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Beta-blocker Administration for Cardiomyocyte Division

Primary Purpose

Tetralogy of Fallot, Double Outlet Right Ventricle

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
N-thymidine
Urine Collection
Echocardiogram
Cardiac MRI
Propranolol Hydrochloride
Placebo
Physical Exam
Specimen Collection
Sponsored by
Bernhard Kuhn
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tetralogy of Fallot focused on measuring Tetralogy of Fallot, Double Outlet Right Ventricle

Eligibility Criteria

30 Days - 44 Days (Child)All SexesDoes not accept healthy volunteers

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.

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,
  • DORV variant
  • infants of diabetic mothers, asthma or underlying respiratory disease,
  • presence of metal implants in infants.

Sites / Locations

  • UPMC Children's Hospital of PittsburghRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Propranolol

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Hypertrophy as assessed by echocardiography
Analysis of the impact of propranolol on Right Ventricle Myocardial Volume
Hypertrophy as assessed by Cardiac MR
Analysis of the impact of propranolol on Right Ventricle Myocardial Volume
Hypertrophy assessed by microscopy
Analysis of the impact of propranolol on cardiomyocytes cross sectional area

Full Information

First Posted
January 13, 2021
Last Updated
June 5, 2023
Sponsor
Bernhard Kuhn
Collaborators
University of Pittsburgh
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1. Study Identification

Unique Protocol Identification Number
NCT04713657
Brief Title
Beta-blocker Administration for Cardiomyocyte Division
Official Title
Mechanistic Clinical Trial of Beta-Blocker Administration For Reactivating Cardiomyocyte Division In Tetrology of Fallot
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 16, 2022 (Actual)
Primary Completion Date
February 1, 2026 (Anticipated)
Study Completion Date
February 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Bernhard Kuhn
Collaborators
University of Pittsburgh

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tetralogy of Fallot, Double Outlet Right Ventricle
Keywords
Tetralogy of Fallot, Double Outlet Right Ventricle

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
double-blinded, placebo-controlled (1:1) randomized, single-center trial
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Propranolol
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
N-thymidine
Other Intervention Name(s)
Thymidine
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Urine Collection
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Echocardiogram
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Cardiac MRI
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Propranolol Hydrochloride
Other Intervention Name(s)
Propranolol
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Physical Exam
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Specimen Collection
Intervention Description
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.
Primary Outcome Measure Information:
Title
Cardiomyocyte Division
Description
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.
Time Frame
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 Measure Information:
Title
Hypertrophy as assessed by echocardiography
Description
Analysis of the impact of propranolol on Right Ventricle Myocardial Volume
Time Frame
At 1 month and at time of surgery
Title
Hypertrophy as assessed by Cardiac MR
Description
Analysis of the impact of propranolol on Right Ventricle Myocardial Volume
Time Frame
At 1 month and at time of surgery
Title
Hypertrophy assessed by microscopy
Description
Analysis of the impact of propranolol on cardiomyocytes cross sectional area
Time Frame
At time of Surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Days
Maximum Age & Unit of Time
44 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Shannon Janzef, MSN, RN, CBC
Phone
412.692.5760
Email
janzefs@upmc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Elizabeth Hartigan, RN
Phone
412-692-7060
Email
elizabeth.hartigan@chp.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bernhard Kuhn, MD
Organizational Affiliation
UPMC Children's Hospital of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
UPMC Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shannon Janzef, MSN, RN, CBC
Phone
412-692-5760
Email
janzefs@upmc.edu
First Name & Middle Initial & Last Name & Degree
Elizabeth Hartigan, RN
Phone
4126927060
Email
elizabeth.hartigan@chp.edu
First Name & Middle Initial & Last Name & Degree
Bernhard Kuhn, MD
First Name & Middle Initial & Last Name & Degree
Philip Adams, MD
First Name & Middle Initial & Last Name & Degree
Adam Christopher, MD
First Name & Middle Initial & Last Name & Degree
Tarek Alsaied, MD
First Name & Middle Initial & Last Name & Degree
Jennifer Johnson, DO
First Name & Middle Initial & Last Name & Degree
Laura Olivieri, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34265312
Citation
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.
Results Reference
derived

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Beta-blocker Administration for Cardiomyocyte Division

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