daily at approximately 7:00AM for 7 weeks.

    Number of subjects in period 1
    		Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Started
    113
    112
    111
    Completed
    80
    74
    42
    Not completed
    33
    38
    69
         Randomization error
    -
    -
    1
         Subject wanted dose reduction
    -
    1
    -
         Unable to swallow capsule
    2
    1
    1
         'Exclusion criteria met '
    1
    -
    -
         Adverse event
    5
    2
    4
         Participation in 489-326 required
    1
    -
    -
         Medical monitor decision
    -
    -
    1
         Sponsor decision
    1
    -
    -
         'Lack of availability '
    -
    1
    -
         Withdrawal by subject
    4
    5
    5
         Protocol violation
    3
    3
    2
         Personal reason
    3
    -
    -
         Moved to another country
    -
    1
    -
         Lost to follow-up
    -
    1
    -
         Performed final visit on phone
    -
    1
    -
         Lack of efficacy
    11
    22
    54
         Due to holiday season
    2
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lisdexamfetamine Dimesylate
    Reporting group description
    		 Lisdexamfetamine Dimesylate was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Reporting group title
    Methylphenidate Hydrochloride
    Reporting group description
    		 Methylphenidate Hydrochloride was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered orally once-daily at approximately 7:00AM for 7 weeks.

    Reporting group values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo Total
    Number of subjects
    		 113 112 111 336
    Age categorical
    Units: Subjects
        6-12 years
    		 79 81 80 240
        13-17 years
    		 34 31 31 96
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.8 ± 2.87 10.8 ± 2.63 11 ± 2.81 -
    Gender categorical
    Units: Subjects
        Female
    		 24 21 19 64
        Male
    		 89 91 92 272
    Region of enrollment
    Units: Subjects
        France
    		 10 9 11 30
        Hungary
    		 11 10 11 32
        Spain
    		 13 14 14 41
        Poland
    		 3 4 3 10
        Belgium
    		 4 3 4 11
        Netherlands
    		 1 0 0 1
        Germany
    		 36 36 35 107
        United Kingdom
    		 8 10 9 27
        Italy
    		 9 9 7 25
        Sweden
    		 18 17 17 52

    End points

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    End points reporting groups
    Reporting group title
    Lisdexamfetamine Dimesylate
    Reporting group description
    		 Lisdexamfetamine Dimesylate was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Reporting group title
    Methylphenidate Hydrochloride
    Reporting group description
    		 Methylphenidate Hydrochloride was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered orally once-daily at approximately 7:00AM for 7 weeks.

    Primary: Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at up to 7 Weeks

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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 up to 7 Weeks
    End point description
    The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. A decrease in score indicates an improvement in ADHD symptomology. This end point analysed the Full Analysis set (FAS), defined as all subjects who were randomized and who took at least 1 dose of investigational product.
    End point type
    Primary
    End point timeframe
    Baseline and up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    98
    103
    104
    Units: scores on a scale
        least squares mean (standard error)
    -24.3 ± 1.16
    -18.7 ± 1.14
    -5.7 ± 1.13
    Statistical analysis title
    		 Analysis of ADHD-RS-IV Total Score-LDX
    Comparison groups
    Placebo v Lisdexamfetamine Dimesylate
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -18.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.5
         upper limit
    		 -15.7
    Statistical analysis title
    		 Analysis of ADHD-RS-IV Total Score-MPH
    Comparison groups
    Placebo v Methylphenidate Hydrochloride
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.9
         upper limit
    		 -10.2

    Secondary: Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores

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    End point title
    		 Percent of Subjects With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores
    End point description
    The CGI-I consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale. The end point analysed the FAS, defined as all subjects who were randomized and who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    100
    104
    104
    Units: percent of subjects
        number (not applicable)
    78
    60.6
    14.4
    Statistical analysis title
    		 Analysis of CGI-I-LDX
    Comparison groups
    Placebo v Lisdexamfetamine Dimesylate
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    63.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53
         upper limit
    		 74.1
    Statistical analysis title
    		 Analysis of CGI-I-MPH
    Comparison groups
    Placebo v Methylphenidate Hydrochloride
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentages
    Point estimate
    46.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34.6
         upper limit
    		 57.7

