Propranolol for Congenital Heart Disease

Recruiting at 2 trial locations

Overseen By Rashida Blackwood, BS, MPH

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Weill Medical College of Cornell University

Must not be taking: Propranolol interactions

Disqualifiers: Congenital AV block, Asthma, others

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 2-8 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Heart failure is a common long-term complication in patients with congenital heart disease (CHD). Medical treatments to promote regeneration of new healthy heart muscle cells have the potential to provide new heart failure treatments for these patients. The development of such therapies is limited by the poor understanding of the ways in which heart muscles grow after birth. Investigators have learned that humans without heart disease generate new heart muscles cells up to the age of 20 years old and that this is decreased in patients with congenital heart disease like Tetralogy of Fallot. Investigators are trying to determine if treatment with a medicine called Propranolol can increase heart muscle cell proliferation and, with that, normalize heart growth. Investigators will examine discarded heart muscle tissue that is obtained during surgery for the presence of new heart muscle cells. Propranolol is approved by the Food and Drug Administration (FDA) to treat a certain kind of benign tumor in infants (hemangioma), but it is not currently approved by the FDA to increase heart muscle growth.

Will I have to stop taking my current medications?

The trial requires that participants do not take medications that interact with propranolol. If you are on such medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Propranolol Hydrochloride for Congenital Heart Disease?

Propranolol has shown significant benefits in treating heart failure in children with congenital heart disease, improving heart function and reducing symptoms without serious side effects. Additionally, it is effective in treating infantile hemangiomas, indicating its safety and efficacy in pediatric use. ^{1 2 3 4 5}

Is propranolol generally safe for humans?

Propranolol has been widely used since the 1960s and is generally considered safe, but it can cause some side effects like bradycardia (slow heart rate). It has been safely used for conditions like infantile hemangiomas, but potential side effects should be monitored. ^{2 4 6 7 8}

How does the drug propranolol differ from other treatments for congenital heart disease?

Propranolol is unique for congenital heart disease as it is a beta-blocker that helps manage heart failure symptoms by improving heart function and reducing stress on the heart, unlike traditional treatments like digoxin and diuretics, which lack strong evidence from randomized trials. It is administered with careful dosage adjustments based on heart rate, making it a tailored approach for infants with severe heart failure. ^{2 3 4 5 9}

Research Team

Bernhard Kuhn, MD

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

This trial is for male and female infants under 45 days old with specific heart conditions (Tetralogy of Fallot or double outlet right ventricle) who weigh over 2 kg and can tolerate feeding by mouth. It's not for babies born before 35 weeks, those with certain EKG results, on medications that affect propranolol, have diabetic mothers, respiratory issues, or metal implants.

Inclusion Criteria

My infant has a specific heart condition, is under 45 days old, weighs more than 2 kg, and can tolerate feeding.

My condition is diagnosed as DORV.

Exclusion Criteria

You are less than 35 weeks pregnant.

My child was born to a diabetic mother or has asthma or another respiratory condition.

My infant has a metal implant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Propranolol or placebo starting at 1 month of age until surgical repair, which occurs at 3-9 months of age

2-8 months

Regular monitoring visits as per protocol

Surgical Intervention

Surgical repair of Tetralogy of Fallot, during which heart muscle tissue is collected for analysis

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment and surgery

4 weeks

Treatment Details

Interventions

• Propranolol Hydrochloride

Trial Overview The study tests if Propranolol can help grow new heart muscle cells in infants with congenital heart disease. It involves a comparison between Propranolol and a placebo while monitoring through cardiac MRI, echocardiograms, urine collection, physical exams and specimen collection from surgery.

Participant Groups

Group I: Propranolol Active Control 7 Interventions

The target dose of Propranolol hydrochloride for this study target dose for this study will be 4 mg/kg/day divided in 4 doses. The concentration of propranolol solution is 20 mg/5 mL. Additionally, labeled syringes will be provided to families for accurate weight-based dosing. Treatment with propranolol will begin at 1 month of age and continue until surgical repair, which happens usually at 3 - 9 months of age.

Group II: Placebo Placebo Group 7 Interventions

Placebo will be given in a volume that corresponds to the patient's weight. Additionally, labeled syringes will be provided to families for accurate weight-based dosing. Treatment with placebo will begin at 1 month of age and continue until surgical repair, which happens usually at 3 - 9 months of age. There is no current standard of care for pharmacologic therapy for infants with ToF. As such, there are no alternative treatments, and the placebo group is standard of care.

Propranolol Hydrochloride is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Inderal for:

• Hypertension
• Angina pectoris
• Arrhythmias
• Migraine prophylaxis
• Performance anxiety

Approved in European Union as Inderal for:

• Hypertension
• Angina pectoris
• Arrhythmias
• Migraine prophylaxis
• Performance anxiety

Approved in Canada as Inderal for:

• Hypertension
• Angina pectoris
• Arrhythmias
• Migraine prophylaxis
• Performance anxiety

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Bernhard Kuhn

Lead Sponsor

Trials

1

Recruited

40+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 22 infants with congestive heart failure due to pulmonary overcirculation, those treated with Propranolol showed significantly better clinical outcomes, including lower heart failure scores and shorter hospital stays compared to those treated with Captopril.

