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Evaluating Treatment of ADHD in Children With Down Syndrome (DS+ADHD Pilot)

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ClinicalTrials.gov Identifier: NCT04219280
Recruitment Status : Not yet recruiting
First Posted : January 7, 2020
Last Update Posted : January 9, 2020
Sponsor:
Collaborator:
University of California, Davis
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:

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.

Therefore, the investigators propose a pilot clinical trial to support the first randomized clinical trial of stimulant medication in children with DS+ADHD. The purpose of this study is to inform sample size estimates for the larger clinical trial. 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. Further, children will take part in the pilot methylphenidate clinical trial to inform measures retained and desired sample size for the future clinical trial.


Condition or disease Intervention/treatment Phase
Down Syndrome ADHD Drug: Quillivant XR Drug: Placebos Phase 1 Phase 2

Detailed Description:

The purpose of this study is to conduct a small pilot clinical trial of stimulant medication treatment (i.e., methylphenidate (MPH)) in children with DS+ADHD to inform sample size estimates and power calculations for a larger clinical trial. In sum, this study will directly address issue related to under-utilization of stimulant treatment in children with DS+ADHD, and it has the potential to significantly improve the outcomes of approximately 45,000 children with DS+ADHD nationwide.

To achieve this, 30 children with DS+ADHD, between the ages of 6.00-17.99 years, will be invited to participate in a pilot clinical trial across two sites. Following pre-screening to determine study eligibility, children with DS+ADHD will be assessed at 14 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 pilot 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 height and weight. Weekly diagnostic and health assessments will be conducted to monitor the safety and efficacy of MPH during this phase. Further, this weekly monitoring will ultimately guide the selection of the participant's optimal dose. At the seventh visit, participants will enter Phase 2 of the pilot 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 pilot 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 six-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 31) will include diagnostic, behavioral, cognitive, functioning, and health assessments to evaluate change across time.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description: Phase 1 is a Sequential model, Phase 2-3 is a Crossover model, Phase 4 is a Single-Group model.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluating Assessment and Medication Treatment of ADHD in Children With Down Syndrome
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Down Syndrome

Arm Intervention/treatment
Active Comparator: Quillivant XR
Once-daily, long-lasting MPH solution with the following dosing schedules: 10mg/20mg/30mg/40mg for children 20-25kg, 20mg/30mg/40mg/50mg for children 26-30kg, and 20mg/33mg/46mg/60mg for children > 30 mg.
Drug: Quillivant XR
Long-lasting liquid solution of Quillivant XR.

Placebo Comparator: Placebo
Liquid-based suspension to match the color and banana-flavor of Quillivant XR.
Drug: Placebos
Liquid solution to mimic the color and taste of Quillivant XR.




Primary Outcome Measures :
  1. Change from baseline in ADHD Symptoms as measured by parent and teacher report on the Vanderbilt ADHD Parent and Teacher Rating Scales. [ Time Frame: Baseline, Weeks 1-7, Weeks 11, 16, 19, 23, 27, 31 ]
    A 49-item parent-report measure used to assess parents 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.

  2. Change from baseline in heart rate as measured by an electrocardiogram performed at standard amplitude and speed (10mm/mV and 25mm/sec). [ Time Frame: Baseline, Weeks 1-7, Week 11, Week 31 ]
    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.

  3. Change from baseline in PR interval as measured by an electrocardiogram performed at standard amplitude and speed (10mm/mV and 25mm/sec). [ Time Frame: Baseline, Weeks 1-7, Week 11, Week 31 ]
    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.

  4. Change from baseline in QTc interval as measured by an electrocardiogram performed at standard amplitude and speed (10mm/mV and 25mm/sec). [ Time Frame: Baseline, Weeks 1-7, Week 11, Week 31 ]
    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.


Secondary Outcome Measures :
  1. Change in ADHD-symptom severity as measured by parent report and clinical observation on the Clinician Global Impression Severity and Improvement Scales. [ Time Frame: Baseline, Weeks 1-7, Week 31 ]
    The CGI is a single-item, 7-point Likert-rating scale designed to measure symptomatic severity and change at a specific time as compared to baseline. The CGI-Severity Scale ranges from 1-7, with lower scores indicating better outcomes (1 = Normal, not at all ill; 2 = Minimally ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; 7 = Very severely ill). The CGI-Improvement Scale ranges from 1-7, with higher scores indicating better outcomes (1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = Unchanged; 5 = Slightly worse; 6 = Much worse; 7 = Very much worse). Data will be entered into SPSS to evaluate improvement across time.

  2. Change in child behaviors from baseline as measured by parent and teacher report on the Aberrant Behavior Checklist - Community (ABC). [ Time Frame: Baseline, Week, Week 7, Week 31 ]
    A 58-item measure completed by parents and teachers to assess symptoms of problem behaviors, specifically features of social withdrawal, irritability, inappropriate speech, hyperactivity, and stereotypies. Each item is scored on a 0-3 scale (0 = Not at all a Problem; 1 = The behavior is a problem, but slight in degree; 2 = The problem is Moderately serious; 3 = The problem is severe in degree). Scoring yields T-scores for 5 sub-scales, with lower scores meaning better outcomes. Data will be entered into SPSS and used as a behavioral outcome measure.

  3. Change in child behaviors from baseline as measured by parent and teacher report on the Achenbach Child Behavior Checklist (CBCL). [ Time Frame: Baseline, Week 6, Week 7, Week 31 ]
    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.

