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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
ICIN - Netherlands Heart Institute
Information provided by (Responsible Party):
Berto J Bouma, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT02010905
First received: December 6, 2013
Last updated: December 10, 2013
Last verified: December 2013
  Purpose

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 Intervention Phase
Tetralogy of Fallot
Heart Defects, Congenital
Ventricular Dysfunction, Right
Drug: Losartan
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System

Resource links provided by NLM:


Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • Right ventricular ejection fraction [ Time Frame: two years ] [ Designated as safety issue: No ]
    RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)


Secondary Outcome Measures:
  • RV volumes (CMR) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • pulmonary regurgitation (CMR and echocardiography) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • aortic root diameter (CMR and echocardiography) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • echocardiographic parameters for RV and LV function [ Time Frame: one year and two years ] [ Designated as safety issue: No ]
  • maximal exercise capacity (VO2 max) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • hospitalization for heart failure [ Time Frame: two years ] [ Designated as safety issue: No ]
  • the prevalence of (supra) ventricular arrhythmias [ Time Frame: within two years ] [ Designated as safety issue: No ]
  • the serum ntproBNP levels [ Time Frame: one year and two years ] [ Designated as safety issue: No ]
  • NYHA class [ Time Frame: two years ] [ Designated as safety issue: No ]
  • Quality of life (SF 36 and SQUASH) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • death [ Time Frame: two years ] [ Designated as safety issue: No ]
  • RV mass (CMR) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • LV EF (CMR) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • LV volumes (CMR) [ Time Frame: two years ] [ Designated as safety issue: No ]
  • LV mass (CMR) [ Time Frame: two years ] [ Designated as safety issue: No ]

Estimated Enrollment: 120
Study Start Date: December 2013
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02010905

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
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ICIN - Netherlands Heart Institute
  More Information

No publications provided

Responsible Party: Berto J Bouma, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT02010905     History of Changes
Other Study ID Numbers: NL44943.018.13
Study First Received: December 6, 2013
Last Updated: December 10, 2013
Health Authority: Netherlands: Centrale Commissie Mensgebonden Onderzoek

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Losartan

Additional relevant MeSH terms:
Heart Defects, Congenital
Congenital Abnormalities
Tetralogy of Fallot
Ventricular Dysfunction, Right
Ventricular Dysfunction
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Losartan
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 15, 2014