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

• ClinicalTrials.gov Identifier: NCT02010905
• Recruitment Status: Unknown
• First Posted: December 13, 2013
• Last Update Posted: December 22, 2015
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborator: The Interuniversity Cardiology Institute of the Netherlands
• Information provided by (Responsible Party): Berto J Bouma, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information

• First Submitted Date: December 6, 2013
• First Posted Date: December 13, 2013
• Last Update Posted Date: December 22, 2015
• Study Start Date: December 2013
• Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 10, 2013)

Right ventricular ejection fraction [ Time Frame: two years ]

RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02010905 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: October 17, 2014)

• 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 ]

Original Secondary Outcome Measures (submitted: December 10, 2013)

• 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 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
• Official Title: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System

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: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Losartan
• Drug: Placebo

Study Arms

• Active Comparator: Losartan 150mg daily
  Losartan: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
  Intervention: Drug: Losartan
• Placebo Comparator: Placebo 150mg daily
  Placebo: white film-coated biconvex tablet (50mg) with a diameter of 8mm. One time daily three tablets.
  Intervention: Drug: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: December 10, 2013): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 2018
• Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT02010905
• Other Study ID Numbers: NL44943.018.13
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Berto J Bouma, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Study Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: The Interuniversity Cardiology Institute of the Netherlands
• Investigators: Not Provided
• PRS Account: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Verification Date: December 2015