Early Versus Later Re-valving in Tetralogy of Fallot With Free Pulmonary Regurgitation

Early Versus Later Re-valving in Tetralogy of Fallot With Free Pulmonary Regurgitation - Combined Cross-sectional and Prospective, Multi-centre, Randomized, Parallel-group Clinical Trial

Tetralogy of Fallot (ToF) is a congenital heart defect with four major features including right ventricular outflow tract obstruction. About 25 children are born with this condition in Denmark every year. Corrective surgery is usually performed within the first year. In 50 % of patients, enlargement with a patch is necessary to achieve relief of the outflow tract obstruction. This however results in severe pulmonary regurgitation, which eventually leads to volume overload, right ventricular dysfunction and arrhythmia. To avoid these late complications, pulmonary valve replacement with a prosthesis if performed when patients meet the current guideline criteria. Most patients meet the guideline criteria for revalving when they are between 20 and 30 years of age. The current guidelines however, are based solely on retrospective studies and novel research reveals that in more than 50 % of patients who are treated according to current practice, right ventricular volumes and function as well as exercise capacity and burden of arrhythmia do not normalize or improve. 500 patients with ToF will be enrolled in a multicentre, cross-sectional study, which will yield information about the long-term outcomes after initial repair of ToF, as well as suggestions about the optimal timing for re-valving. Among patients included in the cross-sectional study, 120 patients with free pulmonary regurgitation, will be randomized evenly for early or later re-valving with at least 10-years of follow-up, for evaluation of long-term efficacy and safety of early re-valving.

Study Overview

• Status: Recruiting
• Conditions: Tetralogy of Fallot; Pulmonary Regurgitation
• Intervention / Treatment: Procedure: Pulmonary valve replacement

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mathis Gröning, MD, DMSc; Phone Number: +45 42404489; Email: mathis.groening@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Not yet recruiting
    • Aarhus University Hospital
    • Contact: Dorte G Nielsen, MD, PhD
    • Sub-Investigator: Dorte G Nielsen, MD, PhD
    • Sub-Investigator: Kim Munk, MD, PhD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Mathis Gröning, MD; Phone Number: +45 35456238; Email: mathis.groening@regionh.dk
    • Principal Investigator: Lars Søndergaard, Professor
    • Sub-Investigator: Morten H Smerup, MD, PhD
    • Sub-Investigator: Mathis Gröning, MD
  • Odense, Denmark, 5000
    • Not yet recruiting
    • Odense University Hospital
    • Contact: Henrik Nissen, MD, PhD
    • Sub-Investigator: Henrik Nissen, MD, PhD
    • Sub-Investigator: Helle Andersen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ToF with pulmonary stenosis repaired with a TAP within the first two years of life.
2. RVOT anatomy is suitable for implantation of an adult sized conduit ( 18 mm homograft or Contegra graft) as assessed by MRI.

Exclusion Criteria:

1. ToF with pulmonary atresia, ToF with common atrioventricular canal, ToF with absent pulmonary valve syndrome, major aortopulmonary collateral arteries and other significant associated anomalies.
2. Palliation with a shunt (Blalock-Taussig or central) at any time.
3. The patient is symptomatic.
4. Sustained supraventricular or ventricular arrhythmia.
5. RVEDVi > 140 mL/m2 as assessed by MRI (appendix 1).
6. RVESVi > 60 mL/m2 as assessed by MRI.
7. RVEF < 50 % as assessed by MRI.
8. Moderate or severe tricuspid regurgitation as assessed by echocardiography or MRI.
9. Significant residual lesions requiring intervention (e.g. ventricular septal defect, aortic regurgitation, branch pulmonary artery stenosis).
10. Co-morbidity preventing exercise testing (e.g. genetics, neuro-cognitive dysfunction, physical disability).
11. Contraindication for MRI (e.g. permanent pacemaker, intra-cardiac defibrillator, intracranial ferro-magnetic device).
12. Pregnancy at time of inclusion.
13. Age < 12 or unable to comply with instructions given during MRI or exercise testing.

