Guanfacine for Hyperactivity in Children With Down Syndrome (HYPEbeGONE_DS)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Guanfacine for Hyperactivity in Children With Down Syndrome (HYPEbeGONE_DS)

Conditions
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Hyperactivity in Children With Down Syndrome, Impulsivity in Children With Down Syndrome

Intervention / Treatment
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* Drug: Guanfacine Hydrochloride Immediate Release
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion: 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. Participant has clinical diagnosis of non-mosaic DS. Participant is between 6 and 12 years of age (inclusive) at time of consent. Participant weight is ≥ 25 kg. Participant has clinically significant symptoms of hyperactivity, inattention and impulsivity manifested as minimum scores of the following rating scales within 30 days of randomization: A minimum score of 18 on the parent-reported ABC-H subscale, AND 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. Participant has co-morbid medical screening and clearance to proceed with a non-stimulant medication trial with GIR within 30 days of randomization. Participant is willing and able to comply with study procedures, including adherence to medication dosing schedule. Exclusion: Participant has received guanfacine (any formulation) within 30 days of randomization. Participant has received any of the following concomitant medication classes within 30 days of randomization: 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) Strong CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St. John's wort) 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 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. Participant is currently in or plans to participate in another interventional study. Participant has a known hypersensitivity to guanfacine. Participant has had a previous guanfacine treatment failure, as determined by their primary treating physician. Participant has had a change in another medication intended to treat symptoms of hyperactivity, inattention, and impulsivity within the last 2 weeks. Participant has had a seizure within the last 6 months. Participant has had a change in their anti-convulsant dose within the last 4 weeks. Participant has a cardiac-related condition including: Significant symptomatic bradycardia; 2nd degree or 3rd degree (complete) heart block; Baseline heart rate (HR) or systolic blood pressure (BP) > 2 standard deviations (SD) below mean for age as determined by medical examination; 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; Known history of congenital heart disease which requires ongoing care for monitoring or management will require clearance by cardiology prior to enrollment. 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). Participant has untreated thyroid disease. Participant has a known hepatic impairment defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2x the upper limit of normal (ULN) for age. Participant has known impending or renal failure defined as: Anuria diagnosed within 12 hours prior to enrollment; Requiring renal replacement therapy. Participant is pregnant. Participant has any condition which would make the participant, in the opinion of the investigator, unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 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: Parallel Assignment
Interventional Model Description: Participants will be randomized 2:1 to GIR or placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Guanfacine Hydrochloride Immediate Release<br>Eligible participants will receive GIR for up to 8 weeks. The treatment period will consist of study product administration from day 0 through day 56 with a masked dose-escalation period from day 0 through day 49. | Drug: Guanfacine Hydrochloride Immediate Release<br>* 0.5 mg capsules<br>|
| Placebo Comparator: Placebo<br>Eligible participants will receive Placebo for up to 8 weeks.The treatment period will consist of study product administration from day 0 through day 56 with a masked dose-escalation period from day 0 through day 49. | Drug: Placebo<br>* Matching placebo capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in parent-rated ABC-H (Aberrant Behavior Checklist-Hyperactivity) subscale core | Change from baseline to Week 8 of the ABC-H subscale score. The ABC-H is a subscale of the ABC. Each of the 16 items is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). The total score range is 0 to 48, where a higher score indicates endorsement of greater hyperactivity. Rating based on patient's behavior in last 4 weeks. | Baseline to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in parent-rated ABC-H (Aberrant Behavior Checklist-Hyperactivity) subscale core | Change from baseline to Week 4 of the ABC-H subscale score. The ABC-H is a subscale of the ABC. Each of the 16 items is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). The total score range is 0 to 48, where a higher score indicates endorsement of greater hyperactivity. Rating based on patient's behavior in last 4 weeks. | Baseline to Week 4 | 
| Proportion of participants with a CGI-I (Clinical Global Impression-Improvement) score of 2 or better at Week 4 | CGI-I specific to hyperactivity, inattention and impulsivity behaviors. The CGI-I is a seven-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. | Baseline to Week 4 | 
| Proportion of participants with a CGI-I (Clinical Global Impression-Improvement) score of 2 or better at Week 8 | CGI-I specific to hyperactivity, inattention and impulsivity behaviors. The CGI-I is a seven-point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. | Baseline to Week 8 | 
| Safety of GIR (guanfacine immediate release) | Number of participants with adverse events (AEs), serious adverse events (SAEs), or events of special interest (ESIs). | Baseline through Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperactivity, impulsivity, inattention