Beta-blocker Administration for Cardiomyocyte Division

Mechanistic Clinical Trial of Beta-Blocker Administration For Reactivating Cardiomyocyte Division In Tetrology of Fallot

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.

Study Overview

• Status: Recruiting
• Conditions: Tetralogy of Fallot; Double Outlet Right Ventricle
• Intervention / Treatment: Other: N-thymidine; Other: Urine Collection; Procedure: Echocardiogram; Procedure: Cardiac MRI; Drug: Propranolol Hydrochloride; Procedure: Physical Exam; Other: Specimen Collection; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Shannon Janzef, MSN, RN, CBC; Phone Number: 412.692.5760; Email: janzefs@upmc.edu
• Study Contact Backup: Name: Elizabeth Hartigan, RN; Phone Number: 412-692-7060; Email: elizabeth.hartigan@chp.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • UPMC Children's Hospital of Pittsburgh
      • Contact: Shannon Janzef, MSN, RN, CBC; Phone Number: 412-692-5760; Email: janzefs@upmc.edu
      • Contact: Elizabeth Hartigan, RN; Phone Number: 4126927060; Email: elizabeth.hartigan@chp.edu
      • Principal Investigator: Bernhard Kuhn, MD
      • Sub-Investigator: Philip Adams, MD
      • Sub-Investigator: Adam Christopher, MD
      • Sub-Investigator: Tarek Alsaied, MD
      • Sub-Investigator: Jennifer Johnson, DO
      • Sub-Investigator: Laura Olivieri, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 month (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female infants < 45 days of age with a diagnosis of tetralogy of Fallot with pulmonary stenosis or double outlet right ventricle, tetralogy type by echocardiogram, who weigh greater than 2 kg at the time of consent and are tolerating enteral feeds.
• DORV variant

Exclusion Criteria:

