Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System (Redefine)
|ClinicalTrials.gov Identifier: NCT02010905|
Recruitment Status : Unknown
Verified December 2015 by Berto J Bouma, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA).
Recruitment status was: Recruiting
First Posted : December 13, 2013
Last Update Posted : December 22, 2015
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.
|Condition or disease||Intervention/treatment||Phase|
|Tetralogy of Fallot Heart Defects, Congenital Ventricular Dysfunction, Right||Drug: Losartan Drug: Placebo||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||120 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System|
|Study Start Date :||December 2013|
|Estimated Primary Completion Date :||January 2018|
|Estimated Study Completion Date :||January 2018|
Active Comparator: Losartan 150mg daily
Losartan: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
Placebo Comparator: Placebo 150mg daily
Placebo: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
- Right ventricular ejection fraction [ Time Frame: two years ]RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)
- RV volumes (CMR) [ Time Frame: two years ]
- pulmonary regurgitation (CMR and echocardiography) [ Time Frame: two years ]
- aortic root diameter (CMR and echocardiography) [ Time Frame: two years ]
- echocardiographic parameters for RV and LV function [ Time Frame: one year and two years ]
- maximal exercise capacity (VO2 max) [ Time Frame: two years ]
- hospitalization for heart failure [ Time Frame: two years ]
- the prevalence of (supra) ventricular arrhythmias [ Time Frame: within two years ]
- the serum ntproBNP levels [ Time Frame: one year and two years ]
- NYHA class [ Time Frame: two years ]
- Quality of life (SF 36 and SQUASH) [ Time Frame: two years ]
- death [ Time Frame: two years ]
- RV mass (CMR) [ Time Frame: two years ]
- LV EF (CMR) [ Time Frame: two years ]
- LV volumes (CMR) [ Time Frame: two years ]
- LV mass (CMR) [ Time Frame: two years ]
- serum Galectin-3 levels [ Time Frame: two years ]
- circulating microRNA's [ Time Frame: two years ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02010905
|Academic Medical Center||Recruiting|
|Principal Investigator: J.P. Bokma|
|Principal Investigator: B.J.M. Mulder|
|Principal Investigator: B.J. Bouma|
|Universitair Medisch Centrum Groningen||Active, not recruiting|
|Leids Universitair Medisch Centrum||Recruiting|
|St Antonius ziekenhuis||Active, not recruiting|
|St Radboud Universitair Medisch Centrum||Active, not recruiting|
|Universitair Medisch Centrum Utrecht||Active, not recruiting|