Pediatric REPlAcement of the PulmonaRy ValvE in Tetralogy of Fallot - (TOFandPVR)

Pediatric REPlAcement of the PulmonaRy ValvE in Tetralogy of Fallot - The PREPARE-TOF Study

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect with the vast majority of survivors of corrective surgery left with some degree of right ventricular (RV) volume overload due to pulmonary regurgitation (PR) which cause RV enlargement with right heart failure, diminished biventricular function, ventricular arrhythmia, sudden death and decreased exercise performance over time. Pulmonary valve replacement (PVR) has been thought to ameliorate these complications but the timing of replacement has yet to be determined with equipoise at the moment in this decision making process. As nearly all studies in this regard are retrospective with much less data in pediatric TOF than adults, this pilot trial sets the stage to create a prospective randomized trial in the teenage years.

Study Overview

• Status: Terminated
• Conditions: Tetralogy of Fallot
• Intervention / Treatment: Procedure: PVR

Detailed Description

The purpose of this research study is to gather information on adolescents and young adults to help understand and improve the lives of patients with TOF.

Some patients diagnosed with TOF will have a procedure called pulmonary valve replacement (PVR) and some will not. PVR is done for valves that are too damaged to be repaired. This requires a surgeon or an expert in a procedure called cardiac catheterization to replace the damaged pulmonary valve with a valve made of tissue or a mechanical valve. Multiple studies in adult TOF patients have suggested that PVR may lessen many clinical symptoms but no one is sure if it truly does. There is little information about PVR in adolescence but it is thought that lessening the amount of leakage of the pulmonary valve at a young age may avoid future complications such as right heart failure or abnormal beats of your heart. There is no agreement among cardiologists, surgeons or other healthcare providers as to whether PVR truly helps avoid complications in the future and if it does, when PVR should be done. Using the information in this study, we hope to find out if PVR in adolescents is helpful in both the short and long term.

The Investigators believe the results of this study will help provide doctors with enough information to support a future large scale research study to further evaluate the outcomes PVR. This study will involve randomization to either the PVR or no PVR cohort, medical records review, exercise test and Cardiac Magnetic Resonance (CMR) , and questionnaires.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital of Chicago
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hosptial Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Childrens Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males or females with repaired Tetralogy of Fallot (TOF), currently between 13 and 21 years of age.
2. On clinical Cardiac Magnetic Resonance (CMR) : Right Ventricular End-Diastolic Volume Index (RVEDVi) between 140 and 180 cc/m2 inclusive with Right Ventricular End-Diastolic Function (RVEF) > 40% and Left Right Ventricular End-Diastolic (LVEF ) > 50%, RV outflow tract peak velocity < 3 meters/second (if not available this will be skipped); there will be no indexed Right Ventricular end-systolic volume (RVESVi) criteria; by defining RVEDVi and RVEF, Investigators will be inherently defining RVESVi
3. On clinical echocardiogram: RV outflow tract peak velocity < 3 meters/second (if not available this will be skipped), at least mild pulmonary insufficiency and tricuspid regurgitation with an RV pressure estimate < 1/2 systemic pressure.
4. On Exercise Stress Test (EST), aerobic capacity > 60% of predicted.
5. No Q-wave, R-wave, S-wave (QRS) duration criteria on ECG.

Exclusion Criteria:

