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

September 6, 2019 updated by: Lars Soendergaard, Rigshospitalet, Denmark

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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
120

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

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:
        • 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Mean right ventricular end-diastolic volume indexed to body surface area
Time Frame: 3 years after randomization
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
Time Frame: 3 years after randomization
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Right ventricular end-systolic volume indexed to body surface area
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: 30 days after surgery
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.
Time Frame: 30 days after surgery
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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)
Time Frame: Assessed once every year for 10 years after randomization
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)
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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
Time Frame: Assessed once every year for 10 years after randomization
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Rigshospitalet, Denmark

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Odense University Hospital
Aarhus University Hospital

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2019

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2024

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2031

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 25, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 6, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 10, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 10, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 6, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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