• congenital atrio-ventricular block on EKG (PR interval > 120 ms),
• concomitant medication administration that interacts with propranolol,
• patient family is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason,
• gestation age < 35 weeks,
• infants of diabetic mothers, asthma or underlying respiratory disease,
• presence of metal implants in infants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Propranolol; 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.	Other: N-thymidine; 15N-thymidine will be administered to patients in order to quantify cardiomyocyte proliferation. 15N-thymidine will be administered as 5 separate syringes. Each syringe will contain the recommended daily dose based on participants weight. Subjects will be given the labeled thymidine by mouth once a day for 5 consecutive days. The dosing will begin one week after starting the study drug.The caregiver (parent or nurse) will administer the labeled thymidine by mouth via a syringe once a day for 5 consecutive days. They will be provided with a diary to keep track of study drug dosing.; Other Names: Thymidine; Other: Urine Collection; Parents will be asked to keep a diary of the child's feeding and diaper changes during the administration of thymidine. To monitor how the labeled thymidine is processed in the body, investigators will analyze urine from the child's diapers. Each time a diaper is changed, a cotton ball will be placed in the diaper. At the next diaper change, this cotton ball will be removed from the diaper, placed in a Ziploc bag, and stored in the freezer. They will be collected and stored cotton balls starting with the first administration of thymidine until 24 hours after the last administration. The frozen cotton balls may be collected from the home by a nurse or brought by parent to the next clinic visit.; Procedure: Echocardiogram; On Study Day 1 to obtain baseline assessment of cardiac size. A second research dedicated echocardiogram will be done after being anesthetized for surgery. Echocardiography is routinely performed to determine right ventricle (RV) structure of the heart and function in ToF/PS and is non-invasive.; Procedure: Cardiac MRI; A limited study protocol will be performed using the feed-and-bundle technique at the time of study enrollment, The feed and bundle technique is utilized so that the infant will be as comfortable as possible and asleep during the procedure. This is done to prevent the risk of sedation and allow for a more natural sleep. The baby is undressed, prepared with ECG-leads and an oxygen saturation probe, and fed. With this "feed, swaddle, and sleep" technique, scanning times of 30-60 minutes can be achieved, which provides the stillness needed for accurate visualization of the heart. A second CMR, with the same limited study protocol, will be performed under general anesthesia prior to surgical repair. It does not pose any risk of radiation exposure and will not require IV placement or contrast administration for a limited assessement of the right ventricle.; Drug: Propranolol Hydrochloride; For patients who are randomized to receive propranolol, The target dose for this study will be 4 mg/kg/day divided in 4 doses. The first dose will be given in the Pediatric Clinical and Translational Research Center (PCTRC) at 1mg/kg. Parents will administer propranolol (1 mg/kg po x 4 doses per day). Parents will be instructed to administer propranolol with feeding or soon after feeding, but not before feeding. families will also be given instructions for regarding 15N-thymidine dosing frequency and interval and provided with a log sheet to record administered and missed doses of propranolol and 15N-thymidine.; Other Names: Propranolol; Procedure: Physical Exam; On Study Day 1; monthly until surgery in conjunction with patient's clinical cardiology appointment; and at the time of surgery. Will include vital signs.; Other: Specimen Collection; On the morning of surgery, after IV access is obtained for anesthesia 2 ml of blood will be collected for analysis. A small piece of heart tissue and fat that has already been removed during surgery will be collected for analysis.
Placebo Comparator: Placebo; 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.	Other: N-thymidine; 15N-thymidine will be administered to patients in order to quantify cardiomyocyte proliferation. 15N-thymidine will be administered as 5 separate syringes. Each syringe will contain the recommended daily dose based on participants weight. Subjects will be given the labeled thymidine by mouth once a day for 5 consecutive days. The dosing will begin one week after starting the study drug.The caregiver (parent or nurse) will administer the labeled thymidine by mouth via a syringe once a day for 5 consecutive days. They will be provided with a diary to keep track of study drug dosing.; Other Names: Thymidine; Other: Urine Collection; Parents will be asked to keep a diary of the child's feeding and diaper changes during the administration of thymidine. To monitor how the labeled thymidine is processed in the body, investigators will analyze urine from the child's diapers. Each time a diaper is changed, a cotton ball will be placed in the diaper. At the next diaper change, this cotton ball will be removed from the diaper, placed in a Ziploc bag, and stored in the freezer. They will be collected and stored cotton balls starting with the first administration of thymidine until 24 hours after the last administration. The frozen cotton balls may be collected from the home by a nurse or brought by parent to the next clinic visit.; Procedure: Echocardiogram; On Study Day 1 to obtain baseline assessment of cardiac size. A second research dedicated echocardiogram will be done after being anesthetized for surgery. Echocardiography is routinely performed to determine right ventricle (RV) structure of the heart and function in ToF/PS and is non-invasive.; Procedure: Cardiac MRI; A limited study protocol will be performed using the feed-and-bundle technique at the time of study enrollment, The feed and bundle technique is utilized so that the infant will be as comfortable as possible and asleep during the procedure. This is done to prevent the risk of sedation and allow for a more natural sleep. The baby is undressed, prepared with ECG-leads and an oxygen saturation probe, and fed. With this "feed, swaddle, and sleep" technique, scanning times of 30-60 minutes can be achieved, which provides the stillness needed for accurate visualization of the heart. A second CMR, with the same limited study protocol, will be performed under general anesthesia prior to surgical repair. It does not pose any risk of radiation exposure and will not require IV placement or contrast administration for a limited assessement of the right ventricle.; Procedure: Physical Exam; On Study Day 1; monthly until surgery in conjunction with patient's clinical cardiology appointment; and at the time of surgery. Will include vital signs.; Other: Specimen Collection; On the morning of surgery, after IV access is obtained for anesthesia 2 ml of blood will be collected for analysis. A small piece of heart tissue and fat that has already been removed during surgery will be collected for analysis.; Drug: Placebo; For patients who are randomized to receive placebo, the first dose will be given in the Pediatric Translational Research Center (PCTRC) and will be based on the patients weight. Parents will administer placebo 4 doses per day. Treatment with placebo will begin at 1 month of age and continue until surgical repair, which happens usually at 3 - 9 months of age.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiomyocyte Division	To quantify cardiomyocyte division, investigators will utilize previously established MIMS (membrane introduction mass spectrometry) approach. Briefly, investigators will administer 5 enteral doses of 15N-thymidine to all patients at 1 month after birth. Cardiomyocytes that have undergone DNA replication after the intake of 15N-thymidine will incorporate the stable isotope into their DNA.	At the time of complete surgical repair, at approximately 3-9 months old, it is expected that a piece of RV myocardium will be resected. This tissue will be collected and analyzed using a multiple isotope mass spectrometer.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypertrophy as assessed by echocardiography	Analysis of the impact of propranolol on Right Ventricle Myocardial Volume	At 1 month and at time of surgery
Hypertrophy as assessed by Cardiac MR	Analysis of the impact of propranolol on Right Ventricle Myocardial Volume	At 1 month and at time of surgery
Hypertrophy assessed by microscopy	Analysis of the impact of propranolol on cardiomyocytes cross sectional area	At time of Surgery

Collaborators and Investigators

• Sponsor: Bernhard Kuhn
• Collaborators: University of Pittsburgh
• Investigators: Principal Investigator: Bernhard Kuhn, MD, UPMC Children's Hospital of Pittsburgh

Publications and helpful links

General Publications

• El Khoudary SR, Fabio A, Yester JW, Steinhauser ML, Christopher AB, Gyngard F, Adams PS, Morell VO, Viegas M, Da Silva JP, Da Silva LF, Castro-Medina M, McCormick A, Reyes-Mugica M, Barlas M, Liu H, Thomas D, Ammanamanchi N, Sada R, Cuda M, Hartigan E, Groscost DK, Kuhn B. Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot. Int J Cardiol. 2021 Sep 15;339:36-42. doi: 10.1016/j.ijcard.2021.07.020. Epub 2021 Jul 12.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2022
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: January 13, 2021
• First Submitted That Met QC Criteria: January 13, 2021
• First Posted (Actual): January 19, 2021

Study Record Updates

• Last Update Posted (Actual): June 6, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Tetralogy of Fallot; Double Outlet Right Ventricle
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Septal Defects; Heart Septal Defects, Ventricular; Transposition of Great Vessels; Tetralogy of Fallot; Double Outlet Right Ventricle; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: STUDY20020132

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No