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
Experimental: Early re-valving; 60 patients who are assigned to early re-valving undergo pulmonary valve replacement within 3 months from randomization.	Procedure: Pulmonary valve replacement; Surgical implantation of an adult-sized (≥ 18 mm) homograft or Contegra graft as right ventricle-to-pulmonary artery conduit under cardiopulmonary bypass through a sternotomy.
Experimental: Later re-valving; 60 patients who are assigned to later re-valving undergo pulmonary valve replacement when the current European guideline criteria are met.	Procedure: Pulmonary valve replacement; Surgical implantation of an adult-sized (≥ 18 mm) homograft or Contegra graft as right ventricle-to-pulmonary artery conduit under cardiopulmonary bypass through a sternotomy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean right ventricular end-diastolic volume indexed to body surface area	Right ventricular end-diastolic volume (mL) indexed by body surface area (m2) will be assessed in both the early re-valving group and later re-valving group for calculation of the mean in each group and analysis of statistical significance of the difference will be performed. Higher right ventricular end-diastolic volumes are considered a worse outcome.	3 years after randomization
Rate of deceased patients (all-cause mortality) and total number of patients	The rate of deceased patients (irrespective of the cause of death) and total number of patients will be calculated for both the early and later re-valving group and analysis of statistical significance of the difference between the groups will be performed.	3 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right ventricular end-systolic volume indexed to body surface area	Right ventricular end-systolic volume (mL) indexed by body surface area (m2) will be assessed in both the early re-valving group and later re-valving group for calculation of the mean in each group and analysis of statistical significance of the difference will be performed. Higher right ventricular end-systolic volumes are considered a worse outcome.	Assessed once every year for 10 years after randomization
Right ventricular ejection fraction	Right ventricular ejection fraction (%) will be assessed in both the early re-valving group and later re-valving group for calculation of the mean in each group and analysis of statistical significance of the difference will be performed. Lower right ventricular ejection fraction are considered a worse outcome.	Assessed once every year for 10 years after randomization
Left ventricular end-diastolic volume indexed to body surface area	Left ventricular end-diastolic volume (mL) indexed by body surface area (m2) will be assessed in both the early re-valving group and later re-valving group for calculation of the mean in each group and analysis of statistical significance of the difference will be performed. Higher left ventricular end-diastolic volumes are considered a worse outcome.	Assessed once every year for 10 years after randomization
Left ventricular end-systolic volume indexed to body surface area	Left ventricular end-diastolic volume (mL) indexed by body surface area (m2) will be assessed in both the early re-valving group and later re-valving group for calculation of the mean in each group and analysis of statistical significance of the difference will be performed. Higher left ventricular end-systolic volumes are considered a worse outcome.	Assessed once every year for 10 years after randomization
Left ventricular ejection fraction	Left ventricular ejection fraction (%) will be assessed in both the early re-valving group and later re-valving group for calculation of the mean in each group and analysis of statistical significance of the difference will be performed. Lower left ventricular ejection fraction are considered a worse outcome.	Assessed once every year for 10 years after randomization
Rate of patients with procedure-related bleeding and total number of patients	The rate of patients with bleeding classified as minor, major and life-threatening bleeding (BARC classification) related to the re-valving procedure and the total number of patients will be calculated in both the early and later re-valving group and the difference between the groups will be analyzed for statistical significance.	30 days after surgery
Rate of patients with procedure-related acute kidney injury and total number of patients.	The rate of acute kidney injury categorized as stage one, two and three (KDIGO classification) and the total number of patients will be calculated in both the early and later re-valving group and the difference will be analyzed for statistical significance.	30 days after surgery
Composite-rate of all-cause mortality and disabling stroke	The rate of patients who decease due to cardiovascular causes and patients who suffer from a disabling stroke after the time of randomization will be calculated for both the early and later re-valving group and the difference will be analyzed for statistical significance	Assessed once every year for 10 years after randomization
Rate of patients deceased due to cardiovascular causes and total number of patients	The rate of patients who decease due to a cardiovascular cause and the total number of patients will be calculated in both the early and later re-valving group and the difference will be analyzed for statistical significance	Assessed once every year for 10 years after randomization
