Children with Down syndrome (DS) have a 3-5 time greater prevalence of Attention Deficit Hyperactivity Disorder (ADHD) than typically developing (TD) children. Despite this higher risk of ADHD, rates of stimulant medication treatment are disproportionately low in children with DS+ADHD, even though stimulants are the most efficacious ADHD treatment and are recommended by consensus guidelines for use in children with intellectual disability and ADHD. The investigators propose the first randomized clinical trial (RCT) of stimulant medication in children with DS+ADHD. This RCT may provide evidence regarding the short- and long-term safety and efficacy of stimulant use in children with DS+ADHD, both with and without CHD. All children enrolled in the study will complete a comprehensive assessment battery evaluating ADHD diagnostic criteria, as well as behavioral, cognitive, academic, and functional impairments.
The purpose of this study is to conduct a clinical trial of stimulant medication treatment (i.e., methylphenidate (MPH)) in children with DS+ADHD to determine methylphenidate's efficacy in remediating behavioral, cognitive, and functional impairments in children with DS+ADHD and to assess the short- and long-term safety of stimulant treatment in children with DS+ADHD with a specific focus on cardiac safety. It has the potential to significantly improve the outcomes of approximately 45,000 children with DS+ADHD nationwide. To achieve this, 100 children with DS+ADHD, between the ages of 6.00-17.99 years, will be invited to participate in a clinical trial across four sites. Following pre-screening to determine study eligibility, children with DS+ADHD will be assessed at 13 different times points. The first pre-medication visit will include baseline intelligence, diagnostic, behavioral, cognitive, health, and functioning assessments. The second through sixth visits will begin Phase 1 of the clinical trial, and during this time, participants will begin the lowest dose of MPH and titrate incrementally upward per pediatric guidelines based on the participant's weight. Bieekly diagnostic and health assessments will be conducted to monitor the safety and efficacy of MPH during this phase. Further, this biweekly monitoring will ultimately guide the selection of the participant's optimal dose. At the seventh visit, participants will enter Phase 2 of the clinical trial where they will be randomized to receive an optimal dose of MPH (as determined by the assessments conducted throughout the titration phase) or the placebo. This visit will involve a repeat of most of the baseline measures. The eighth visit will initiate Phase 3 of the clinical trial in which participants will crossover to the study intervention not previously assigned during Phase 2. For example, a participant who was assigned his or her optimal dose during Phase 2 will receive the placebo during Phase 3, and vice versa. Further, this visit will involve a repeat of the assessments conducted during Phase 2 which allows each participants to serve as his or her own control, contributing data both while on an optimal dose of MPH and while on the placebo. Prior to commencing Phase 4, MPH non-responders or placebo responders will be removed from the study and referred for non-study (clinical) treatment. Participants for whom MPH is judged to be effective and tolerable based on clinician ratings and parent/teacher reports will be invited to undergo an open label trial with their optimal MPH dose for a four-month maintenance period. During this phase, participants will undergo monthly diagnostic and health assessments to monitor the safety and efficacy of his or her optimal dose of MPH. The final visit (week 30) will include diagnostic, behavioral, cognitive, functioning, and health assessments to evaluate change across time.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
100
Long-lasting liquid solution of Quillivant XR.
Liquid solution to mimic the color and taste of Quillivant XR.
University of California Davis MIND Institute
Sacramento, California, United States
Boston Children's Hospital
Boston, Massachusetts, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Mean magnitude of change in ADHD Symptoms as measured by parent and teacher report on the Vanderbilt ADHD Parent and Teacher Rating Scales, compared to placebo, during the optimal MPH dosage period. [ Time Frame: Phase 2, Phase 3 ]
A 49-item parent-report measure used to assess parent and teacher perceptions of youth's school and social functioning. The first 47 items assess symptoms of inattention, hyperactivity, combined inattention and hyperactivity, oppositional-defiant disorder, conduct disorder, and anxiety/depression. These items are scored on a 0-3 scale (0 = Never; 1 = Occasionally; 2 = Often; 3 = Very Often). The next two items measure impairment in performance and are scored on a 1-5 scale (1 = Above Average; 3 = Average; 5 = Problematic). For both sub-scales, lower scores mean better outcomes. Data will be entered into SPSS and used as a diagnostic outcome measure.
