Guanfacine for Hyperactivity in Down Syndrome

(HYP01 Trial)

Not currently recruiting at 14 trial locations

Overseen By Christie Milleson

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Rachel G. Greenberg, MD, MB, MHS

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Psychiatric disorders, Cardiac conditions, Seizures, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether guanfacine, a medication, can reduce hyperactivity, impulsivity, and inattention in children with Down syndrome. Researchers aim to determine the treatment's effectiveness after eight weeks. Participants will be divided into two groups: one receiving guanfacine and the other a placebo (a non-active treatment for comparison). Suitable candidates have Down syndrome and noticeable issues with hyperactivity and inattention. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong CYP3A4 inhibitors and inducers, at least 30 days before starting the study. If you are on medications for hyperactivity, inattention, or impulsivity, you should not have changed them in the last 2 weeks before joining the trial.

Is there any evidence suggesting that guanfacine hydrochloride immediate release is likely to be safe for humans?

Research has shown that guanfacine immediate release (GIR) is generally safe for children with Down syndrome. Studies found that about half of these children responded well to guanfacine for treating ADHD symptoms. Many used the medication long-term without major problems.

Few patients experienced side effects, indicating that negative reactions were rare. Overall, based on previous studies, the medication appears safe for this group. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for hyperactivity in Down syndrome?

Unlike the standard treatments for hyperactivity in Down syndrome, which often include behavioral therapies and medications like stimulants or non-stimulant options such as atomoxetine, guanfacine hydrochloride immediate release (GIR) works differently. GIR is unique because it targets specific receptors in the brain, known as alpha-2 adrenergic receptors, which help in reducing hyperactivity and improving focus without the stimulant effects. Researchers are excited about GIR because it offers a potential new approach with a different mechanism of action, providing an alternative for those who may not respond well to current medications. Additionally, the immediate-release formulation of guanfacine could allow for more flexible dosing and potentially quicker results.

What evidence suggests that guanfacine might be an effective treatment for hyperactivity in Down syndrome?

Research shows that guanfacine, a medication often used for ADHD, may help manage hyperactivity and inattention. Studies have found that guanfacine affects brain areas related to attention and impulse control, which can be challenging for children with Down syndrome. While most research focuses on its extended-release form, the immediate-release version, which participants in this trial may receive, is expected to offer similar benefits. Evidence suggests that non-stimulant medications like guanfacine can effectively reduce hyperactivity symptoms. These findings support the potential of guanfacine immediate release to help children with Down syndrome manage hyperactive behaviors. ^{2 3 6 7 8}

Who Is on the Research Team?

Rachel Greenberg

Principal Investigator

DCRI

Are You a Good Fit for This Trial?

This trial is for children aged 6-12 with Down syndrome who are hyperactive or impulsive. They must weigh at least 25 kg and have a certain level of severity in their symptoms as reported by parents and clinicians. Participants should not have taken guanfacine or strong CYP3A4 inhibitors recently.

Inclusion Criteria

I weigh at least 25 kg.

I have significant symptoms of ADHD as confirmed by recent tests.

I have been diagnosed with Down syndrome that is not mosaic.

Exclusion Criteria

I have taken guanfacine in the last 30 days.

Participant has received any of the following concomitant medication classes within 30 days of randomization: Strong CYP3A4 inhibitors, Strong CYP3A4 inducers, Participant has a psychiatric comorbidity 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, 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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive guanfacine immediate release (GIR) or placebo for up to 8 weeks with weekly dose escalation determined via telephone assessment

8 weeks

4 visits (in-person), 6 visits (telephone)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a Telephone Safety Assessment 5 days after final study product administration

1 week

1 visit (telephone)

Open-label extension (optional)

Participants who received GIR may opt to remain on GIR and transition to open-label GIR per standard of care or taper off

What Are the Treatments Tested in This Trial?

