Study to Evaluate Safety & Efficacy of d-Amphetamine Transdermal System vs Placebo in Children & Adolescents With ADHD

Study Overview
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Brief Summary
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This study will evaluate safety and efficacy of d-Amphetamine Transdermal System for the treatment of Attention Deficit Hyperactivity Disorder in children and adolescents.

Detailed Description
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The study will consist of a four-week screening period, a 3-day wash-out period (if applicable), a five-week open-label, step-wise dose optimization period and two-week double blind randomized crossover treatment period with weekly classroom assessments and a safety follow-up by telephone 7 - 10 days after last dose of study drug.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Crossover, Laboratory Classroom Study to Evaluate the Safety and Efficacy of d-Amphetamine Transdermal Drug Delivery System (d-ATS) Compared to Placebo in Children and Adolescents With ADHD

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: d-Amphetamine Transdermal Patch
* Drug: Placebo patch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gender: Male or female Age: Between 6 and 17 years of age (inclusive) Race: All eligible Females of child-bearing potential must have agreed to practice a clinically accepted method of contraception during the study and for at least 1 month prior to study dosing and 1 month following completion of the study. Acceptable contraceptive methods included abstinence, oral contraception, surgical sterilization (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), intrauterine device, diaphragm in addition to spermicidal foam and condom on male partner, or systemic contraception (e.g., Norplant System) Must have met Diagnostic and Statistical Manual of Mental Disorders, 4th edition - Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD combined, hyperactive/impulsive subtype, or predominately inattentive subtype The Screening and Baseline visit ADHD-RS-IV total score must have been ≥90% of the general population of children by age and gender Able to wear a patch for 9 hours (for children and, if applicable, for adolescents, parent or caregiver must be present to apply and remove the patches and maintain the used and unused patches in a secure, controlled area of the home) Functioning at an age-appropriate level intellectually as determined by an intelligence quotient (IQ) of ≥80 on the Wechsler Abbreviated Scale of Intelligence II™ (WASI II™) vocabulary and matrix reasoning components Must have been able to complete PERMP assessment Must have provided parental consent (signed ICF) and obtained written/verbal assent from the subject Subject and parent(s)/ caregiver must have been willing and able to comply with all the protocol requirements and parent(s) or caregiver must be able to provide transportation for the subject to and from the analog classroom sessions Exclusion Criteria: Blood pressure outside the 95th percentile for age and gender Pulse of <50 (age 6 - 17), or >120 (age 6 - 12), or >125 (age 13 - 17) Known non-responder to amphetamine treatment Documented allergy, intolerance, or hypersensitivity to amphetamine Currently taking an ADHD medication that is providing symptom control with no residual impairment at home or school and has acceptable tolerability and adherence Recent history (within the past 6 months) of suspected substance abuse or dependence disorder (including nicotine) History of seizures during the last 2 years (excluding infantile febrile seizures), a tic disorder (exclusive of transient tic disorder), a current diagnosis, and/or a family history of Tourette's Disorder. Mild medication-induced tics were not exclusionary Any psychiatric disorder that could interfere with study participation or the safety of the subject or other participants, such as conduct disorder (CD) or oppositional defiant disorder (ODD) with a history of prominent aggressive outbursts. Children meeting CD or ODD but without prominent aggression will be allowed to enroll at the discretion of the Investigator Autism or Asperger's Disorder Family history (first degree relatives) of sudden cardiac death Current controlled (requiring medication) or uncontrolled comorbid psychiatric conditions such as post-traumatic stress disorder, psychosis, bipolar illness, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder, was considered a suicide risk, had recent (last 6 months) suicidal ideation, or any lifetime self-harm event History of abnormal thyroid function Has a body mass index (BMI) for age greater than 95th percentile per Centers for Disease Control BMI (for gender-specific charts) Known history of symptomatic cardiovascular disease, advanced 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 Any skin abnormality present at the potential application site (i.e., infection, rash, atrophy, excessive fragility or dryness, any cut or abrasion, or tattoo) History of hypersensitivity, allergy to topical medication, preparation, or adhesive dressings Concurrent chronic or significant acute illnesses (such as severe allergic rhinitis or an infectious process requiring antibiotics, unless expected to resolve or has resolved by Day 0) disability or any unstable medical condition that in the Investigator's opinion would lead to difficulty complying with the protocol requirements Used any investigational drug within 30 days of the Screening visit History of physical, sexual, or emotional abuse in the last year Medical history of hepatitis A/B/C or HIV Positive urine drug screen for drugs of abuse