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Mean magnitude of change in Emotion Regulation as measured by parent and teacher report on the BRIEF2, compared to placebo, during the optimal MPH dosage period. [ Time Frame: Phase 2, Phase 3 ]
A 63-item parent and teacher rating scale used to assess everyday skills measuring executive functioning, including inhibition, shifting attention, emotional control, initiating tasks, problem solving, working memory, and monitoring activities. All 63-items are scored on a 3-item scale (N = never, S = Sometimes, O = Often). Scoring is performed through a software which generates T-scores for 13 sub-scales, with borderline and clinical ranges identified. Lower scores on this measure indicate better outcomes. Data will be entered into SPSS and used as a behavioral outcome measure.
Time frame: Baseline, Week 12, Week 14, and Week 30
Mean magnitude change in Externalizing Behaviors as measured by parent and teacher report on the Achenbach Child Behavior Checklist (CBCL/TRF), compared to placebo, during the optimal MPH dosage period. [ Time Frame: Phase 2, Phase 3 ]
A 113-item rating scale used to obtain parent and teacher ratings of problem behaviors, in addition to descriptions of a child's strengths and challenges. All items are scored on a 0-2 scale (0 = Not True; 1 = Somewhat True or Sometimes True; 2 = Very True or Often True). T-scores for 8 sub-scales with borderline and clinical ranges are generated and identified through a scoring software, and lower scores on this measure indicate better outcomes. Data will be entered into SPSS and used as a behavioral outcome measure.
Time frame: Baseline, Week 12, Week 14, and Week 30
Mean magnitude of change in Behavior Regulation as measured by parent and teacher report on the BRIEF2, compared to placebo, during the optimal MPH dosage period. [ Time Frame: Phase 2, Phase 3 ]
A 63-item parent and teacher rating scale used to assess everyday skills measuring executive functioning, including inhibition, shifting attention, emotional control, initiating tasks, problem solving, working memory, and monitoring activities. All 63-items are scored on a 3-item scale (N = never, S = Sometimes, O = Often). Scoring is performed through a software which generates T-scores for 13 sub-scales, with borderline and clinical ranges identified. Lower scores on this measure indicate better outcomes. Data will be entered into SPSS and used as a behavioral outcome measure.
Time frame: Baseline, Week 12, Week 14, and Week 30
Frequency of clinically significant physician-collected cardiac occurrences on MPH - clinically significant change from baseline in ECG findings during the during the MPH titration trial [Phase 1] and the optimal MPH dosage maintenance period [Phase 4].
An ECG will be acquired at standard amplitude and speed (10mm/mV and 25mm/sec), and an electrophysiologist will inspect the recorded ECG for satisfactory quality and findings. The electrodes and lead wires will be applied to the extremities and chest with proper lead placement.The ECG readings will be used to assess the cardiovascular safety of stimulant medication treatment among the participants. Data will be reviewed by a cardiologist, and entered into SPSS to serve as a safety outcome measure.
Time frame: Baseline, Week 8, Week 10, Week 22, and Week 30
Frequency of clinically significant cardiac occurrences on MPH- clinically significant changes for Heart Rate (HR) during the MPH titration trial [Phase 1] and the MPH dosage maintenance period [Phase 4].
HR will be assessed and collected by trained study staff and clinically significant changes will be tracked and assessed based on the participant's age.
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Frequency of clinically significant cardiac occurrences on MPH- clinically significant changes for Blood Pressure (BP) during the MPH titration trial [Phase 1] and the MPH dosage maintenance period [Phase 4].
BP measurement will be acquired by trained study staff or medical staff and clinically significant changes will be tracked and assessed based on the participant's age and height.
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Mean magnitude of change in Heart Rate (HR) compared to participants' pre-trial baseline, on maximum dosage of MPH received during the MPH titration trial [Phase 1] and during the optimal MPH dosage maintenance period [Phase 4].
HR will be acquired at each visit and compared to baseline measurements based on participant's age.
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Mean magnitude of change in Systolic Blood Pressure (SBP) compared to participants' pre-trial baseline, on maximum dosage of MPH received during the MPH titration trial [Phase 1] and during the optimal MPH dosage maintenance period [Phase 4].
SBP will be acquired at each visit and compared to baseline measurements based on participant's age and height.
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Mean magnitude of change in Diastolic Blood Pressure (DBP) compared to participants' pre-trial baseline, on maximum dosage of MPH received during the MPH titration trial [Phase 1] and during the optimal MPH dosage maintenance period [Phase 4].
DBP will be acquired at each visit and compared to baseline measurement based on participant's age and height.
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Frequency of parent-rated MPH side effects
A 19-item parent rating scale used to assess known side effects will be administered at each visit using a 4-item scale (0-None, 1-Mild, 2-Moderate, 3-Severe). A medical interview will be conducted to discuss side effects outside of the scope of this measurement and any unexpected or unrelated side effects or adverse events,
Time frame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
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