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

Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD: a Double-blind Multicentre Prospective Randomized Study.

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 Overview

• Status: Not yet recruiting
• Conditions: Arrhythmogenic Right Ventricular Dysplasia
• Intervention / Treatment: Drug: Spironolactone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Philippe Chevalier, MD, PhD; Phone Number: +33 4 72 35 70 27; Email: philippe.chevalier@chu-lyon.fr
• Study Contact Backup: Name: Roucher Aude, PhD; Phone Number: +33 426739447; Email: aude.roucher@chu-lyon.fr

Study Locations

• France
  • Bron, France
    • Hôpital Cardiologique Louis Pradel
    • Contact: Philippe Chevalier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
• Increased right ventricular volume (> 100ml/m² female; > 110ml/m² male)
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group	Drug: Placebo; Placebo will be taken once a day at the same time of day. The duration of treatment for each patient is 12 months.
Experimental: Spironolactone group	Drug: Spironolactone; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Right ventricle longitudinal strain measured by echocardiography	at year 1
Right ventricle infundibulum diameter measured by echocardiography	at year 1
number of ventricular extrasystoles > 500 on 24h-Holter ECG	at year 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
aneurism measured by echocardiography	Morphologic criterion	at year 3
late potentials measured with high amplification ECG	Rhythmic criterion	at year 3
number of ventricular extrasystoles by stress test	Rhythmic criterion	at year 3
Evolution of functional symptoms by recording adverse events	Functional criteria	at year 3
Number of hospital admissions owing to clinical deterioration		at year 3
arrhythmia burden measured by 24h Holter ECG	according to the genotype of desmosome genes	at year 3
Dosage of MMP9 (Matrix metallopeptidase 9)	Quantification of fibrosis	at year 3
Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)	Quantification of fibrosis	at year 3
Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)	Quantification of fibrosis	at year 3
Dosage of IL6 (Interleukin 6)	Quantification of inflammation	at year 3
Dosage of IL8 (Interleukin 8)	Quantification of inflammation	at year 3
number of ventricular extrasystoles on 24h-Holter ECG		at year 1
number of palpitations		at year 1
number of palpitations		at year 3
number of ventricular tachycardia		at year 1
number of ventricular tachycardia		at year 3
number of dyspnea		at year 1
number of dyspnea		at year 3
number of syncope		at year 1
number of syncope		at year 3
number of sudden death		at year 1
number of sudden death		at year 3
number of thoracic pain		at year 1
number of thoracic pain		at year 3
number of MACE (Major adverse cardiac events)		at year 1
number of MACE (Major adverse cardiac events)		at year 3
number of hospital admissions		at year 1
number of hospital admissions		at year 3
left ventricle diameters measured by echocardiography	Morphologic criterion	at year 1
left ventricle diameters measured by echocardiography	Morphologic criterion	at year 3
left ventricle volumes measured by echocardiography	Morphologic criterion	at year 1
left ventricle volumes measured by echocardiography	Morphologic criterion	at year 3
left ventricle ejection fraction measured by echocardiography	Morphologic criterion	at year 1
left ventricle ejection fraction measured by echocardiography	Morphologic criterion	at year 3
Left ventricular global longitudinal strain measured by echocardiography	Morphologic criterion	at year 1
aneurism measured by echocardiography	Morphologic criterion	at year 1
dyskinesia measured by echocardiography	Morphologic criterion	at year 1
dyskinesia measured by echocardiography	Morphologic criterion	at year 3
evolution of QRS width (50mm/s) on ECG	Morphologic criterion	at year 1
number of ventricular extrasystoles on 24h Holter ECG	Rhythmic criterion	at year 1
sustained ventricular tachycardia on 24h Holter ECG	Rhythmic criterion	at year 1
evolution of PR interval duration on ECG	Rhythmic criterion	at year 1
Evolution of telediastolic right ventricle volume measured by echocardiography	according to the genotype of desmosome genes	at year 3
Dosage of MMP9 (Matrix metallopeptidase 9)	Quantification of fibrosis	at year 1
Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)	Quantification of fibrosis	at year 1
Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)	Quantification of fibrosis	at year 1
Dosage of IL6 (Interleukin 6)	Quantification of inflammation	at year 1
Dosage of IL8 (Interleukin 8)	Quantification of inflammation	at year 1

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Philippe Chevalier, MD, PhD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: July 10, 2018
• First Submitted That Met QC Criteria: July 19, 2018
• First Posted (Actual): July 20, 2018

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 26, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Heart Failure; Right ventricle
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Cardiomyopathies; Heart Defects, Congenital; Cardiovascular Abnormalities; Arrhythmogenic Right Ventricular Dysplasia; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 69HCL18_0038; 2023-505048-20-00 (Other Identifier: EUCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No