    Secondary: Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks

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    End point title
    		 Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks
    End point description
    The CPRS-R consists of 27 questions graded on a scale from 0 (not true at all) to 3 (very much true) with a total score ranging from 0 to 81. Higher scores are indicative of increased ADHD. This scale allows parents to respond on the basis of the child's behavior and help assess ADHD and evaluate problem behavior. This end point analysed the FAS, defined as all subjects who were randomized and who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    96
    99
    100
    Units: scores on a scale
        least squares mean (standard error)
    -24.5 ± 1.7
    -18.4 ± 1.69
    -3.2 ± 1.69
    Statistical analysis title
    		 Analysis of CPRS-R Total Score-LDX
    Comparison groups
    Lisdexamfetamine Dimesylate v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -21.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.5
         upper limit
    		 -17
    Statistical analysis title
    		 Analysis of CPRS-R Total Score-MPH
    Comparison groups
    Placebo v Methylphenidate Hydrochloride
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -15.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.3
         upper limit
    		 -10.9

    Secondary: Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks

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    End point title
    		 Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks
    End point description
    The HUI-2 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 analysed the FAS, defined as all subjects who were randomized and who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    98
    103
    97
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline
    0.811 ± 0.1451
    0.822 ± 0.1377
    0.806 ± 0.146
        Up to 7 weeks
    0.878 ± 0.1322
    0.887 ± 0.1151
    0.843 ± 0.1431
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF) Global T-score at up to 7 Weeks

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    End point title
    		 Change From Baseline in the Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF) Global T-score at up to 7 Weeks
    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 are used to generate T-scores. Higher scores indicate better health. This end point analysed the FAS, defined as all subjects who were randomized and who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    78
    75
    80
    Units: T-scores
        least squares mean (standard error)
    8.6 ± 1.08
    7.1 ± 1.1
    -0.2 ± 1.07
    Statistical analysis title
    		 Analysis of CHIP-CE:PRF Global T-score-LDX
    Comparison groups
    Placebo v Lisdexamfetamine Dimesylate
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.1
         upper limit
    		 11.5
    Statistical analysis title
    		 Analysis of CHIP-CE:PRF Global T-score-MPH
    Comparison groups
    Placebo v Methylphenidate Hydrochloride
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 10

    Secondary: Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks

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    End point title
    		 Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks
    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 analysed the FAS, defined as all subjects who were randomized and who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    79
    83
    87
    Units: scores on a scale
        least squares mean (standard error)
    -0.3 ± 0.04
    -0.3 ± 0.04
    0 ± 0.04
    Statistical analysis title
    		 Analysis of WFIRS-P Global Score-LDX
    Comparison groups
    Lisdexamfetamine Dimesylate v Placebo
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.2
    Statistical analysis title
    		 Analysis of WFIRS-P Global Score-MPH
    Comparison groups
    Placebo v Methylphenidate Hydrochloride
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.1

    Secondary: Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks

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    End point title
    		 Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks
    End point description
    The BPRS-C characterizes psychopathology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology. This end point analysed the Safety Population, defined as all subjects who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    20
    21
    22
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -9.15 ± 11.264
    -9.71 ± 6.936
    -2.59 ± 7.436
    No statistical analyses for this end point

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

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    End point title
    		 Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS is a 19-item semi-structured interview designed to capture suicide-related thoughts and behaviors. This end point analysed the Safety Population, defined as all subjects who took at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to 7 weeks
    End point values
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Number of subjects analysed
    25
    29
    27
    Units: subjects
        Suicidal ideation
    1
    0
    0
        Non-suicidal self injurious behavior
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    56 days
    Adverse event reporting additional description
    Adverse events are reported for the Safety population, defined as all subjects who took at least 1 dose of investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Lisdexamfetamine Dimesylate
    Reporting group description
    		 Lisdexamfetamine Dimesylate was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Reporting group title
    Methylphenidate Hydrochloride
    Reporting group description
    		 Methylphenidate Hydrochloride was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered orally once-daily at approximately 7:00AM for 7 weeks.

