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

Heart Defects, Congenital Clinical Trial

— Redefine  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02010905
• Other study ID #: NL44943.018.13
• Status: Recruiting
• Phase: Phase 2
• First received: December 6, 2013
• Last updated: December 21, 2015
• Start date: December 2013
• Est. completion date: January 2018

Study information

• Verified date: December 2015
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: J.P. Bokma
• Email: j.p.bokma[@]amc.uva.nl
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: January 2018
• Est. primary completion date: January 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• Losartan

• Placebo

Locations

Country	Name	City	State
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

Sponsors (2)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	The Interuniversity Cardiology Institute of the Netherlands

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Right ventricular ejection fraction	RV EF is measured by means of cardiovascular magnetic resonance imaging (CMR)	two years	No
Secondary	RV volumes (CMR)		two years	No
Secondary	pulmonary regurgitation (CMR and echocardiography)		two years	No
Secondary	aortic root diameter (CMR and echocardiography)		two years	No
Secondary	echocardiographic parameters for RV and LV function		one year and two years	No
Secondary	maximal exercise capacity (VO2 max)		two years	No
Secondary	hospitalization for heart failure		two years	No
Secondary	the prevalence of (supra) ventricular arrhythmias		within two years	No
Secondary	the serum ntproBNP levels		one year and two years	No
Secondary	NYHA class		two years	No
Secondary	Quality of life (SF 36 and SQUASH)		two years	No
Secondary	death		two years	No
Secondary	RV mass (CMR)		two years	No
Secondary	LV EF (CMR)		two years	No
Secondary	LV volumes (CMR)		two years	No
Secondary	LV mass (CMR)		two years	No
Secondary	serum Galectin-3 levels		two years	No
Secondary	circulating microRNA's		two years	No