Interventions

• Guanfacine Hydrochloride Immediate Release

Trial Overview The study tests if Guanfacine Hydrochloride Immediate Release (GIR) can help manage hyperactivity/impulsivity and inattention over an 8-week period, compared to a placebo (a pill without any medicine).

How Is the Trial Designed?

Group I: Guanfacine Hydrochloride Immediate Release Active Control 1 Intervention

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.

Group II: Placebo Placebo Group 1 Intervention

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.

Guanfacine Hydrochloride Immediate Release is already approved in United States, European Union for the following indications:

Approved in United States as Tenex for:

• Hypertension
• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in United States as Intuniv for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Intuniv for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Paxneury for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Who Is Running the Clinical Trial?

Rachel G. Greenberg, MD, MB, MHS

Lead Sponsor

Trials

1

Recruited

60+

The Emmes Company, LLC

Industry Sponsor

Trials

149

Recruited

1,052,000+

Peter Ronco

The Emmes Company, LLC

Chief Executive Officer since 2023

BSc from Nottingham University

Dr. Joe Sliman

The Emmes Company, LLC

Chief Medical Officer since 2020

MD from Uniformed Services University of the Health Sciences, MPH from Johns Hopkins University, BSc in Molecular and Cell Biology from Pennsylvania State University

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

In a long-term study of 191 adults with ADHD, guanfacine extended-release (GXR) was found to be safe, with most treatment-emergent adverse events (TEAEs) being mild to moderate, and only 19.9% of patients discontinuing due to TEAEs.

Significant improvements in ADHD symptoms, quality of life, and executive functioning were observed after 50 weeks of GXR treatment, indicating its efficacy as a long-term management option for adults with ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study. Iwanami, A., Saito, K., Fujiwara, M., et al.[2022]

A 12-year-old boy experienced significant toxicity after ingesting three times his usual dose of extended-release guanfacine, leading to prolonged hypertension and subsequent episodes of hypotension, highlighting the drug's potential risks.

The case emphasizes the need for emergency physicians to recognize and manage the unique and prolonged effects of toxicity associated with centrally acting α2-adrenergic agonists like guanfacine, especially as its use for ADHD increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overdose of extended-release guanfacine. Fein, DM., Hafeez, ZF., Cavagnaro, C.[2013]

In a phase 3 safety study of guanfacine extended release (GXR) involving 215 children and adolescents with ADHD, the treatment was well tolerated, with 82.7% experiencing some treatment-emergent adverse events, primarily somnolence and headache.

GXR significantly reduced ADHD symptoms over the 2-year study, with a mean decrease of 19.8 points in the ADHD-RS-IV total score, indicating its efficacy in managing ADHD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of guanfacine extended release in children and adolescents with ADHD. Huss, M., Dirks, B., Gu, J., et al.[2018]

In a study involving 217 children aged 6-12 with ADHD and oppositional symptoms, guanfacine extended release (XR) significantly reduced oppositional behaviors and ADHD symptoms compared to placebo, with effect sizes of 0.59 and 0.92, respectively.

The treatment was generally safe, with most adverse events being mild to moderate, such as somnolence and headache, and most side effects resolved before the end of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial. Connor, DF., Findling, RL., Kollins, SH., et al.[2022]

In a 9-week study involving 461 children and adolescents with ADHD, guanfacine extended release (GXR) significantly improved ADHD symptoms when added to a stable dose of psychostimulants, outperforming placebo.

GXR treatment did not introduce new safety concerns, with most adverse events being mild to moderate, and showed only small decreases in blood pressure and pulse, indicating it is a safe adjunctive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder. Wilens, TE., Bukstein, O., Brams, M., et al.[2022]

Guanfacine extended-release (GXR) has been shown to be an effective treatment for ADHD in children aged 6-12, outperforming placebo in all randomized controlled trials reviewed.

