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History of Changes for Study: NCT02010905
Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System (Redefine)
Latest version (submitted December 21, 2015) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 December 10, 2013 None (earliest Version on record)
2 October 17, 2014 Recruitment Status, Study Status, Contacts/Locations, Eligibility and Outcome Measures
3 December 21, 2015 Recruitment Status, Study Status and Sponsor/Collaborators
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Study NCT02010905
Submitted Date:  December 10, 2013 (v1)

Open or close this module Study Identification
Unique Protocol ID: NL44943.018.13
Brief Title: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System (Redefine)
Official Title: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
Secondary IDs:
Open or close this module Study Status
Record Verification: December 2013
Overall Status: Active, not recruiting
Study Start: December 2013
Primary Completion: January 2017 [Anticipated]
Study Completion: May 2017 [Anticipated]
First Submitted: December 6, 2013
First Submitted that
Met QC Criteria:
December 10, 2013
First Posted: December 13, 2013 [Estimate]
Last Update Submitted that
Met QC Criteria:
December 10, 2013
Last Update Posted: December 13, 2013 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Responsible Party: Principal Investigator
Investigator: Berto J Bouma
Official Title: MD, PhD
Affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators: ICIN - Netherlands Heart Institute
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module 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.

Detailed Description:
Open or close this module Conditions
Conditions: Tetralogy of Fallot
Heart Defects, Congenital
Ventricular Dysfunction, Right
Keywords: Losartan
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 120 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Active Comparator: Losartan 150mg daily
Losartan: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
Drug: Losartan
Placebo Comparator: Placebo 150mg daily
Placebo: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
Drug: Placebo
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Right ventricular ejection fraction
[ Time Frame: two years ]

RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)
Secondary Outcome Measures:
1. RV volumes (CMR)
[ Time Frame: two years ]

2. pulmonary regurgitation (CMR and echocardiography)
[ Time Frame: two years ]

3. aortic root diameter (CMR and echocardiography)
[ Time Frame: two years ]

4. echocardiographic parameters for RV and LV function
[ Time Frame: one year and two years ]

5. maximal exercise capacity (VO2 max)
[ Time Frame: two years ]

6. hospitalization for heart failure
[ Time Frame: two years ]

7. the prevalence of (supra) ventricular arrhythmias
[ Time Frame: within two years ]

8. the serum ntproBNP levels
[ Time Frame: one year and two years ]

9. NYHA class
[ Time Frame: two years ]

10. Quality of life (SF 36 and SQUASH)
[ Time Frame: two years ]

11. death
[ Time Frame: two years ]

12. RV mass (CMR)
[ Time Frame: two years ]

13. LV EF (CMR)
[ Time Frame: two years ]

14. LV volumes (CMR)
[ Time Frame: two years ]

15. LV mass (CMR)
[ Time Frame: two years ]

Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
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
Open or close this module Contacts/Locations
Locations: Netherlands
Academic Medical Center
Amsterdam, Netherlands
Universitair Medisch Centrum Groningen
Groningen, Netherlands
Leids Universitair Medisch Centrum
Leiden, Netherlands
St Antonius ziekenhuis
Nieuwegein, Netherlands
St Radboud Universitair Medisch Centrum
Nijmegen, Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, Netherlands
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links:
Available IPD/Information:

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