Clinical trial NCT03593317: Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD
Official title: Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD: a Double-blind Multicentre Prospective Randomized Study.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Arrhythmogenic Right Ventricular Dysplasia
Keywords: Heart Failure
Right ventricle
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2018-07-20
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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: 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.

Primary outcomes:
measure: Right ventricle longitudinal strain measured by echocardiography
timeFrame: at year 1
measure: Right ventricle infundibulum diameter measured by echocardiography
timeFrame: at year 1
measure: number of ventricular extrasystoles > 500 on 24h-Holter ECG
timeFrame: at year 1
Secondary outcomes:
measure: number of ventricular extrasystoles on 24h-Holter ECG
timeFrame: at year 1
measure: number of palpitations
timeFrame: at year 1
measure: number of palpitations
timeFrame: at year 3
measure: number of ventricular tachycardia
timeFrame: at year 1
measure: number of ventricular tachycardia
timeFrame: at year 3
measure: number of dyspnea
timeFrame: at year 1
measure: number of dyspnea
timeFrame: at year 3
measure: number of syncope
timeFrame: at year 1
measure: number of syncope
timeFrame: at year 3
measure: number of sudden death
timeFrame: at year 1
measure: number of sudden death
timeFrame: at year 3
measure: number of thoracic pain
timeFrame: at year 1
measure: number of thoracic pain
timeFrame: at year 3
measure: number of MACE (Major adverse cardiac events)
timeFrame: at year 1
measure: number of MACE (Major adverse cardiac events)
timeFrame: at year 3
measure: number of hospital admissions
timeFrame: at year 1
measure: number of hospital admissions
timeFrame: at year 3
measure: left ventricle diameters measured by echocardiography
timeFrame: at year 1
measure: left ventricle diameters measured by echocardiography
timeFrame: at year 3
measure: left ventricle volumes measured by echocardiography
timeFrame: at year 1
measure: left ventricle volumes measured by echocardiography
timeFrame: at year 3
measure: left ventricle ejection fraction measured by echocardiography
timeFrame: at year 1
measure: left ventricle ejection fraction measured by echocardiography
timeFrame: at year 3
measure: Left ventricular global longitudinal strain measured by echocardiography
timeFrame: at year 1
measure: aneurism measured by echocardiography
timeFrame: at year 1
measure: aneurism measured by echocardiography
timeFrame: at year 3
measure: dyskinesia measured by echocardiography
timeFrame: at year 1
measure: dyskinesia measured by echocardiography
timeFrame: at year 3
measure: evolution of QRS width (50mm/s) on ECG
timeFrame: at year 1
measure: number of ventricular extrasystoles on 24h Holter ECG
timeFrame: at year 1
measure: sustained ventricular tachycardia on 24h Holter ECG
timeFrame: at year 1
measure: evolution of PR interval duration on ECG
timeFrame: at year 1
measure: late potentials measured with high amplification ECG
timeFrame: at year 3
measure: number of ventricular extrasystoles by stress test
timeFrame: at year 3
measure: Evolution of functional symptoms by recording adverse events
timeFrame: at year 3
measure: Number of hospital admissions owing to clinical deterioration
timeFrame: at year 3
measure: Evolution of telediastolic right ventricle volume measured by echocardiography
timeFrame: at year 3
measure: arrhythmia burden measured by 24h Holter ECG
timeFrame: at year 3
measure: Dosage of MMP9 (Matrix metallopeptidase 9)
timeFrame: at year 1
measure: Dosage of MMP9 (Matrix metallopeptidase 9)
timeFrame: at year 3
measure: Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)
timeFrame: at year 1
measure: Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)
timeFrame: at year 3
measure: Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)
timeFrame: at year 1
measure: Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)
timeFrame: at year 3
measure: Dosage of IL6 (Interleukin 6)
timeFrame: at year 1
measure: Dosage of IL6 (Interleukin 6)
timeFrame: at year 3
measure: Dosage of IL8 (Interleukin 8)
timeFrame: at year 1
measure: Dosage of IL8 (Interleukin 8)
timeFrame: at year 3
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens Picardie
city: Bron
country: France
facility: Hôpital Cardiologique Louis Pradel
city: Clermont-ferrand
country: France
facility: Hôpital Gabriel Montpied
city: Dijon
country: France
facility: CHU Dijon
city: Grenoble
country: France
facility: Hôpital Michallon
city: Marseille
country: France
facility: Hôpital de la Timone
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve
city: Nantes
country: France
facility: Hôpital Laennec
city: Nimes
country: France
facility: Groupe Hospitalo Universitaire Caremeau
city: Paris
country: France
facility: Hôpital Pitié Salpetrière
city: Pessac
country: France
facility: Hôpital de Haut-Lévêque
city: Strasbourg
country: France
facility: Nouvel Hôpital Civil
city: Toulouse
country: France
facility: Hôpital Rangueil
Study officials:
affiliation: Hospices Civils de Lyon
name: Philippe Chevalier, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: