ADHD
Conditions
Brief summary
The main aim of this study is to see if giving LDX to children and adolescents aged 6-17 years with ADHD decreases symptoms of ADHD.
Interventions
30, 50 or 70mg capsule once per day (Overencapsulated)
DRUGMethylphenidate Hydrochloride
18, 36, or 54mg tablet one per day (Overencapsulated)
DRUGPlacebo
Placebo capsule once per day (Overencapsulated)
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is a male or female aged 6-17 years inclusive at the time of consent. 2. Subject must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD based on a detailed psychiatric evaluation. 3. Subject must have a Baseline ADHD-RS-IV total score ≥28. 4. Subject has blood pressure measurements within the 95th percentile for age, gender, and height at Screening and Baseline. 5. Subject is able to swallow a capsule.
Exclusion criteria
1. Subject has failed to respond to more than one adequate course (dose and duration) of stimulant therapy. One course must have been a long-acting formulation. 2. Subject has a conduct disorder. Oppositional Defiant Disorder is not exclusionary. 3. Subject is currently considered a suicide risk, has previously made a suicide attempt or has a prior history of, or is currently, demonstrating active suicidal ideation. 4. Subject has glaucoma. 5. Subject weighs less than 22.7kg (50lbs). 6. Subject is significantly overweight based on Centre for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts at Screening. Significantly overweight is defined as a BMI \>97th percentile for this study. 7. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or methylphenidate. 8. Subject has a documented allergy, hypersensitivity, or intolerance to any excipients in the test or reference products. 9. Subject has a history of seizures (other than infantile febrile seizures), a tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder. 10. Subject has a known history of symptomatic cardiovascular disease, advance arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. 11. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. 12. Subject is well controlled on their current ADHD medication with acceptable tolerability. 13. Subject has a pre-existing severe gastrointestinal tract narrowing (pathologic or iatrogenic).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at up to 7 Weeks | Baseline and up to 7 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks | Baseline and up to 7 weeks | The Conner's Parent rating Scale-revised short version (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. |
| Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Baseline and up to 7 weeks | 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. |
| 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 | Baseline and up to 7 weeks | 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. |
| Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores | Up to 7 weeks | 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. |
| Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks | Baseline and up to 7 weeks | 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. |
| Columbia-Suicide Severity Rating Scale (C-SSRS) | Up to 7 weeks | C-SSRS is a 19-item semi-structured interview designed to capture suicide-related thoughts and behaviors. |
| Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks | Baseline and up to 7 weeks | 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. |
Countries
Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lisdexamfetamine Dimesylate (LDX) Lisdexamfetamine Dimesylate (LDX, Vyvanse®, SPD489) was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period) at doses of either 30, 50, or 70 mg. | 111 |
| Methylphenidate Hydrochloride Methylphenidate Hydrochloride (Concerta®, OROS MPH) was administered orally once-daily at approximately 7:00AM for 7 weeks (4-week dose optimization period and a 3-week dose maintenance period) at doses of either 18, 36, or 54 mg. | 111 |
| Placebo Placebo was administered orally once-daily at approximately 7:00AM for 7 weeks. | 110 |
| Total | 332 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 | 4 |
| Overall Study | Due to holiday season | 2 | 0 | 1 |
| Overall Study | Exclusion criteria met | 1 | 0 | 0 |
| Overall Study | Lack of availability | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 11 | 22 | 54 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Medical monitor decision | 0 | 0 | 1 |
| Overall Study | Moved to another country | 0 | 1 | 0 |
| Overall Study | Participation in 489-326 required | 1 | 0 | 0 |
| Overall Study | Performed final visit on phone | 0 | 1 | 0 |
| Overall Study | Personal reason | 3 | 0 | 0 |
| Overall Study | Protocol Violation | 3 | 3 | 2 |
| Overall Study | Randomization error | 0 | 0 | 1 |
| Overall Study | Sponsor decision | 1 | 0 | 0 |
| Overall Study | Subject wanted dose reduction | 0 | 1 | 0 |
| Overall Study | Unable to swallow capsule | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 5 |
Baseline characteristics
| Characteristic | Lisdexamfetamine Dimesylate (LDX) | Methylphenidate Hydrochloride | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 10.9 years STANDARD_DEVIATION 2.87 | 10.9 years STANDARD_DEVIATION 2.63 | 11.0 years STANDARD_DEVIATION 2.82 | 10.9 years STANDARD_DEVIATION 2.77 |
| Age, Customized 13-17 years | 34 Participants | 31 Participants | 31 Participants | 96 Participants |
| Age, Customized 6-12 years | 77 Participants | 80 Participants | 79 Participants | 236 Participants |
| Region of Enrollment Belgium | 4 Participants | 3 Participants | 4 Participants | 11 Participants |
| Region of Enrollment France | 10 Participants | 9 Participants | 11 Participants | 30 Participants |
| Region of Enrollment Germany | 36 Participants | 36 Participants | 35 Participants | 107 Participants |
| Region of Enrollment Hungary | 11 Participants | 10 Participants | 11 Participants | 32 Participants |
| Region of Enrollment Italy | 9 Participants | 9 Participants | 7 Participants | 25 Participants |
| Region of Enrollment Netherlands | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Poland | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Region of Enrollment Spain | 13 Participants | 14 Participants | 14 Participants | 41 Participants |
| Region of Enrollment Sweden | 18 Participants | 17 Participants | 17 Participants | 52 Participants |
| Region of Enrollment United Kingdom | 8 Participants | 10 Participants | 9 Participants | 27 Participants |
| Sex: Female, Male Female | 24 Participants | 21 Participants | 19 Participants | 64 Participants |
| Sex: Female, Male Male | 87 Participants | 90 Participants | 91 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 80 / 111 | 72 / 111 | 63 / 110 |
| serious Total, serious adverse events | 3 / 111 | 2 / 111 | 3 / 110 |
Outcome results
Primary
Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at up to 7 Weeks
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.
