PK/PD Pediatric ADHD Classroom Study

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the association between blood drug levels and the corresponding scores of commonly used behavioral instruments based upon data collected following administration of three different methylphenidate hydrochloride extended-release drug products in children with ADHD.

Detailed Description
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This is a randomized, double-blind, 4-treatment and 4-period crossover study conducted in a school laboratory environment to evaluate the hour-by-hour behavioral instrument scores and hour-by-hour PK of 3 different extended-release MPH formulations as well as placebo in children with ADHD. The complete study consists of three periods: Screening, Dose Titration and Double-Blind Crossover in a Laboratory Classroom. The double-blind phase will consist of four periods (or four weeks): each week will consist of blinded administration with one of the three active methylphenidate hydrochloride treatments or placebo from Sunday through Saturday. On the last day of each period (Saturday), study participants will be evaluated in a laboratory classroom setting. On Saturdays, the blinded doses of each study drug will be administered at the school site by study staff on the morning of the test laboratory classroom day. On the other days, the medication will be taken in the morning at home.

Official Title
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Pharmacokinetic Pharmacodynamic Studies of Methylphenidate Extended Release Products in Pediatric Attention Deficit Hyperactivity Disorder

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: Methylphenidate HCl ER tablets 1
* Drug: Placebo
* Drug: Methylphenidate HCl ER tablets 2
* Drug: Methylphenidate HCl ER for suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female outpatients Ages 6-12 years at time of screening Judged by the investigator to be physically healthy and suitable for participation in the study Diagnosis of DSM-5ADHD combined, predominantly inattentive or hyperactive/impulsive presentation, per clinical evaluation and confirmed by the MINI-KID Clinical Global Impressions-Severity (CGI-S) ≥ 3 ≥ 90th percentile normative value for gender and age on the ADHD RS-IV total score at screening or baseline Study participant has a parent/legal guardian who is willing and able to give written informed consent for him/her to participate in the study Study participant must be able to give assent to participate in the trial Study participant and legal guardian must be able to speak and understand English Able to tolerate multiple finger pricks Willing to comply with all study procedures Exclusion Criteria: Current (last month) psychiatric diagnosis other than specific phobia, motor skills disorders, oppositional defiant disorder, sleep disorders, elimination disorders, adjustment disorders, learning disorders, or communication disorders. Participants with school phobia or separation anxiety will not be eligible Cognitively impaired, in the investigator's opinion Any clinically significant chronic medical condition that, in the judgment of the investigator, may interfere with the participant's ability to participate in the study Seizure disorder excluding a history of febrile seizures Thyroid disease Tourette's disorder or chronic tic disorder (mild medication induced tics are allowed) Serious cardiac condition including cardiomyopathy, serious arrhythmias, structural cardiac disorders, or severe hypertension Glaucoma Current or recent (within the past 6 months) DSM-5 drug dependence or substance abuse (excluding nicotine and caffeine) Pregnant or nursing females. Females must have a negative urine pregnancy test at screening as well as four additional visits and must be abstinent or use adequate and reliable contraception throughout the study Currently treated and satisfied with ADHD medication Current psychotropic medications other than sedative hypnotics for sleep Use of atomoxetine, clonidine, guanfacine or a monoamine oxidase inhibitor within 28 days of the baseline visit Participation in another investigational medication study within 30 days prior to screening Clinically significant abnormal laboratory result, electrocardiogram (ECG) result, physical examination, or vital signs at screening that the investigator considers to be inappropriate to allow participation in the study Planned use of prohibited drugs from the baseline visit through the end of the trial History of allergic reaction or a known or suspected sensitivity to any substance that is contained in the study drugs Food allergies that are determined by the PI as too severe to be easily accommodated for during the study Inability to swallow study medication