Composite-rate of patients who suffer from disabling strokes or transient ischemic attacks	The rate of patients who suffer from a disabling stroke og transient ischemic attack after the time of randomization will be calculated in both the early and later re-valving group and the difference will be analyzed for statistical significance	Assessed once every year for 10 years after randomization
Mean New York Heart Association class	The mean New York Heart Association Class categorized as 1-4 will be assessed in both the early and later re-valving group and the difference will be analyzed for statistical significance. Higher mean values are considered a worse outcome.	Assessed once every year for 10 years after randomization
Mean health-associated quality of life (adults)	The mean health-asssociated quality of life will be assessed in both the early and later revalving group and the difference will be analyzed for statistical significance. EQ-5D-3L will be used for assessment. The questionnaires are available in Danish. Higher values are considered better outcomes.	Assessed once every year for 10 years after randomization
Mean health-associated quality of life (children)	The mean health-associated quality of life will be assessed in both the early and later re-valving group and the difference will be analyzed for statistical significance. EQ-5D-Y will be used for assessment. The questionnaires are available in Danish. Higher values are considered better outcomes.	Assessed once every year for 10 years after randomization
Rate of patients with new sustained supraventricular or ventricular arrhythmia and the total number of patients	The rate of patients with new supraventricular or ventricular arrhythmia and the total number of patients will be calculated for both the early and later re-valving group and the difference will be analyzed for statistical significance.	Assessed once every year for 10 years after randomization
Mean peak oxygen consumption during cardiopulmonary exercise testing	The mean peak oxygen consumption (VO2/min) indexed to body weight (kg) will be assessed for patients in both the early and later re-valving group and the difference in means will be analyzed for statistical significance. Higher mean values are considered a better outcomes.	Assessed once every year for 10 years after randomization
Median time until structural valve deterioration in patients who are re-valved during the study	The median time until structural valve deterioration defined as time until need for valve replacement in patients who are revalved during the study will be calculated.	Assessed once every year for 10 years after randomization
Rate of patients who are re-valved during the course of the study and suffer from endocarditis and the total number of patients who are revalved during the study	The rate of patients who suffer from endocarditis after re-valving during the course of the study and the total number of patients who are revalved during the study will be calculated	Assessed once every year for 10 years after randomization
Rate of patients who are re-valved during the course of the study and suffer from prosthetic valve thrombosis and the total number of patients who are revalved during the study	The rate of patients who suffer from prosthetic valve thrombosis after re-valving during the course of the study and the total number of patients who are revalved during the study will be calculated	Assessed once every year for 10 years after randomization
Mean number of contacts to the health system	The mean number of contacts to the health system defined as composite of hospital admissions, outpatient contacts and contacts to the general practitioner will be calculated in both the early and later re-valving group and the difference will be analyzed for statistical significance	Assessed once every year for 10 years after randomization
Mean number of children for female patients	The mean number of children will be assessed for female patient in both the early and later re-valving group and the difference will be analyzed for statistical significance	Assessed once every year for 10 years after randomization

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Aarhus University Hospital
• Investigators: Principal Investigator: Lars Søndergaard, MD, DMSc, Rigshospitalet, Denmark; Study Chair: Morten H Smerup, MD, PhD, Rigshospitalet, Denmark; Study Chair: Dorte G Nielsen, MD, PhD, Aarhus University Hospital; Study Chair: Kim Munk, MD, PhD, Aarhus University Hospital; Study Chair: Henrik Nissen, MD, PhD, Odense University Hospital; Study Chair: Helle Andersen, MD, Odense University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2031

Study Registration Dates

• First Submitted: February 25, 2019
• First Submitted That Met QC Criteria: September 6, 2019
• First Posted (Actual): September 10, 2019

Study Record Updates

• Last Update Posted (Actual): September 10, 2019
• Last Update Submitted That Met QC Criteria: September 6, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Valve Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Tetralogy of Fallot; Pulmonary Valve Insufficiency
• Other Study ID Numbers: VD-2018-512

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