Time frame: Baseline and up to 7 weeks
Population: Full Analysis set (FAS) defined as all subjects who were randomized and who took at least 1 dose of investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at up to 7 Weeks | -24.3 Scores on a scale | Standard Error 1.16 |
| Methylphenidate Hydrochloride | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at up to 7 Weeks | -18.7 Scores on a scale | Standard Error 1.14 |
| Placebo | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth Edition (ADHD-RS-IV) Total Score at up to 7 Weeks | -5.7 Scores on a scale | Standard Error 1.13 |
p-value: <0.00195% CI: [-21.5, -15.7]ANCOVA
p-value: <0.00195% CI: [-15.9, -10.2]ANCOVA
Secondary
Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks
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.
Time frame: Baseline and up to 7 weeks
Population: Safety Population defined as all subjects who took at least 1 dose of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks | -9.15 Scores on a scale | Standard Deviation 11.264 |
| Methylphenidate Hydrochloride | Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks | -9.71 Scores on a scale | Standard Deviation 6.936 |
| Placebo | Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at up to 7 Weeks | -2.59 Scores on a scale | Standard Deviation 7.436 |
Secondary
Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks
The Conner's Parent rating Scale-revised short version (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.
Time frame: Baseline and up to 7 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks | -24.5 Scores on a scale | Standard Error 1.7 |
| Methylphenidate Hydrochloride | Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks | -18.4 Scores on a scale | Standard Error 1.69 |
| Placebo | Change From Baseline in Conner's Parent Rating Scale - Revised (CPRS-R) Total Score at up to 7 Weeks | -3.2 Scores on a scale | Standard Error 1.69 |
p-value: <0.00195% CI: [-25.5, -17]ANCOVA
p-value: <0.00195% CI: [-19.3, -10.9]ANCOVA
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
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.
Time frame: Baseline and up to 7 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | 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 | 8.6 T-scores | Standard Error 1.08 |
| Methylphenidate Hydrochloride | 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 | 7.1 T-scores | Standard Error 1.1 |
| Placebo | 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 | -0.2 T-scores | Standard Error 1.07 |
p-value: <0.00195% CI: [6.1, 11.5]ANCOVA
p-value: <0.00195% CI: [4.6, 10]ANCOVA
Secondary
Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks
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.
Time frame: Baseline and up to 7 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks | -0.3 Scores on a scale | Standard Error 0.04 |
| Methylphenidate Hydrochloride | Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks | -0.3 Scores on a scale | Standard Error 0.04 |
| Placebo | Change From Baseline in Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at up to 7 Weeks | 0.0 Scores on a scale | Standard Error 0.04 |
p-value: <0.00195% CI: [-0.4, -0.2]ANCOVA
p-value: <0.00195% CI: [-0.3, -0.1]ANCOVA
Secondary
Columbia-Suicide Severity Rating Scale (C-SSRS)
C-SSRS is a 19-item semi-structured interview designed to capture suicide-related thoughts and behaviors.
Time frame: Up to 7 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal ideation | 1 participants |
| Lisdexamfetamine Dimesylate (LDX) | Columbia-Suicide Severity Rating Scale (C-SSRS) | Non-suicidal self injurious behavior | 1 participants |
| Methylphenidate Hydrochloride | Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal ideation | 0 participants |
| Methylphenidate Hydrochloride | Columbia-Suicide Severity Rating Scale (C-SSRS) | Non-suicidal self injurious behavior | 0 participants |
| Placebo | Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal ideation | 0 participants |
| Placebo | Columbia-Suicide Severity Rating Scale (C-SSRS) | Non-suicidal self injurious behavior | 0 participants |
Secondary
Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks
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.
Time frame: Baseline and up to 7 weeks
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Baseline | 0.811 Scores on a scale | Standard Deviation 0.1451 |
| Lisdexamfetamine Dimesylate (LDX) | Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Up to 7 weeks | 0.878 Scores on a scale | Standard Deviation 0.1322 |
| Methylphenidate Hydrochloride | Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Baseline | 0.822 Scores on a scale | Standard Deviation 0.1377 |
| Methylphenidate Hydrochloride | Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Up to 7 weeks | 0.887 Scores on a scale | Standard Deviation 0.1151 |
| Placebo | Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Baseline | 0.806 Scores on a scale | Standard Deviation 0.146 |
| Placebo | Health Utilities Index-2 (HUI-2) Scores at up to 7 Weeks | Up to 7 weeks | 0.843 Scores on a scale | Standard Deviation 0.1431 |
Secondary
Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores
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.
Time frame: Up to 7 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lisdexamfetamine Dimesylate (LDX) | Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores | 78.0 percentage of participants |
| Methylphenidate Hydrochloride | Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores | 60.6 percentage of participants |
| Placebo | Percentage of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) Scores | 14.4 percentage of participants |
p-value: <0.00195% CI: [53, 74.1]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [34.6, 57.7]Cochran-Mantel-Haenszel