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: d-Amphetamine Transdermal patch<br>The study was conducted in 2 parts: a 5-week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period. Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received study patches everyday for one week, then subjects were crossed-over to receive the placebo treatment. d-Amphetamine Transdermal System: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied. | Drug: d-Amphetamine Transdermal Patch<br>* The study was conducted in 2 parts: a 5 week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period. Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.<br>* Other names: Amphetamine;|
| Placebo Comparator: Placebo patch<br>The study was conducted in 2 parts: a 5-week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period. Subjects who reached the optimal dose by end of dose optimization treatment period were randomized to receive double-blind treatment. Participants first received placebo patches everyday for one week, then subjects were crossed-over to receive the study treatment. Placebo patch: Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied. | Drug: Placebo patch<br>* The study was conducted in 2 parts: a 5 week, open-label, step-wise Dose Optimization Period and a 2-week, randomized, cross-over Double-Blind Treatment Period. Patches will be worn for 9 hours every day. After 9 hours the patch will be removed. Every day a new patch will be applied.<br>* Other names: Sham treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Total Score During the Double-Blind Treatment Period | The SKAMP total score comprises all 13 items. The SKAMP was designed for independent observers to rate 13 items representing 2 factors of classroom behavior: attention (SKAMP-A) and deportment (SKAMP-D), as well as quality of work. Items are specific to place (classroom setting) & time (during a typical classroom period), & the scale is used to assess multiple ratings taken within a day. The SKAMP-D subscale evaluates deportment, including interacting with other children, interacting with adults, remaining quiet according to classroom rules, & staying seated according to classroom rules. The SKAMP-A subscale is a measure of attention & evaluates getting started on assignments, sticking with tasks, attending to an activity, and making activity transitions. The SKAMP quality of work subscale includes 3 items: completing assigned work, performing work accurately, and being careful and neat while writing or drawing. Scores range from 0-78 with higher scores indicating worse impairment. | Mean SKAMP Total Score of SKAMP Total Scores from 9 different time points including (1, 2, 3, 4.5, 6, 7, 9, 10, 12 hours post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Onset of Efficacy Measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Total Score | Onset of efficacy defined as the time of the first assessment time showing statistical significance between d-ATS and placebo. The time point for the reported data are SKAMP scores (LS mean) from 2 hours post-dose. The SKAMP total score comprises all 13 items. The SKAMP was designed for independent observers to rate 13 items representing 2 factors of classroom behavior: attention (SKAMP-A) and deportment (SKAMP-D), as well as quality of work. Items are specific to place (classroom setting) & time (during a typical classroom period), & the scale is used to assess multiple ratings taken within a day. Scores range from 0-78 with higher scores indicating worse impairment. | Onset of efficacy defined as the time of the first assessment time showing statistical significance between d-ATS and placebo. 2 hours post-dose in Double-Blind Treatment Period | 
| Duration of Effect for d-Amphetamine and Placebo Treatment | Duration of Effect is the difference between the End of Effect and Onset of Effect in hours, where End of Effect is the first time point after Onset of Effect at which the 50% reduction in SKAMP total score from pre-dose is not observed. | Duration of Effect was from onset (2 hours post-dose) and up to 12 hours post-dose (p<0.001) | 
| Permanent Product Measure of Performance (PERMP) Scores Including PREMP-C and PREMP-A From Different Timepoints Post-dose | To assess efficacy of d-ATS compared to placebo as measured by the PERMP-C (number of correct answers) and PERMP-A (number of attempted answers) score. The PERMP is an age-adjusted written math test, of 10 minutes' duration administered at multiple time points. Subjects are given 5 pages of 80 math problems (400 total problems) and are instructed to work at their desks and to complete as many problems as possible in 10 minutes. Performance is measured as the number of problems attempted (PERMP-A) and the number of problems worked correctly (PERMP-C). The scores range from 0-800 with higher scores indicating better performance. | 1,2, 3, 4.5,6,7,9,10 and 12 hours post-dose from double-blind treatment period | 
| Change in the Clinician-rated Scale of ADHD Symptoms Based on DSM-IV-TR Criteria (ADHD-RS-IV). | The ADHD-RS-IV is based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria to assess efficacy of d-ATS compared to placebo. The ADHD-RS-IV scale was developed to measure the behaviors of children with ADHD, and it consists of 18 items designed to reflect current symptomatology of ADHD based on DSM-IV criteria. Each item is scored from a range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0 to 54. Note: Week 6 is the first week of the double-blind treatment period, week 7 is the second week of the double-blind treatment period. | Averaged from week 6 and week 7 results during the Double-Blind Cross-Over treatment period. | 
| Conners Parent Rating Scale Revised Short Form (CPRS-R:S) Total Scores From Week 6 and Week 7 | The CPRS-R:S evaluates problem behaviors as reported by the parent or alternative caregivers. The CPRS-R:S total score comprises 27 items and covers a subset of the subscales and items on the long parent form. The score ranges from 0-81 calculated from summed subscales scores. Higher score is considered a worse outcome for ADHD patients. Note: Week 6 is the first week of the double-blind treatment period, week 7 is the second week of the double-blind treatment period. | Combined analysis by treatment groups from week 6 and week 7 (averaged) | 
| Number of Responders Evaluated by Clinical Global Impression (CGI-I) Scale by Treatments From the Double-blind Treatment Period | The CGI scale permits a global evaluation of the subject's improvement over time. During the Dose Optimization Period and the Double-Blind Treatment Period, the investigator assessed the subject's improvement relative to symptoms prior to dosing, using the CGI-I Scale. For CGI-I scale, the responders are defined as subjects achieving a score of Very much improved or Much improved or The non-responders are defined as subjects achieving a score of Minimally improved on the clinician-rated CGI global improvement item or No change or Minimally worse or Much worse or Very much worse Then the number of responders are calculated by treatment arms. Note: Week 6 is the first week of the double-blind treatment period, week 7 is the second week of the double-blind treatment period. | the double-blind treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD