Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities

Sensitivity of the NIH Toolbox Cognition Battery to Stimulant Treatment in Intellectual Disabilities

This study is a randomized, double-blind, placebo-controlled, crossover trial of extended-release liquid methylphenidate (XRMPH) to evaluate the sensitivity of the NIH Toolbox Cognition Battery (NIHTB-CB) to changes in cognition in children and adolescents ages 6 to 17 with intellectual disability (D) and comorbid Attention Deficit Hyperactivity Disorder (ADHD). The sample will include 68 males or females (expected male: female ratio of 1.8:1 with ID and ADHD as determined by structured diagnostic interview and Conners 3 scores. Additional inclusion criteria will include Full Scale IQ above 50 and mental age greater than or equal to 3 years. In addition, participants must be able to complete NIHTB-CB testing and provide valid scores at baseline. After baseline testing, participants will then be randomized to drug or placebo in a 1:1 ratio (N=34 per group) at the end of the baseline visit. XRMPH in oral suspension supplied as Quillivant XR in 5 mg/ml (Tris Pharma, Monmouth Junction, NJ) will be the active treatment. The XRMPH or matching placebo will be started at a dose of 0.3 mg/kg/day and individually titrated over two weeks. Phone calls at the end of weeks 1, 2, and 3 will be used to collect adverse event and response data. If there is no evidence of side effects and ongoing symptoms of ADHD, the dose will be increased to 0.5 mg/kg/day at one week and 0.7 mg/kg/day at 2 weeks (maximum dose of 60 mg per day consistent with FDA labeled use in youth). The Clinical Global Impression (CGI) will be used as a guide to define optimal dose. If side effects occur the dose will be reduced to the dose level at which there were no side effects. Final optimal dose will be established by the end of week 3 and this will be maintained for 2 weeks until 5 weeks post randomization, at which time the follow-up parent and teacher Conners scales, NIHTB-CB, Go/No-Go, and PedsQL will be completed. Participants will have a washout period of 1 week, will then complete re-assessment at the second baseline, and then will cross over to the other treatment (Quillivant to placebo; placebo to Quillivant), also in a double-blind fashion. In the second treatment arm, patients will have the same titration, monitoring and treatment periods as in the first arm, again followed by repeated assessments at the conclusion of 5 weeks. The accrual of participants and number of visits is shown in the Timeline per 6-month period.

Study Overview

• Status: Enrolling by invitation
• Conditions: Intellectual Disability; Down Syndrome; Attention Deficit Hyperactivity Disorder; Fragile X Syndrome
• Intervention / Treatment: Drug: Methylphenidate Oral Solution

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • Uc Davis Mind Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• IQ below 80
• Mental age 3.0 or higher (Stanford Binet)
• Diagnosis of Intellectual Disability
• Diagnosis of ADHD
• Ability to complete valid NIHTB-CB tests at screening/baseline

Exclusion Criteria:

• stimulant use within 2 weeks prior to randomization
• history of a sensitivity reaction to stimulants
• presence of significant comorbid psychiatric or medical disorder/illness deemed by the site physician as inappropriate for stimulant use (uncontrolled epilepsy, bipolar disorder, psychosis, severe OCD, hypertension, tachycardia hypertension, failure to thrive, psychosis for example)
• a household resident with a current substance abuse disorder

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Methylphenidate Oral Solution; The XRMPH or matching placebo will be started at a dose of 0.3 mg/kg/day and individually titrated over two weeks. Phone calls at the end of weeks 1, 2, and 3 will be used to collect adverse event and response data. If there is no evidence of side effects and ongoing symptoms of ADHD, the dose will be increased to 0.5 mg/kg/day at one week and 0.7 mg/kg/day at 2 weeks (maximum dose of 60 mg per day consistent with FDA labeled use in youth).
Active Comparator: Methylphenidate	Drug: Methylphenidate Oral Solution; The XRMPH or matching placebo will be started at a dose of 0.3 mg/kg/day and individually titrated over two weeks. Phone calls at the end of weeks 1, 2, and 3 will be used to collect adverse event and response data. If there is no evidence of side effects and ongoing symptoms of ADHD, the dose will be increased to 0.5 mg/kg/day at one week and 0.7 mg/kg/day at 2 weeks (maximum dose of 60 mg per day consistent with FDA labeled use in youth).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite score of NIHTB-CB Flanker, Dimensional Change Card Sort, List Sorting and Speeded Matching tests.	The composite score is calculated as the average of the non-age adjusted standard scores of each of these four tests. These standard scores have a mean of 100 and SD of 15. A minimum of 3/4 valid scores is required to calculate an average composite score.	11 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Conners 3 ADHD Rating Scale Inattention Scale	11 weeks
Conners 3 ADHD Rating Scale Hyperactivity/Impulsivity Scale	11 weeks

Collaborators and Investigators

• Sponsor: University of California, Davis
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2023
• Primary Completion (Estimated): September 29, 2026
• Study Completion (Estimated): September 29, 2026

Study Registration Dates

• First Submitted: March 8, 2022
• First Submitted That Met QC Criteria: March 17, 2022
• First Posted (Actual): March 29, 2022

Study Record Updates

• Last Update Posted (Estimated): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Congenital Abnormalities; Neurodevelopmental Disorders; Abnormalities, Multiple; Heredodegenerative Disorders, Nervous System; Genetic Diseases, X-Linked; Attention Deficit and Disruptive Behavior Disorders; Sex Chromosome Disorders; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; X-Linked Intellectual Disability; Intellectual Disability; Attention Deficit Disorder with Hyperactivity; Fragile X Syndrome; Down Syndrome; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carboxylic Acids; Piperidines; Acids, Carbocyclic; Phenylacetates; Methylphenidate
• Other Study ID Numbers: 1970634; 5R01HD076189-08 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes