Guanfacine for Hyperactivity in Children With Down Syndrome (HYPEbeGONE_DS)

The purpose of this study is to determine efficacy of guanfacine immediate release (GIR) for the treatment of hyperactivity/impulsivity and inattention in children 6-12 years of age with Down syndrome (DS) after 8 weeks of treatment.

This is a randomized, double-blind, placebo-controlled flexibly dosed trial of guanfacine immediate release (GIR) in children with Down syndrome (DS) and symptoms of hyperactivity, inattention, and impulsivity. Participants will undergo a screening period of up to 29 days. Eligible participants meeting study criteria will be randomized 2:1 GIR or placebo. There are a total of up to 4 in person visits (screening, baseline, at Week 4, and at Week 8). Participants will receive GIR or placebo for up to 8 weeks. Weekly dose escalation will be determined via a telephone assessment at Weeks 1-3 and Weeks 4-7. Unmasking of participant and site staff will occur at the week 8, in-person visit. After unmasking, participants who were randomized to receive GIR will be given the option to 1) remain on GIR and to transition to open-label GIR per standard of care or 2) taper off of GIR. A Telephone Safety Assessment will be conducted for all participants, at 5 (+2) days after final study product administration. Blood specimens will be collected at the Week 4 and Week 8 visits for Pharmacokinetic (PK) analyses and lab assessments. Participants will be asked to keep a daily study diary and will complete study measures at screening/baseline, Week 4 and Week 8. Parents/Caregivers will need to complete the Study Diary during the bridge/taper period for those who are in the GIR arm.

Eligibility Criteria:
Inclusion:

1. Parent/Legal Guardian can understand the consent process and is willing to provide informed consent/HIPAA authorization prior to the conduct of any study-related procedures. When applicable, the minor participant is willing to provide assent.
2. Participant has clinical diagnosis of non-mosaic DS.
3. Participant is between 6 and 12 years of age (inclusive) at time of consent.
4. Participant weight is ≥ 25 kg.
5. Participant has clinically significant symptoms of hyperactivity, inattention and impulsivity manifested as minimum scores of the following rating scales within 30 days of randomization:

   1. A minimum score of 18 on the parent-reported ABC-H subscale, AND
   2. A minimum score of moderate or greater (≥ 4) on the clinician reported Clinical Global Impression Severity (CGI-S) score specific to hyperactivity, inattention and impulsivity behaviors.
6. Participant has co-morbid medical screening and clearance to proceed with a non-stimulant medication trial with GIR within 30 days of randomization.
7. Participant is willing and able to comply with study procedures, including adherence to medication dosing schedule.

Exclusion:

1. Participant has received guanfacine (any formulation) within 30 days of randomization.
2. Participant has received any of the following concomitant medication classes within 30 days of randomization:

   1. Strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole)
   2. Strong CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St. John's wort)
3. Participant has a psychiatric comorbidity, such as major depressive disorder, bipolar disorder, obsessive-compulsive disorder, or a psychotic disorder, that requires a pharmacological treatment other than guanfacine
4. For participants ≥ 8 years old at the time of consent, participant has a history of suicidality or positive screen on Ask Suicide-Screening Questions (asQ) Tool.
5. Participant is currently in or plans to participate in another interventional study.
6. Participant has a known hypersensitivity to guanfacine.
7. Participant has had a previous guanfacine treatment failure, as determined by their primary treating physician.
8. Participant has had a change in another medication intended to treat symptoms of hyperactivity, inattention, and impulsivity within the last 2 weeks.
9. Participant has had a seizure within the last 6 months.
10. Participant has had a change in their anti-convulsant dose within the last 4 weeks.
11. Participant has a cardiac-related condition including:

    1. Significant symptomatic bradycardia;
    2. 2nd degree or 3rd degree (complete) heart block;
    3. Baseline heart rate (HR) or systolic blood pressure (BP) \> 2 standard deviations (SD) below mean for age as determined by medical examination;
    4. History of aborted sudden cardiac death, unexplained syncope or near syncope, or historical use of a pacemaker as determined by medical history will require clearance by cardiology prior to enrollment;
    5. Known history of congenital heart disease which requires ongoing care for monitoring or management will require clearance by cardiology prior to enrollment.
12. Participant has a history of untreated severe obstructive sleep apnea defined as obstructive apnea hypopnea index (OAHI) ≥ 10 events per hour or aortic regurgitation (AR). Participants with an OAHI index \> 10/hr are eligible if managed with continuous positive airway pressure (CPAP).
13. Participant has untreated thyroid disease.
14. Participant has a known hepatic impairment defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2x the upper limit of normal (ULN) for age.
15. Participant has known impending or renal failure defined as:

    1. Anuria diagnosed within 12 hours prior to enrollment;
    2. Requiring renal replacement therapy.
16. Participant is pregnant.
17. Participant has any condition which would make the participant, in the opinion of the investigator, unsuitable for the study.