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Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System (Redefine)

Primary Purpose

Tetralogy of Fallot, Heart Defects, Congenital, Ventricular Dysfunction, Right

Status
Unknown status
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Losartan
Placebo
Sponsored by
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tetralogy of Fallot focused on measuring Losartan

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria: adult age and mentally competent; and Tetralogy of Fallot; and right ventricular dysfunction, defined as right ventricular ejection fraction 50% or lower as measured by Cardiovascular Magnetic Resonance Imaging (CMR). Not more than moderate tricuspid or pulmonary regurgitation or more than moderate pulmonary stenosis as measured by CMR or echocardiography.

Exclusion Criteria:

  • Incapable of giving informed consent
  • Hypersensitivity to losartan or any of its help substances
  • Contraindications for CMR
  • Previous or current angioedema whether or not in relation to the use of an ACE inhibitor or ARB
  • Known bilateral renal artery stenosis
  • Current symptomatic hypotension
  • Estimated glomerular filtration rate of 30 ml/min or lower
  • Plasma potassium level of 5,5 mmol/L or higher
  • Moderate to severe liver disease: Child Pugh class B or C
  • Raised plasma transaminases level more than three times upper normal limit
  • Current treatment of hypertension with an ACE-inhibitor or ARB, which cannot be discontinued
  • Current treatment with potassium chloride, trimethoprim, tacrolimus or cyclosporine which cannot be discontinued
  • Pregnant or nursing women
  • Desire to have children within the study period

Sites / Locations

  • Academic Medical CenterRecruiting
  • Universitair Medisch Centrum Groningen
  • Leids Universitair Medisch CentrumRecruiting
  • St Antonius ziekenhuis
  • St Radboud Universitair Medisch Centrum
  • Universitair Medisch Centrum Utrecht

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Losartan 150mg daily

Placebo 150mg daily

Arm Description

Losartan: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.

Placebo: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.

Outcomes

Primary Outcome Measures

Right ventricular ejection fraction
RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)

Secondary Outcome Measures

RV volumes (CMR)
pulmonary regurgitation (CMR and echocardiography)
aortic root diameter (CMR and echocardiography)
echocardiographic parameters for RV and LV function
maximal exercise capacity (VO2 max)
hospitalization for heart failure
the prevalence of (supra) ventricular arrhythmias
the serum ntproBNP levels
NYHA class
Quality of life (SF 36 and SQUASH)
death
RV mass (CMR)
LV EF (CMR)
LV volumes (CMR)
LV mass (CMR)
serum Galectin-3 levels
circulating microRNA's

Full Information

First Posted
December 6, 2013
Last Updated
December 21, 2015
Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators
The Interuniversity Cardiology Institute of the Netherlands
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1. Study Identification

Unique Protocol Identification Number
NCT02010905
Brief Title
Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
Acronym
Redefine
Official Title
Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Unknown status
Study Start Date
December 2013 (undefined)
Primary Completion Date
January 2018 (Anticipated)
Study Completion Date
January 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators
The Interuniversity Cardiology Institute of the Netherlands