However, GXR did not demonstrate efficacy in adolescents, and while adverse effects were generally mild to moderate, there were high rates of early discontinuation in long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focus on Guanfacine Extended-release: A Review of its Use in Child and Adolescent Psychiatry. Elbe, D., Reddy, D.[2021]

Extended-release guanfacine (Intuniv) significantly improves symptoms of inattention and hyperactivity-impulsivity in children and adolescents with ADHD, with effective doses ranging from 1 to 4 mg/day compared to placebo.

While GXR does not cause significant ECG changes, it can lead to mild heart rate slowing and lower blood pressure, necessitating monitoring of vital signs, especially in children with a history of cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guanfacine extended release in the treatment of attention deficit hyperactivity disorder in children and adolescents. Connor, DF., Rubin, J.[2017]

In a post-hoc analysis of two pivotal trials involving 631 children and adolescents with ADHD, extended-release guanfacine (GXR) significantly reduced core ADHD symptoms, particularly in those with predominantly inattentive and combined types, compared to placebo.

GXR treatment led to greater reductions in hyperactivity-impulsivity and inattentiveness scores across all randomized dose groups, supporting its efficacy as a treatment for ADHD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of guanfacine extended release in the treatment of combined and inattentive only subtypes of attention-deficit/hyperactivity disorder. Sallee, FR., Kollins, SH., Wigal, TL.[2021]

Guanfacine, an alpha-2A adrenergic agonist used for ADHD, was found to prolong QTc intervals at both therapeutic and supratherapeutic doses, but it also demonstrated a stabilizing effect on cardiac restitution, reducing the risk of arrhythmias.

In a study of 60 healthy subjects, guanfacine reduced the QT/TQ ratio, indicating a protective effect on heart rhythm, while a comparator drug, moxifloxacin, showed a trend toward increased arrhythmia risk, highlighting guanfacine's unique safety profile despite QT prolongation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ECG restitution (beat-to-beat QT-TQ interval analysis) to assess arrhythmogenic risk of QTc prolongation with guanfacine. Fossa, AA., Zhou, M., Robinson, A., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06042257?cond=NCT06042257&rank=1

Guanfacine for Hyperactivity in Children With Down ... This is a randomized, double-blind, placebo-controlled flexibly dosed trial of guanfacine immediate release (GIR) in children with Down syndrome (DS) and ...

2. pediatrictrials.org pediatrictrials.org/hyp01study/

Guanfacine for Hyperactivity in Children With Down ... This study aims to investigate how Guanfacine Immediate Release (GIR) affects children with DS who have hyperactivity/ADHD and inattention.

3. waisman.wisc.edu waisman.wisc.edu/2025/06/04/guanfacine-for-hyperactivity-in-children-with-down-syndrome-stanley/

Guanfacine for Hyperactivity in Children with Down ... The purpose of this research study is to learn more about how guanfacine immediate release (abbreviated as GIR) acts in the bodies of children ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4494608/

Clinical utility of guanfacine extended release in the treatment ... The XR formulation of guanfacine, compared with the immediate-release formulation, is more effective for the long-term management of ADHD and is associated with ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S016372582100142X

Evidence-based pharmacological treatment options for ... The non-stimulants atomoxetine, clonidine and guanfacine have been shown to be efficacious in treating ADHD, but their effect sizes compared to placebo are ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38483962/

Guanfacine for the Treatment of Attention-Deficit ... Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26936058/

Guanfacine Use in Children With Down Syndrome and ... Medication was generally well tolerated and the incidence of treatment emergent side effects remained low. Keywords: Alpha2a-adrenergic agonist; Down syndrome; ...

8. kennedykrieger.org kennedykrieger.org/research/participate-in-research/down-syndrome-studies/guanfacine-for-hyperactivity-in-children-with-down-syndrome

Guanfacine for Hyperactivity in Children with Down ... This research study is being conducted to determine the efficacy of guanfacine immediate release (GIR) for the treatment of hyperactivity/impulsivity and ...