Clinical trial NCT04219280: Evaluating Treatment of ADHD in Children with Down Syndrome
Official title: Evaluating Assessment and Medication Treatment of ADHD in Children with Down Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Down Syndrome
ADHD
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: University of California, Davis
name: University of Pittsburgh Medical Center
name: Boston Children's Hospital, Boston, MA, USA
First posted: 2020-01-07
Enrollment: 100
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Phase 1 is a Sequential model, Phase 2-3 is a Crossover model, Phase 4 is a Single-Group model.
Primary purpose: TREATMENT

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.

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: 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.

Eligibility criteria: 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:

  1. QTc on baseline ECG\>470ms or QTC \> 500 in patients with repaired CHD, as determined by ECG
  2. Brugada pattern, as determined by ECG
  3. Baseline heart rate or systolic blood pressure \> 2 SD above mean for age as determined by medical examination.
  4. 2nd or 3rd degree AV block, as determined by ECG
  5. History of aborted sudden cardiac death or unexplained syncope as determined by medical history
  6. History of a single ventricle as determined by medical history
  7. Valvular regurgitation or stenosis \> mild, as determined by ECHO
  8. Moderate or greater ventricular dysfunction, as determined by ECHO
  9. Pulmonary hypertension, defined as right ventricular pressure \>33% systemic pressure or septal position consistent with \>mild right ventricular hypertension, as determined by ECHO
  10. Use of a pacemaker as determined by medical history
  11. Wolff Parkinson White/pre-ventricular excitation, as determined by ECG
  12. Atrial, junctional, or ventricular tachyarrhythmia, as determined by ECG
  13. Frequent premature ventricular contractions (PVCs) or premature atrial contractions (PACs), as determined by ECG
  14. 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
  15. Moderate or larger atrial septal defect, as determined by ECHO
  16. Ventricular septal defect \> small by ECHO
  17. Valvar stenosis \> mild by ECHO
  18. 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:

  1. Right ventricular enlargement/right axis deviation, as determined by ECG
  2. Intraventricular conduction delay \>120ms in child \>12 years old or \>100ms in child \<8 years old, as determined by ECG
  3. 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).

Primary outcomes:
measure: 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 ]
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
measure: 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 ]
timeFrame: Baseline, Week 12, Week 14, and Week 30
Secondary outcomes:
measure: 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 ]
timeFrame: Baseline, Week 12, Week 14, and Week 30
measure: 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 ]
timeFrame: Baseline, Week 12, Week 14, and Week 30
measure: 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].
timeFrame: Baseline, Week 8, Week 10, Week 22, and Week 30
measure: 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].
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
measure: 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].
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
measure: 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].
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
measure: 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].
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
measure: 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].
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
measure: Frequency of parent-rated MPH side effects
timeFrame: Baseline, Weeks 2-14, Weeks 18, 22, 26, and 30
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis MIND Institute
state: California
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Anna Esbensen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Tanya Froehlich, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California Davis MIND Institute
name: Kathleen Angkustsiri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Medical Center
name: Benjamin Handen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Sabrina Sargado, MD
role: PRINCIPAL_INVESTIGATOR
References: