Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD

Phase 2RecruitingNCT03593317

Hospices Civils de Lyon120 enrolled

Overview

Arrhythmogenic right ventricular dysplasia (ARVD) is a rare cardiomyopathy characterized by the progressive replacement of cardiomyocytes by fatty and fibrous tissue in the right ventricle (RV). These infiltrations lead to cardiac electrical instability and ventricular arrhythmia. Current treatment for ARVD is empirical and essentially based on treatment of arrhythmia. Thus, there is no validated treatment that will prevent the deterioration of the RV function in patients with ARVD. The investigator's hypothesis is that the use of anti-fibrotic medications will prevent or at least reduce the deterioration of the RV function. The aim of this project is to evaluate the effect of spironolactone, a Potassium-sparing diuretic on ventricular myocardial remodeling and on arrhythmia burden in patients with ARVD. The trial is a double-blind parallel multicenter prospective randomized phase II drug study. Patients will be randomized in the two groups: spironolactone or placebo. 13 centers in France will enroll the 120 patients (60 per group). Patients will be followed for 3 years (6 months, 1 year and 3 years) with all examinations (ECG, HA ECG, 24-hour Holter, trans-thoraciqc echocardiography (TTE), biological analyses) according to standard of care. A decrease in right and/or left ventricular deterioration and in arrhythmia burden are expected in ARVD patients treated with spironolactone. This reduction will improve the quality of life of patients and will reduce the number of hospitalizations and the risk of terminal heart failure.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

120

Conditions

Arrhythmogenic Right Ventricular Dysplasia

Interventions

SpironolactoneDRUG

The doses used in the study are the doses used in standard clinical practice. Initial dose is 25 mg/day until study end . The duration of treatment for each patient is 12 months.

PlaceboDRUG

Placebo will be taken once a day at the same time of day. The duration of treatment for each patient is 12 months.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * \>18years old * Diagnosis of ARVD based on Task Force criteria. Two major criteria: 1 morphologic and one rhythmic or 1 major and 2 minor criteria established by the European Society of Cardiology/International Society and Federation of Cardiology. * Left Ventricular Ejection Fraction \>40% * Written informed consent. Exclusion Criteria: * Patients under judicial protection. * Female patient who is pregnant or lactating, or is of child bearing potential (defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤ 55 years or 12 months if \> 55 years) and who did not agree to use highly effective methods of birth control throughout the study. * No health insurance. * Right heart failure patient (RV volume\>150ml). * Spironolactone contraindication: anuria, hyperkalemia (K+\>5 mmol/l), renal failure (DFGCréat\>22 mL/min/1,73 m2), end-stage liver failure, Addison's Disease, hypersensitivity to spironolactone or to any of the excipients (patients with galactose intolerance, lapp lactase deficiency or glucose or galactose malabsorption syndrome), association with eplerenone, association with other hyperkalemic diuretics, association with potassium salts, not recommended in cirrhotic patients (natraemia\<125 mmol/l) or in patients likely to present an acidosis. * Mandatory indication for a combination of ACE inhibitor and sartan or renin inhibitor (each authorized separately). * Acute phase of systemic disease. * Uncompensated hypothyroidism. * Acute hyperthyroidism. * Normal right ventricular volume. * Heart transplantation. * Swallowing disorders. * Participation in any other interventional clinical investigation that may have an impact on our study.

Locations (13)

