PK/PD Pediatric ADHD Classroom Study

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

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.

Study Overview

• Status: Completed
• Conditions: Attention Deficit Hyperactivity Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Methylphenidate HCl ER tablets 1; Drug: Methylphenidate HCl ER tablets 2; Drug: Methylphenidate HCl ER for suspension

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Center for Psychiatry and Behavioral Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and female outpatients
2. Ages 6-12 years at time of screening
3. Judged by the investigator to be physically healthy and suitable for participation in the study
4. Diagnosis of DSM-5ADHD combined, predominantly inattentive or hyperactive/impulsive presentation, per clinical evaluation and confirmed by the MINI-KID
5. Clinical Global Impressions-Severity (CGI-S) ≥ 3
6. ≥ 90th percentile normative value for gender and age on the ADHD RS-IV total score at screening or baseline
7. 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
8. Study participant must be able to give assent to participate in the trial
9. Study participant and legal guardian must be able to speak and understand English
10. Able to tolerate multiple finger pricks
11. Willing to comply with all study procedures

Exclusion Criteria:

1. 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
2. Cognitively impaired, in the investigator's opinion
3. 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
4. Seizure disorder excluding a history of febrile seizures
5. Thyroid disease
6. Tourette's disorder or chronic tic disorder (mild medication induced tics are allowed)
7. Serious cardiac condition including cardiomyopathy, serious arrhythmias, structural cardiac disorders, or severe hypertension
8. Glaucoma
9. Current or recent (within the past 6 months) DSM-5 drug dependence or substance abuse (excluding nicotine and caffeine)
10. 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
11. Currently treated and satisfied with ADHD medication
12. Current psychotropic medications other than sedative hypnotics for sleep
13. Use of atomoxetine, clonidine, guanfacine or a monoamine oxidase inhibitor within 28 days of the baseline visit
14. Participation in another investigational medication study within 30 days prior to screening
15. 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
16. Planned use of prohibited drugs from the baseline visit through the end of the trial
17. History of allergic reaction or a known or suspected sensitivity to any substance that is contained in the study drugs
18. Food allergies that are determined by the PI as too severe to be easily accommodated for during the study
19. Inability to swallow study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methylphenidate HCl ER tablets 1; 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
Placebo Comparator: Placebo; 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
Active Comparator: Methylphenidate HCl ER tablets 2; 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
Active Comparator: Methylphenidate HCl ER for suspension; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Food and Drug Administration (FDA); Center for Psychiatry And Behavioral Medicine Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: August 24, 2015
• First Submitted That Met QC Criteria: August 26, 2015
• First Posted (Estimate): August 31, 2015

Study Record Updates

• Last Update Posted (Actual): December 10, 2019
• Last Update Submitted That Met QC Criteria: November 23, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: ADHD; Attention Deficit Hyperactivity Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity; Hyperkinesis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Methylphenidate
• Other Study ID Numbers: 2015P001113; 5U01FD005240 (U.S. FDA Grant/Contract)