1. Any condition judged by the patient's physician that would cause this trial to be detrimental to the patient.
2. Specific forms of TOF excluded are those with endocardial cushion defects, TOF with absent pulmonary valve and TOF with multiple aorto-pulmonary collaterals requiring unifocalization.
3. Unilateral branch pulmonary artery stenosis (one lung receives < 25% of total flow)
4. Contraindication to non-sedated exercise CMR (e.g. pacemaker/implanted cardioverter defibrillator); need for sedation
5. If data available, moderate or greater tricuspid regurgitation on echocardiogram or CMR or Qp/Qs > 1.5
6. Significant strokes/hemiplegia or inability to exercise
7. Genetic syndrome/developmental delay which would make QOL and EST date uninterpretable
8. Pregnancy
9. Previous pulmonary valve replacement (PVR)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: PVR Arm; PVR arm will undergo PVR via catheter or surgery	Procedure: PVR; Subjects will undergo PVR via surgery or cardiac catheterization. PVR using cardiac catheterization may require a much shorter hospital stay than traditional heart surgery. If the valve is repaired by surgery, this will require open heart surgery to directly implant a pulmonary valve
No Intervention: No PVR; No PVR group will continue with medical management

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Randomized to PVR Via Catheter or Surgery	Participants will be randomized by computer by the statistician at the Data Coordinating Center (DCC) at Northwestern University (NU) who will maintain the schedule; this will be a 2:1 randomization of PVR to no-PVR. There will be no blinding and the assignment will not be concealed from the investigators. There will be no stratifications within each group.	2-3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of PVR on Biventricular Strain	Mechanisms of the effects of PVR in the definitive trial will be measured by obtaining preliminary data on biventricular strain.	12-18 months
Quality of Life (QOL)	Quality of life will be measured using the Pediatric Cardiac Quality of Life Inventory (PCQLI) - to measure quality of life. The PCQLI has been used for over 10 years and is a validated quality of life metric. The PCQLI measures disease-specific, pediatric health related quality of life and generates 3 scores, namely, total, disease impact subscale, and psychosocial impact subscale. Each subscale score has a maximum of 50 points, and their sum yields the total score. Higher scores represent better perceived pediatric health related quality of life	12-18 months
Exercise Performances	This will be determined by exercise test performed to assess parameters such as oxygen consumption (VO2) at ventilatory anaerobic threshold (VAT) and normalized for age	12-18 months
Prevalence of Arrhythmias	This will be determined by reviewing Holter monitoring data to assess the prevalence of arrhythmias. This will also provide the endpoints for the larger, longer term trial	12-18 months
Effects of Pulmonary Valve Replacement (PVR) on Diffuse Fibrosis	This will be measured by obtaining preliminary data on the difference between patients randomized to PVR and no PVR in regard to diffuse fibrosis (DF).	12-18 months
Effects of PVR on Exercise in the Magnetic Resonance (MR) Scanner	Mechanisms of the effects of PVR in the definitive trial will be measured by obtaining preliminary data on the difference between patients randomized to PVR and no PVR in regard to performing exercise cardiac magnetic resonance (CMR).	12-18 months

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Mark Fogel, MD, The Childrens Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2018
• Primary Completion (Actual): January 16, 2021
• Study Completion (Actual): January 16, 2021

Study Registration Dates

• First Submitted: August 2, 2018
• First Submitted That Met QC Criteria: August 14, 2018
• First Posted (Actual): August 16, 2018

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Tetralogy of Fallot
• Other Study ID Numbers: 18-015046; R34HL142142-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Principal Investigator (PI) is responsible for data management and accuracy of records. The PI may assign designated qualified individuals to collect the information. Only investigators' on this protocol and assigned research staff on this protocol will have access to the data. Data will be entered into a REDcap database by a member of the study team. All data and records generated during this study will be kept confidential in accordance with Institutional and HIPAA policies on subject privacy. The study team will not use such data and records for any purpose other than conducting the study. In order to keep protected health information from disclosure, each patient will be given a unique identification number. The key to this code will be kept in a locked file in one of the study investigator's offices. Any data that is transmitted to any Data Coordinating Center (DCC) will be de-identified by the enrolling site
• IPD Sharing Time Frame: 2-3 years
• IPD Sharing Access Criteria: All future studies using these patients will require separate Institutional Review Board (IRB) approved protocols and consent forms. Only investigators' on this protocol and assigned research staff on this protocol will have access to the data
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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