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Rationale: The prevalence of adult patients with congenital heart disease (CHD) has steadily increased over the last decades, due to the advances in cardiac surgery. A large number of these patients cope with right ventricular (RV) volume or pressure overload, largely caused by residual lesions after cardiac surgery in childhood. Previous RV overload due to pulmonary regurgitation in Tetralogy of Fallot (TOF) can lead to RV dysfunction. These findings warrant close surveillance of RV function, and adequate and evidence-based pharmacological therapy to reduce both morbidity and mortality in this young patient group. The renin-angiotensin-aldosterone system (RAAS) is activated in patients with ventricular failure, irrespective of the effected (left or right) ventricle. Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB's) are drugs which act as inhibitors of RAAS. Previously, large trials have demonstrated the beneficial effect of angiotensin converting enzyme (ACE) inhibitors on morbidity and mortality in patients with acquired left ventricular (LV) dysfunction. ARB's have a similar effect as ACE inhibitors in patients with acquired LV dysfunction but discontinuation because of side effects such as cough is less frequent. In TOF patients with RV overload due to pulmonary regurgitation, pulmonary valve replacement leads to a decrease in RV size and pulmonary regurgitation. Current guidelines advise empiric use of RAAS inhibitors for right ventricular dysfunction in adult patients with congenital heart disease. However, the actual effect of RAAS inhibition on right ventricular dysfunction in adult TOF patients without severe valvular lesions has not been sufficiently investigated. Therefore, we set-up the proposed study, and hypothesize that ARB's have a beneficial effect on RV ejection fraction in adult TOF patients with RV dysfunction without severe valvular lesions. Objective: to improve RV ejection fraction in adult TOF patients with RV dysfunction without severe valvular lesions. Study design: a prospective, multicenter, double-blind, randomized, placebo-controlled trial. Follow up two years Study population: adult patients with Tetralogy of Fallot with right ventricular dysfunction, defined as right ventricular ejection fraction < 50% and without severe valvular lesions Intervention: patients are randomized to receive either losartan 150 mg once daily, or placebo in the same regimen. Main study parameters/endpoints: the primary endpoint is difference in change in RV ejection fraction, determined by cardiovascular magnetic resonance imaging (CMR), between the treatment and the control group at two years follow-up. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All investigations, except blood analysis, are non-invasive and free of risk. The burden for the patients mainly consists of the time that is consumed by the visits to the clinic. At these visits time will be consumed by: history taking and physical investigation (15 minutes); quality of life score (15 minutes); laboratory tests (6 times venopuncture, total amount of blood withdrawn approximately 90ml). Cardiopulmonary exercise testing (1hour), echocardiography (15 minutes) and CMR (45 minutes) are part of regular medical care. Adverse effects from losartan are usually limited and consist of dizziness due to hypotension, renal impairment, hyperkalemia and liver impairment. We expect no change or an increase in RV function in the intervention group compared to the control group over the two-year follow up period, which would be a great benefit for this young study population.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tetralogy of Fallot, Heart Defects, Congenital, Ventricular Dysfunction, Right
Keywords
Losartan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Losartan 150mg daily
Arm Type
Active Comparator
Arm Description
Losartan: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
Arm Title
Placebo 150mg daily
Arm Type
Placebo Comparator
Arm Description
Placebo: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
Intervention Type
Drug
Intervention Name(s)
Losartan
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Right ventricular ejection fraction
Description
RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)
Time Frame
two years
Secondary Outcome Measure Information:
Title
RV volumes (CMR)
Time Frame
two years
Title
pulmonary regurgitation (CMR and echocardiography)
Time Frame
two years
Title
aortic root diameter (CMR and echocardiography)
Time Frame
two years
Title
echocardiographic parameters for RV and LV function
Time Frame
one year and two years
Title
maximal exercise capacity (VO2 max)
Time Frame
two years
Title
hospitalization for heart failure
Time Frame
two years
Title
the prevalence of (supra) ventricular arrhythmias
Time Frame
within two years
Title
the serum ntproBNP levels
Time Frame
one year and two years
Title
NYHA class
Time Frame
two years
Title
Quality of life (SF 36 and SQUASH)
Time Frame
two years
Title
death
Time Frame
two years
Title
RV mass (CMR)
Time Frame
two years
Title
LV EF (CMR)
Time Frame
two years
Title
LV volumes (CMR)
Time Frame
two years
Title
LV mass (CMR)
Time Frame
two years
Title
serum Galectin-3 levels
Time Frame
two years
Title
circulating microRNA's
Time Frame
two years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: In order to be eligible to participate in this study, a subject must meet all of the following criteria: adult age and mentally competent; and Tetralogy of Fallot; and right ventricular dysfunction, defined as right ventricular ejection fraction 50% or lower as measured by Cardiovascular Magnetic Resonance Imaging (CMR). Not more than moderate tricuspid or pulmonary regurgitation or more than moderate pulmonary stenosis as measured by CMR or echocardiography. Exclusion Criteria: Incapable of giving informed consent Hypersensitivity to losartan or any of its help substances Contraindications for CMR Previous or current angioedema whether or not in relation to the use of an ACE inhibitor or ARB Known bilateral renal artery stenosis Current symptomatic hypotension Estimated glomerular filtration rate of 30 ml/min or lower Plasma potassium level of 5,5 mmol/L or higher Moderate to severe liver disease: Child Pugh class B or C Raised plasma transaminases level more than three times upper normal limit Current treatment of hypertension with an ACE-inhibitor or ARB, which cannot be discontinued Current treatment with potassium chloride, trimethoprim, tacrolimus or cyclosporine which cannot be discontinued Pregnant or nursing women Desire to have children within the study period
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
J.P. Bokma
Email
j.p.bokma@amc.uva.nl
First Name & Middle Initial & Last Name or Official Title & Degree
B.J. Bouma
Email
b.j.bouma@amc.uva.nl
Facility Information:
Facility Name
Academic Medical Center
City
Amsterdam
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
J.P. Bokma
First Name & Middle Initial & Last Name & Degree
B.J.M. Mulder
First Name & Middle Initial & Last Name & Degree
B.J. Bouma
Facility Name
Universitair Medisch Centrum Groningen
City
Groningen
Country
Netherlands
Individual Site Status
Active, not recruiting
Facility Name
Leids Universitair Medisch Centrum
City
Leiden
Country
Netherlands
Individual Site Status
Recruiting
Facility Name
St Antonius ziekenhuis
City
Nieuwegein
Country
Netherlands
Individual Site Status
Active, not recruiting
Facility Name
St Radboud Universitair Medisch Centrum
City
Nijmegen
Country
Netherlands
Individual Site Status
Active, not recruiting
Facility Name
Universitair Medisch Centrum Utrecht
City
Utrecht
Country
Netherlands
Individual Site Status
Active, not recruiting

12. IPD Sharing Statement

Citations:
PubMed Identifier
29222139
Citation
Bokma JP, Winter MM, van Dijk AP, Vliegen HW, van Melle JP, Meijboom FJ, Post MC, Berbee JK, Boekholdt SM, Groenink M, Zwinderman AH, Mulder BJM, Bouma BJ. Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot. Circulation. 2018 Apr 3;137(14):1463-1471. doi: 10.1161/CIRCULATIONAHA.117.031438. Epub 2017 Dec 8.
Results Reference
derived

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Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System

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