Propranolol also resulted in improved heart function, as indicated by lower left atrial and end-diastolic ventricular pressures, while Captopril did not effectively suppress angiotensin converting enzyme levels at the doses used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of low dose captopril versus propranolol therapy in infants with severe congestive failure due to left-to-right shunts. Buchhorn, R., Ross, RD., Hulpke-Wette, M., et al.[2019]

The study analyzed data from the Canadian Adverse Drug Reaction Monitoring Program to assess the potential link between propranolol hydrochloride and bradycardia, finding that the signals for bradycardia were not statistically significant despite some high calculated statistics.

Although the results did not confirm a strong association between propranolol and bradycardia, the authors suggest that further investigation using larger databases is warranted due to the observed trends.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic class-specific signal detection of bradycardia associated with propranolol hydrochloride. Gavali, DK., Kulkarni, KS., Kumar, A., et al.[2021]

In a study of 70 patients with coronary heart disease (CHD) experiencing angina attacks, the combination of propranolol and syndnopharm therapy resulted in a positive clinical effect for 83.6% of patients.

The combination therapy also showed a positive change in ECG results for 64.2% of patients, suggesting enhanced efficacy, particularly for those who are intolerant to nitrates and do not have significant heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effectiveness of combined administration of obsidan and sidnofarm in patients with ischemic heart disease at a polyclinic]. Borisov, AV.[2013]

Propranolol hydrochloride is an effective treatment for infantile hemangiomas (IHs), showing significant reductions in volume, color, and elevation after 6 months of treatment in a study of 40 children aged 9 weeks to 5 years.

The treatment was safe, with no significant adverse effects like hypoglycemia or hypotension reported, and IH growth stopped within 4 weeks for those receiving propranolol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled trial of propranolol for infantile hemangiomas. Hogeling, M., Adams, S., Wargon, O.[2022]

In children with congenital heart disease, heart failure is prevalent in up to 20% of cases, necessitating effective medical therapy before or after surgery.

Propranolol has shown significant benefits in managing heart failure symptoms and improving heart function without serious side effects, making it a promising treatment option for infants with severe heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-Blockers in Children with Congenital Heart Disease Before a Corrective Procedure. Buchhorn, R.[2019]

Long-acting propranolol (Inderal LA) provides a controlled release of the medication, maintaining higher plasma concentrations over 24 hours compared to conventional tablets, which helps ensure consistent beta-adrenoceptor blockade.

This formulation is equally effective for treating conditions like angina pectoris, hypertension, and hyperthyroidism, while potentially improving patient adherence to treatment due to simplified dosing regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting propranolol (Inderal LA): pharmacokinetics, pharmacodynamics and therapeutic use. Mishriki, AA., Weidler, DJ.[2019]

In a study of 108 infants treated with oral propranolol for infantile hemangiomas, the medication was found to cause statistically significant but asymptomatic decreases in blood pressure and heart rate, indicating it is generally safe for use in this population.

No arrhythmias were detected during treatment, and while mild sleep disturbances were noted in some infants, overall heart rhythm and circadian patterns remained stable, suggesting that extensive monitoring may not be necessary for safety assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral propranolol for infantile hemangiomas: a prospective study on the role of 48-hour Holter monitoring in additional safety assessment. Petrovic, J., Trifunovic, B., Vukomanovic, G., et al.[2018]

In a study of 198 hospitalized patients, 10% experienced adverse reactions to practolol, primarily affecting cardiac function, with some reactions being life-threatening.

Practolol and propranolol showed similar rates of cardiovascular complications, but practolol was also associated with skin reactions, indicating a broader range of potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reactions to practolol in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program. Pfeifer, HJ., Greenblatt, DJ., Koch-Weser, J.[2019]

Topical propranolol hydrochloride gel was found to be effective and safe for treating superficial infantile hemangiomas, with 44.83% of patients showing good improvement and 13.79% achieving excellent results based on a study of 51 cases.

The treatment demonstrated significantly better responses in superficial hemangiomas compared to other types, indicating its targeted efficacy, with no adverse effects reported during the study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical propranolol hydrochloride gel for superficial infantile hemangiomas. Wang, L., Xia, Y., Zhai, Y., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Effectiveness of low dose captopril versus propranolol therapy in infants with severe congestive failure due to left-to-right shunts. [2019]

2. India pubmed.ncbi.nlm.nih.gov

Therapeutic class-specific signal detection of bradycardia associated with propranolol hydrochloride. [2021]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Effectiveness of combined administration of obsidan and sidnofarm in patients with ischemic heart disease at a polyclinic]. [2013]

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

A randomized controlled trial of propranolol for infantile hemangiomas. [2022]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Beta-Blockers in Children with Congenital Heart Disease Before a Corrective Procedure. [2019]

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

Long-acting propranolol (Inderal LA): pharmacokinetics, pharmacodynamics and therapeutic use. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Oral propranolol for infantile hemangiomas: a prospective study on the role of 48-hour Holter monitoring in additional safety assessment. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Adverse reactions to practolol in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program. [2019]

9. China pubmed.ncbi.nlm.nih.gov

Topical propranolol hydrochloride gel for superficial infantile hemangiomas. [2021]