    Serious adverse events
    		 Lisdexamfetamine Dimesylate Methylphenidate Hydrochloride Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 111 (2.70%)
    2 / 111 (1.80%)
    3 / 110 (2.73%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 111 (0.90%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hematoma
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 111 (0.90%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 111 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 110 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    0 / 110 (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 Methylphenidate Hydrochloride Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 111 (72.07%)
    72 / 111 (64.86%)
    63 / 110 (57.27%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 111 (2.70%)
    1 / 111 (0.90%)
    1 / 110 (0.91%)
         occurrences all number
    7
    1
    1
    Weight decreased
         subjects affected / exposed
    15 / 111 (13.51%)
    5 / 111 (4.50%)
    0 / 110 (0.00%)
         occurrences all number
    15
    5
    0
    Injury, poisoning and procedural complications
    Joint sprain
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 111 (3.60%)
    1 / 110 (0.91%)
         occurrences all number
    0
    4
    1
    Wrong drug administered
         subjects affected / exposed
    4 / 111 (3.60%)
    2 / 111 (1.80%)
    1 / 110 (0.91%)
         occurrences all number
    4
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 111 (3.60%)
    2 / 111 (1.80%)
    1 / 110 (0.91%)
         occurrences all number
    4
    2
    1
    Headache
         subjects affected / exposed
    16 / 111 (14.41%)
    22 / 111 (19.82%)
    22 / 110 (20.00%)
         occurrences all number
    21
    30
    27
    Migraine
         subjects affected / exposed
    3 / 111 (2.70%)
    1 / 111 (0.90%)
    0 / 110 (0.00%)
         occurrences all number
    4
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 111 (4.50%)
    1 / 111 (0.90%)
    3 / 110 (2.73%)
         occurrences all number
    5
    1
    3
    Irritability
         subjects affected / exposed
    4 / 111 (3.60%)
    4 / 111 (3.60%)
    0 / 110 (0.00%)
         occurrences all number
    6
    5
    0
    Pyrexia
         subjects affected / exposed
    3 / 111 (2.70%)
    5 / 111 (4.50%)
    0 / 110 (0.00%)
         occurrences all number
    3
    5
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 111 (5.41%)
    4 / 111 (3.60%)
    6 / 110 (5.45%)
         occurrences all number
    6
    4
    10
    Abdominal upper pain
         subjects affected / exposed
    8 / 111 (7.21%)
    9 / 111 (8.11%)
    6 / 110 (5.45%)
         occurrences all number
    15
    10
    9
    Diarrhea
         subjects affected / exposed
    5 / 111 (4.50%)
    2 / 111 (1.80%)
    3 / 110 (2.73%)
         occurrences all number
    8
    2
    3
    Nausea
         subjects affected / exposed
    12 / 111 (10.81%)
    8 / 111 (7.21%)
    3 / 110 (2.73%)
         occurrences all number
    14
    8
    4
    Vomiting
         subjects affected / exposed
    4 / 111 (3.60%)
    4 / 111 (3.60%)
    1 / 110 (0.91%)
         occurrences all number
    5
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 111 (2.70%)
    8 / 111 (7.21%)
    0 / 110 (0.00%)
         occurrences all number
    3
    8
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 111 (0.00%)
    3 / 110 (2.73%)
         occurrences all number
    1
    0
    4
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    4 / 111 (3.60%)
    3 / 111 (2.70%)
    1 / 110 (0.91%)
         occurrences all number
    4
    3
    1
    Initial insomnia
         subjects affected / exposed
    3 / 111 (2.70%)
    7 / 111 (6.31%)
    1 / 110 (0.91%)
         occurrences all number
    3
    7
    1
    Insomnia
         subjects affected / exposed
    16 / 111 (14.41%)
    9 / 111 (8.11%)
    0 / 110 (0.00%)
         occurrences all number
    16
    9
    0
    Sleep disorder
         subjects affected / exposed
    6 / 111 (5.41%)
    2 / 111 (1.80%)
    1 / 110 (0.91%)
         occurrences all number
    6
    2
    1
    Tic
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 111 (2.70%)
    2 / 110 (1.82%)
         occurrences all number
    2
    4
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 111 (3.60%)
    3 / 111 (2.70%)
    1 / 110 (0.91%)
         occurrences all number
    4
    3
    1
    Influenza
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 111 (2.70%)
    0 / 110 (0.00%)
         occurrences all number
    0
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 111 (7.21%)
    14 / 111 (12.61%)
    8 / 110 (7.27%)
         occurrences all number
    9
    14
    9
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 111 (2.70%)
    1 / 111 (0.90%)
    2 / 110 (1.82%)
         occurrences all number
    3
    1
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    12 / 111 (10.81%)
    6 / 111 (5.41%)
    2 / 110 (1.82%)
         occurrences all number
    13
    8
    2
    Decreased appetite
         subjects affected / exposed
    28 / 111 (25.23%)
    17 / 111 (15.32%)
    3 / 110 (2.73%)
         occurrences all number
    31
    21
    3

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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