Fibrosis and the Fontan

NCT04901975 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 20-0177161R01HL149139-01A1
• Study Type: interventional
• Target: 145
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to non-invasively characterize the fibrotic consequences of single ventricle physiology, its possible solution and effect on lymphatics. This project investigates the response to acute imposition of Fontan hemodynamics by examining the interrelationship between liver and cardiac fibrosis/dysfunction and lymphatic congestion along with a pilot trial of the antifibrotic agent, spironolactone, to prevent these consequences and to determine if MRI can discern these differences. The combination of serum biomarkers and MRI form a powerful non-invasive tool in putting together this complicated web of dysfunction.

Conditions

Single-ventricle

Outcome Measures

Primary Outcomes (4)

• Liver elastography by MRE prior to and after Fontan

  Measured by MRE for viscoelastic properties of the liver, primarily stiffness

  up to 1 year

• Liver elastography by T1rho prior to and after Fontan

  Measured by T1rho mapping for further viscoelastic properties of the liver, primarily hepatic fibrosis

  up to 1 year

• Heart tissue characterization by T1 mapping prior to and after Fontan

  Measured by T1 mapping using global extracellular volume (ECV)

  up to 1 year

• Heart tissue characterization prior to and after Fontan

  Percentage of myocardial mass which demonstrates delayed enhancement

  up to 1 year

Secondary Outcomes (3)

• Serum biomarkers of fibrosis

  up to 1 year

• Lymphatic dysfunction by MRE prior to and after Fontan

  up to 1 year

• Lymphatic dysfunction T1rho prior to and after Fontan

  up to 1 year

Study Arms (5)

Spironolactone

EXPERIMENTAL

Children will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers immediately prior to the Fontan operation. All SV children will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Spironolactone is a mild diuretic. Drug dosage will be those used clinically and per the CHOP formulary: 3 mg/kg/day in divided doses every 6-24 hours; the drug will be weight adjusted every \~0.5 kg with a maximum dosage of 200 mg/24 hours. Maximum single dose is 100 mg. Spironolactone administration will begin after the Fontan procedure in the hospital prior to discharge or at the first outpatient visit \~ 2 weeks after discharge.

Drug: Spironolactone

Observational

NO INTERVENTION

Children will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers immediately prior to the Fontan operation. All SV children, whether they received spironolactone or not, will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Demographics and medical history will be collected again along with adverse events. Children will also undergo CMR for evaluation of hemodynamics, ventricular function (including strain), computational modeling and lymphatic abnormalities. A few of these patients will be undergoing CMR for clinical reasons and study CMR related and study MRI related imaging and blood draws will be performed in coordination with their clinical care (ie these sequences will be added on to their clinical sequences).

Control

NO INTERVENTION

The purpose of this study is to non-invasively characterize the fibrotic consequences of SV physiology, its possible solution and effect on lymphatics. This project investigates the response to acute imposition of Fontan hemodynamics by examining the interrelationship between liver and cardiac fibrosis/dysfunction and lymphatic congestion (figure 1) along with a pilot trial of the antifibrotic agent, spironolactone, to prevent these consequences and to determine if MRI can discern these differences. The combination of serum biomarkers and MRI form a powerful non-invasive tool in putting together this complicated web of dysfunction. Control subjects who are non-SV patients but who have normal heart function who are undergoing CMR for evaluation (eg patients undergoing CMR for vascular ring evaluation, family history of congenital heart disease but found to be normal, etc) will have study related MRI and CMR sequences performed.

Observational - 1A

NO INTERVENTION

Subjects who were enrolled in this study in Spironolactone arm and patient's family would like to continue participation. All SV children, whether they received spironolactone or not, will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Demographics and medical history will be collected again along with adverse events. Children will also undergo CMR for evaluation of hemodynamics, ventricular function (including strain), computational modeling and lymphatic abnormalities. A few of these patients will be undergoing CMR for clinical reasons and study CMR related and study MRI related imaging and blood draws will be performed in coordination with their clinical care (ie these sequences will be added on to their clinical sequences).

Observational - 1B

NO INTERVENTION

Subjects who were enrolled in other studies with intervention. All SV children, whether they received spironolactone or not, will undergo characterization and measurement of liver and cardiac fibrosis with MRI and cardiac magnetic resonance (CMR) as well as serum biomarkers \~1 year after the Fontan operation. Demographics and medical history will be collected again along with adverse events. Children will also undergo CMR for evaluation of hemodynamics, ventricular function (including strain), computational modeling and lymphatic abnormalities. A few of these patients will be undergoing CMR for clinical reasons and study CMR related and study MRI related imaging and blood draws will be performed in coordination with their clinical care (ie these sequences will be added on to their clinical sequences).

Interventions

Spironolactone DRUG

Spironolactone is a mild diuretic. Drug dosage will be those used clinically and per the CHOP formulary: 3 mg/kg/day in divided doses every 6-24 hours; the drug will be weight adjusted every \~0.5 kg with a maximum dosage of 200 mg/24 hours. Maximum single dose is 100 mg. Spironolactone, the aldosterone antagonist to be utilized in Specific Aim 2 of this study, is FDA approved, has been on the market for many years and is routinely administered to all types of children with congenital heart disease including SV patients. The choice of which patient this should be administered to is up to the clinician and their patients and therefore, not all SV patients are on this medication.

Spironolactone

Eligibility Criteria

• Age: 1 Year - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Single Ventricle (SV) Patients
• Cohort 1 (Observational Group - no study medication):
• Subjects between 1 and ≤ 6 years of age of either gender.
• Either single left or single right ventricle.
• Subjects who are scheduled to undergo a Fontan operation at CHOP.
• Parents signing informed consent.
• Cohort 1A (formerly part of study drug group who wish continued participation in the observational group):
• Subjects who were enrolled in this study in Cohort 2 and are either non-compliant with the medication, no longer want to take the medication, or have an AE that requires them to stop the medication, and patient's family would like to continue participation
• Patients were on study medication for 6 weeks or less.
• The principal investigator deems it appropriate for the patient to switch to the observational arm.
• Patients signing the observational informed consent form.
• Cohort 1B (observational group - in other studies with intervention):
• Subjects between 1 and ≤6 years of age of either gender.
• Either single left or single right ventricle.
• Subjects who are planned to undergo a Fontan operation at CHOP.

You may not qualify if:

• Cohort 1 (Observational Group - no study medication):
• Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
• Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
• Patient currently taking spironolactone or eplerenone
• Subjects in any study that would preclude participation in the study by altering results
• Cohort 1A (formerly part of study drug group who wish continued participation in the observational group):
• Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
• Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
• Subjects in any study that would preclude participation in the current study.
• Cohort 1B (observational group - in other studies with intervention):
• Subjects with any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
• Any contradiction to a sedated CMR (i.e. presence of a pacemaker).
• Patient currently taking spironolactone or eplerenone
• Subjects in any study that would preclude participation in the current study or studies not approved by principal investigator.
• Cohort 2 (Study Drug Group - Spironolactone):

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19130, United States

RECRUITING

MeSH Terms

Conditions

Univentricular Heart

Interventions

Spironolactone

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Mark Fogel, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mark Fogel, MD

CONTACT

215-590-4040; fogel@chop.edu

Cassandra L Giner, MS

CONTACT

915-503-3642; ginerc@chop.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2021
• First Posted: May 26, 2021
• Study Start: February 11, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: June 8, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)