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methylphenidate HCl ER tablets 1<br>During the open-label optimization phase, one of the methylphenidate hydrochloride extended-release products will be titrated at weekly intervals of 18mg increments until an optimal dose is achieved or a maximum of 72mg per day is reached. During the double-blind phase, participants will receive blinded treatment each week. The dose of each methylphenidate hydrochloride extended-release product will be determined by the optimized dose during the open-label optimization phase | Drug: Methylphenidate HCl ER tablets 1<br> <br> |
| Placebo Comparator: Placebo<br>During the double-blind period, in one of the 4 study weeks, the study participant will take a blinded placebo instead of one of the the 3 active comparators. | Drug: Placebo<br> <br> |
| Active Comparator: Methylphenidate HCl ER tablets 2<br>During the open-label optimization phase, one of the methylphenidate hydrochloride extended-release products will be titrated at weekly intervals of 18mg increments until an optimal dose is achieved or a maximum of 72mg per day is reached. During the double-blind phase, participants will receive blinded treatment each week. The dose of each methylphenidate hydrochloride extended-release product will be determined by the optimized dose during the open-label optimization phase | Drug: Methylphenidate HCl ER tablets 2<br> <br> |
| Active Comparator: Methylphenidate HCl ER for suspension<br>During the open-label optimization phase, one of the methylphenidate hydrochloride extended-release products will be titrated at weekly intervals of 18mg increments until an optimal dose is achieved or a maximum of 72mg per day is reached. During the double-blind phase, participants will receive blinded treatment each week. The dose of each methylphenidate hydrochloride extended-release product will be determined by the optimized dose during the open-label optimization phase | Drug: Methylphenidate HCl ER for suspension<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Permanent Product Measure of Performance (PERMP) for Three Methylphenidate Hydrochloride Extended-release Drug Products | The Permanent Product Measure of Performance (PERMP) involves objective individualized mathematics tests. Scores will be obtained ten times on each classroom day at pre-dose, and at approximately 0.5, 1.5, 2.5, 4, 5, 6, 8, 10 and 12 hours post-dose. PERMP Attempted is reported here. Scale ranges 0 math questions answered to 400 math questions answered. The more number of questions answered (better score), the higher the PERMP Attempted score is. | 0.5, 1.5, 2.5, 4, 5, 6, 8, 10 and 12 hours post-dose on each classroom day | 
| Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale for Three Methylphenidate Hydrochloride Extended-release Drug Products | The Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale is a validated, 13-item rating of subjective impairment of classroom behaviors (0 = normal/no impairment; 1 = slight impairment; 2 = mild impairment; 3 = moderate impairment; 4 = severe impairment; 5 = very severe impairment; 6 = maximal impairment). The SKAMP consists of four subscales: SKAMP-Attention, SKAMP-Deportment, SKAMP-Quality of Work, and SKAMP-Compliance, in addition to SKAMP-Total (reported here). SKAMP-Total is a sum of the four sub-scales and has a range of 0-78. The higher the score, the higher the impairment. Scores will be obtained during each classroom cycle during each full laboratory classroom day at pre-dose, and at 0.5, 1.5, 2.5, 4, 5, 6, 8, 10, and 12 hours post-dose. The scores will be based on the child's behavior during 20 minutes of each cycle. | 0.5, 1.5, 2.5, 4, 5, 6, 8, 10 and 12 hours post-dose on each classroom day | 
| Maximum Drug Concentration Observed (Cmax) for Three Methylphenidate Hydrochloride Extended-release Drug Products | PK samples will be taken eight times on each classroom day at approximately 0.5, 1.5, 2.5, 4, 5, 6, 8, and 12 hours post-dose, and Cmax will be measured. The objectives of this measure is to estimate PK metrics, including Cmax, appropriate for characterizing rate and extent of absorption in each phase of the drug release and the evaluate the disposition and eliminating processes for each medication studied. The minimum value is pg/mL and there is was no maximum defined prior to the interventions. | 0.5, 1.5, 2.5, 4, 5, 6, 8, and 12 hours post-dose on each classroom day | 
| Time to Reach Cmax (Tmax) for Three Methylphenidate Hydrochloride Extended-release Drug Products | PK samples will be taken eight times on each classroom day at approximately 0.5, 1.5, 2.5, 4, 5, 6, 8, and 12 hours post-dose, and Tmax will be measured | 0.5, 1.5, 2.5, 4, 5, 6, 8, and 12 hours post-dose on each classroom day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Attention Deficit Hyperactivity Disorder, ADHD