CHU Amiens Picardie

Amiens, France

NOT_YET_RECRUITING

Hôpital Cardiologique Louis Pradel

Bron, France

RECRUITING

Hôpital Gabriel Montpied

Clermont-Ferrand, France

NOT_YET_RECRUITING

CHU Dijon

Dijon, France

RECRUITING

Hôpital Michallon

Grenoble, France

NOT_YET_RECRUITING

Hôpital de la Timone

Marseille, France

NOT_YET_RECRUITING

Hôpital Arnaud de Villeneuve

Montpellier, France

RECRUITING

Hôpital Laennec

Nantes, France

RECRUITING

Groupe Hospitalo Universitaire Caremeau

Nîmes, France

NOT_YET_RECRUITING

Hôpital Pitié Salpetrière

Paris, France

RECRUITING

...and 3 more locations

Outcomes

Primary Outcomes

Right ventricle longitudinal strain measured by echocardiography

Time frame: at year 1

Right ventricle infundibulum diameter measured by echocardiography

Time frame: at year 1

number of ventricular extrasystoles > 500 on 24h-Holter ECG

Time frame: at year 1

Secondary Outcomes

number of ventricular extrasystoles on 24h-Holter ECG

Time frame: at year 1

number of palpitations

Time frame: at year 1

number of palpitations

Time frame: at year 3

number of ventricular tachycardia

Time frame: at year 1

number of ventricular tachycardia

Time frame: at year 3

number of dyspnea

Time frame: at year 1

number of dyspnea

Time frame: at year 3

number of syncope

Time frame: at year 1

number of syncope

Time frame: at year 3

number of sudden death

Time frame: at year 1

number of sudden death

Time frame: at year 3

number of thoracic pain

Time frame: at year 1

number of thoracic pain

Time frame: at year 3

number of MACE (Major adverse cardiac events)

Time frame: at year 1

number of MACE (Major adverse cardiac events)

Time frame: at year 3

number of hospital admissions

Time frame: at year 1

number of hospital admissions

Time frame: at year 3

left ventricle diameters measured by echocardiography

Morphologic criterion

Time frame: at year 1

left ventricle diameters measured by echocardiography

Morphologic criterion

Time frame: at year 3

left ventricle volumes measured by echocardiography

Morphologic criterion

Time frame: at year 1

left ventricle volumes measured by echocardiography

Morphologic criterion

Time frame: at year 3

left ventricle ejection fraction measured by echocardiography

Morphologic criterion

Time frame: at year 1

left ventricle ejection fraction measured by echocardiography

Morphologic criterion

Time frame: at year 3

Left ventricular global longitudinal strain measured by echocardiography

Morphologic criterion

Time frame: at year 1

aneurism measured by echocardiography

Morphologic criterion

Time frame: at year 1

aneurism measured by echocardiography

Morphologic criterion

Time frame: at year 3

dyskinesia measured by echocardiography

Morphologic criterion

Time frame: at year 1

dyskinesia measured by echocardiography

Morphologic criterion

Time frame: at year 3

evolution of QRS width (50mm/s) on ECG

Morphologic criterion

Time frame: at year 1

number of ventricular extrasystoles on 24h Holter ECG

Rhythmic criterion

Time frame: at year 1

sustained ventricular tachycardia on 24h Holter ECG

Rhythmic criterion

Time frame: at year 1

evolution of PR interval duration on ECG

Rhythmic criterion

Time frame: at year 1

late potentials measured with high amplification ECG

Rhythmic criterion

Time frame: at year 3

number of ventricular extrasystoles by stress test

Rhythmic criterion

Time frame: at year 3

Evolution of functional symptoms by recording adverse events

Functional criteria

Time frame: at year 3

Number of hospital admissions owing to clinical deterioration

Time frame: at year 3

Evolution of telediastolic right ventricle volume measured by echocardiography

according to the genotype of desmosome genes

Time frame: at year 3

arrhythmia burden measured by 24h Holter ECG

according to the genotype of desmosome genes

Time frame: at year 3

Dosage of MMP9 (Matrix metallopeptidase 9)

Quantification of fibrosis

Time frame: at year 1

Dosage of MMP9 (Matrix metallopeptidase 9)

Quantification of fibrosis

Time frame: at year 3

Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)

Quantification of fibrosis

Time frame: at year 1

Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)

Quantification of fibrosis

Time frame: at year 3

Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)

Quantification of fibrosis

Time frame: at year 1

Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)

Quantification of fibrosis

Time frame: at year 3

Dosage of IL6 (Interleukin 6)

Quantification of inflammation

Time frame: at year 1

Dosage of IL6 (Interleukin 6)

Quantification of inflammation

Time frame: at year 3

Dosage of IL8 (Interleukin 8)

Quantification of inflammation

Time frame: at year 1

Dosage of IL8 (Interleukin 8)

Quantification of inflammation

Time frame: at year 3

Central Contacts

Roucher Aude, PhD

CONTACT

426739447 aude.roucher@chu-lyon.fr

Philippe Chevalier, MD, PhD

CONTACT

4 72 35 70 27 philippe.chevalier@chu-lyon.fr

Data from ClinicalTrials.gov

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