Guanfacine for Hyperactivity in Down Syndrome

(HYP01 Trial)

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

60 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Guanfacine Hydrochloride Immediate Release for hyperactivity in Down Syndrome?

Research shows that guanfacine, particularly in its extended-release form, is effective in reducing symptoms of hyperactivity and inattention in children and adolescents with ADHD. This suggests it might also help with similar symptoms in individuals with Down Syndrome. ^{1 2 3 4 5}

Is guanfacine safe for humans?

Guanfacine, used for conditions like ADHD, has been generally safe in humans, but some people experience side effects like drowsiness, headache, and fatigue. It can cause mild changes in heart rate and blood pressure, so monitoring is recommended, especially for those with heart issues. ^{1 2 4 6 7}

How is the drug Guanfacine Hydrochloride Immediate Release unique for treating hyperactivity in Down Syndrome?

Guanfacine Hydrochloride Immediate Release is unique because it is a centrally acting α2-adrenergic agonist, which means it works by affecting certain receptors in the brain to help reduce hyperactivity and impulsivity. This mechanism is different from other treatments for hyperactivity, which may not target these specific brain receptors. ^{1 5 6 8 9}

Research Team

Rachel Greenberg

Principal Investigator

DCRI

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

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]

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]

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]

References

1. Spain pubmed.ncbi.nlm.nih.gov

Guanfacine extended release in the treatment of attention deficit hyperactivity disorder in children and adolescents. [2017]

2. New Zealand 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. [2022]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy of guanfacine extended release in the treatment of combined and inattentive only subtypes of attention-deficit/hyperactivity disorder. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of guanfacine extended release in children and adolescents with ADHD. [2018]

7. United States 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. [2021]

8. Canada pubmed.ncbi.nlm.nih.gov

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

9. United States pubmed.ncbi.nlm.nih.gov

An overdose of extended-release guanfacine. [2013]