  4. Change in executive-functioning skills from baseline as measured by parent and teacher report on the Behavior Rating Inventory of Executive Function - 2 (BRIEF-2). [ Time Frame: Baseline, Week 6, Week 7, Week 31 ]
    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.


Other Outcome Measures:
  1. Change in parental stress from baseline as measured by parent report on the Family Impact Questionnaire (FIQ). [ Time Frame: Baseline, Week 6, Week 7, Week 31 ]
    A 50-item parent report measure designed to measure parental stress beyond the stress of raising a child with a developmental disability, specifically how the child positively and negatively impacts parenting, social relationships, finances, and as applicable, siblings, and marriage.Each of the first 48 items are scored 1-4 (1 = Not at all; 2 = Somewhat; 3 = Much; 4 = Very much), and items 48 and 49 are scored 1-7 (1 = Much easier; 2 = Easier; 3 = Slightly easier; 4 = About the same; 5 = Slightly more difficult; 6 = More difficult; 7 = Much more difficult). Five items on the measure are reverse scored. Scoring yields T-scores for 7 sub-scales, with lower scores indicating better outcomes. Data will be entered into SPSS and used as a parental stress outcome measure.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Documented diagnosis of DS through genetic testing
  • Ages 6.00-17.99 years
  • English is primary language
  • Meet criteria for ADHD on the KSADS
  • Meet criteria for ADHD on Vanderbilt (historically or currently)

Exclusion Criteria:

  • Current ADHD stimulant or non-stimulant medication treatment
  • Nonverbal mental age of at least 36 months (3 years) per parent report
  • Diagnosis of psychosis or bipolar disorder
  • Organic brain injury: history of head trauma with loss of consciousness, epilepsy, or any other organic disorder that could affect brain function
  • Banana allergy (due to bananas serving as an ingredient in the study medication)
  • QTC on baseline ECG>470ms in patients without cardiac surgery; QTC> 500 in patients with repaired CHD
  • Brugada pattern as determined by ECG
  • Complete AV block as determined by ECG
  • WPW/pre-ventricular excitation as determined by ECG
  • Right ventricular enlargement/right axis deviation as determined by ECG
  • Intraventricular conduction delay>120ms>12 years or >100ms < 8 years as determined by ECG
  • Right or left bundle branch block as determined by ECG
  • Atrial, junctional, or ventricular tachyaarhythmias as determined by ECG
  • Frequent PVCs or PACs as determined by ECG
  • Abnormal T waves with inversion in V5V6, bizarre T wave morphology, notched biphasic, ST segment depression suggesting ischemia or inflammation as determined by ECG
  • History of aborted sudden cardiac death or unexplained syncope as determined by medical history
  • History of single ventricle as determined by medical history
  • Moderate or greater AV valve regurgitation as determined by ECHO
  • Moderate or greater ventricular dysfunction as determined by ECHO
  • Pulmonary hypertension, designed as a mean pulmonary arterial pressure or right ventricular pressure without right ventricular outflow tract obstruction > 25mmHG as determined by ECHO
  • Use of pacemaker
  • Baseline heart rate or systolic blood pressure > 2 SD above mean for age
  • Positive pregnancy test

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04219280


Contacts
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Contact: Catelyn Shipp, BS 513-517-7015 ext 77015 Catelyn.Shipp@cchmc.org

Locations
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United States, California
University of California Davis MIND Institute
Sacramento, California, United States, 95817
Contact: Danielle Harris, BS    916-703-0484 ext 30484    dnharris@ucdavis.edu   
Principal Investigator: Kathleen Angkustsiri, MD         
Sub-Investigator: Leonard Abbeduto, PhD         
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Contact: Catelyn Shipp, BS    513-517-7015 ext 77015    Catelyn.Shipp@cchmc.org   
Contact: Emily Hoffman, MEd    513-803-3641 ext 33641    Emily.Hoffman1@cchmc.org   
Principal Investigator: Anna Esbensen, PhD         
Principal Investigator: Tanya Froehlich, MD         
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
University of California, Davis
Investigators
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Principal Investigator: Anna Esbensen, PhD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Tanya Froehlich, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Kathleen Angkustsiri, MD University of California Davis MIND Institute

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT04219280    
Other Study ID Numbers: 2019-1016
First Posted: January 7, 2020    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

The research team will enter information in the clinical trial record at least once per year, and will enter the results of the primary outcomes within one year of the completion of the trial.

The dataset generated and shared will include de-identified demographic information, parent- and teacher-rating scales, side effects and vital signs, cardiac monitoring, and blinded clinical global impressions. The dataset will include all composite variables and scores, with no identifying information included. The data and associated documentation will be made available to users only under a data sharing agreement.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame:

Due to the nature of data collection in a blinded randomized clinical trial, data will be made available upon completion of sampling and primary analyses. Data will also be archived in accordance with the scientific journals in which reports from the project are published.

Prior to publication, findings from the project will be shared broadly at conferences attended by professionals doing intervention work with the children with intellectual and developmental disabilities, and at scientific meetings attended by researchers focused on intellectual and developmental disabilities.

Access Criteria: Data will be shared at the completion of the project according to any and all NIH guidelines. Furthermore, data may be shared with colleagues at other sites in the future, but only under conditions specified by the IRBs at the participating universities and research sites, and in a manner consistent with written informed consent provided by the participants.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Down Syndrome
Syndrome
Disease
Pathologic Processes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Methylphenidate
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents