Evaluating Treatment of ADHD in Children With Down Syndrome

Study Overview
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Brief Summary
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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.

Detailed Description
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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 two 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.

Official Title
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Evaluating Assessment and Medication Treatment of ADHD in Children With Down Syndrome

Conditions
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Down Syndrome, ADHD

Intervention / Treatment
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* Drug: Quillivant XR
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stated willingness to comply with all study procedures and availability for the duration of the study. Male or female, between the ages of 6.00-17.99 years at the time of consent. Able to take oral (liquid) medication. English is primary language. Meets criteria for ADHD (hyperactivity, inattention, or combined) on the KSADS Meets criteria for ADHD (hyperactivity, inattention, or combined) on the Vanderbilt (historically or currently, as indicated by a teacher/professional) Exclusion Criteria: Current use of ADHD stimulant or non-stimulant medication and unwilling to discontinue for >/= 3 days prior to starting the study. Children with psychoses or bipolar disorder based on diagnostic interview with the parent. Organic Brain Injury: Children must not have a history of head trauma with loss of consciousness, epilepsy, or any other organic disorder that could possibly affect brain function. Specific heart conditions including the following: QTc on baseline ECG>470ms or QTC > 500 in patients with repaired CHD, as determined by ECG Brugada pattern, as determined by ECG Baseline heart rate or systolic blood pressure > 2 SD above mean for age as determined by medical examination. 2nd or 3rd degree AV block, as determined by ECG History of aborted sudden cardiac death or unexplained syncope as determined by medical history History of a single ventricle as determined by medical history Valvular regurgitation or stenosis > mild, as determined by ECHO Moderate or greater ventricular dysfunction, as determined by ECHO Pulmonary hypertension, defined as right ventricular pressure >33% systemic pressure or septal position consistent with >mild right ventricular hypertension, as determined by ECHO Use of a pacemaker as determined by medical history Wolff Parkinson White/pre-ventricular excitation, as determined by ECG Atrial, junctional, or ventricular tachyarrhythmia, as determined by ECG Frequent premature ventricular contractions (PVCs) or premature atrial contractions (PACs), as determined by ECG Abnormal T waves with inversion in V5 and/or V6, bizarre T wave morphology, notched biphasic T waves, or ST segment depression suggesting ischemia or inflammation, as determined by ECG Moderate or larger atrial septal defect, as determined by ECHO Ventricular septal defect > small by ECHO Valvar stenosis > mild by ECHO Aortic root dilation > 2SD above mean by ECHO. If participants meet any of the following heart conditions, they must be evaluated for the study by a cardiologist before beginning: Right ventricular enlargement/right axis deviation, as determined by ECG Intraventricular conduction delay >120ms in child >12 years old or >100ms in child <8 years old, as determined by ECG Right or left bundle branch block, as determined by ECG Treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within 14 days. Active titration of non-ADHD, non-MAO psychotropic medication. Stable use of non-ADHD, non-MAO psychotropic medication, defined by no dose changes for >/= 4 weeks before starting the study medication trial, will be allowed. Known hypersensitivity or allergic reactions to methylphenidate or product components such as banana (due to bananas serving as flavoring in the formulation of the project's study interventions - Quillivant XR and the placebo). Severe Obstructive Sleep Apnea (OSA) as rated by McGill index of 4 Pregnancy. (Since there is limited information regarding the safety of Quillivant XR during pregnancy, a pregnancy test will be conducted at the medical screen for female participants who have commenced the menstrual cycle. If pregnancy is indicated, the participant will be excluded from the study as a precautionary measure).

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Phase 1 is a Sequential model, Phase 2-3 is a Crossover model, Phase 4 is a Single-Group model.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Quillivant XR<br>Once-daily, long-lasting MPH solution with the following dosing schedules: 7.5mg/15mg/22.5mg/30mg for children 20-25kg 10mg/20mg/30mg/40mg for children 26-30kg 10mg/22mg/34mg/46mg for children > 30 mg | Drug: Quillivant XR<br>* Long-lasting liquid solution of Quillivant XR.<br>|
| Placebo Comparator: Placebo<br>Liquid-based suspension to match the color and banana-flavor of Quillivant XR. | Drug: Placebo<br>* Liquid solution to mimic the color and taste of Quillivant XR.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline, Week 12, Week 14, and Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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, | Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30 |