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

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ClinicalTrials.gov Identifier: NCT04084132
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : September 10, 2019
Sponsor:
Collaborators:
Aarhus University Hospital
Odense University Hospital
Information provided by (Responsible Party):
Lars Soendergaard, Rigshospitalet, Denmark

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Tetralogy of Fallot Pulmonary Regurgitation Procedure: Pulmonary valve replacement Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2031

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04084132


Contacts
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Contact: Mathis Gröning, MD, DMSc +45 42404489 mathis.groening@regionh.dk

Locations
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Denmark
Aarhus University Hospital Not yet recruiting
Aarhus, Denmark, 8200
Contact: Dorte G Nielsen, MD, PhD         
Sub-Investigator: Dorte G Nielsen, MD, PhD         
Sub-Investigator: Kim Munk, MD, PhD         
Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Mathis Gröning, MD    +45 35456238    mathis.groening@regionh.dk   
Principal Investigator: Lars Søndergaard, Professor         
Sub-Investigator: Morten H Smerup, MD, PhD         
Sub-Investigator: Mathis Gröning, MD         
Odense University Hospital Not yet recruiting
Odense, Denmark, 5000
Contact: Henrik Nissen, MD, PhD         
Sub-Investigator: Henrik Nissen, MD, PhD         
Sub-Investigator: Helle Andersen, MD, PhD         
Sponsors and Collaborators
Rigshospitalet, Denmark
Aarhus University Hospital
Odense University Hospital
Investigators
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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 Documents (Full-Text)

Documents provided by Lars Soendergaard, Rigshospitalet, Denmark:

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Responsible Party: Lars Soendergaard, Clinical Professor, Consultant MD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT04084132     History of Changes
Other Study ID Numbers: VD-2018-512
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Respiratory Insufficiency
Tetralogy of Fallot
Pulmonary Valve Insufficiency
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Heart Valve Diseases
Respiration Disorders
Respiratory Tract Diseases