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

Arrhythmogenic Right Ventricular Dysplasia Clinical Trial

— BRAVE  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03593317
• Other study ID #: 69HCL18_0038
• Secondary ID: 2023-505048-20-0
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 2024
• Est. completion date: March 2028

Study information

• Verified date: December 2023
• Source: Hospices Civils de Lyon
• Contact: Roucher Aude, PhD
• Phone: 426739447
• Email: aude.roucher[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 120
• Est. completion date: March 2028
• Est. primary completion date: March 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Arrhythmogenic Right Ventricular Dysplasia

Intervention

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

Locations

Country	Name	City	State
France	Hôpital Cardiologique Louis Pradel	Bron

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Right ventricle longitudinal strain measured by echocardiography		at year 1
Primary	Right ventricle infundibulum diameter measured by echocardiography		at year 1
Primary	number of ventricular extrasystoles > 500 on 24h-Holter ECG		at year 1
Secondary	number of ventricular extrasystoles on 24h-Holter ECG		at year 1
Secondary	number of palpitations		at year 1
Secondary	number of palpitations		at year 3
Secondary	number of ventricular tachycardia		at year 1
Secondary	number of ventricular tachycardia		at year 3
Secondary	number of dyspnea		at year 1
Secondary	number of dyspnea		at year 3
Secondary	number of syncope		at year 1
Secondary	number of syncope		at year 3
Secondary	number of sudden death		at year 1
Secondary	number of sudden death		at year 3
Secondary	number of thoracic pain		at year 1
Secondary	number of thoracic pain		at year 3
Secondary	number of MACE (Major adverse cardiac events)		at year 1
Secondary	number of MACE (Major adverse cardiac events)		at year 3
Secondary	number of hospital admissions		at year 1
Secondary	number of hospital admissions		at year 3
Secondary	left ventricle diameters measured by echocardiography	Morphologic criterion	at year 1
Secondary	left ventricle diameters measured by echocardiography	Morphologic criterion	at year 3
Secondary	left ventricle volumes measured by echocardiography	Morphologic criterion	at year 1
Secondary	left ventricle volumes measured by echocardiography	Morphologic criterion	at year 3
Secondary	left ventricle ejection fraction measured by echocardiography	Morphologic criterion	at year 1
Secondary	left ventricle ejection fraction measured by echocardiography	Morphologic criterion	at year 3
Secondary	Left ventricular global longitudinal strain measured by echocardiography	Morphologic criterion	at year 1
Secondary	aneurism measured by echocardiography	Morphologic criterion	at year 1
Secondary	aneurism measured by echocardiography	Morphologic criterion	at year 3
Secondary	dyskinesia measured by echocardiography	Morphologic criterion	at year 1
Secondary	dyskinesia measured by echocardiography	Morphologic criterion	at year 3
Secondary	evolution of QRS width (50mm/s) on ECG	Morphologic criterion	at year 1
Secondary	number of ventricular extrasystoles on 24h Holter ECG	Rhythmic criterion	at year 1
Secondary	sustained ventricular tachycardia on 24h Holter ECG	Rhythmic criterion	at year 1
Secondary	evolution of PR interval duration on ECG	Rhythmic criterion	at year 1
Secondary	late potentials measured with high amplification ECG	Rhythmic criterion	at year 3
Secondary	number of ventricular extrasystoles by stress test	Rhythmic criterion	at year 3
Secondary	Evolution of functional symptoms by recording adverse events	Functional criteria	at year 3
Secondary	Number of hospital admissions owing to clinical deterioration		at year 3
Secondary	Evolution of telediastolic right ventricle volume measured by echocardiography	according to the genotype of desmosome genes	at year 3
Secondary	arrhythmia burden measured by 24h Holter ECG	according to the genotype of desmosome genes	at year 3
Secondary	Dosage of MMP9 (Matrix metallopeptidase 9)	Quantification of fibrosis	at year 1
Secondary	Dosage of MMP9 (Matrix metallopeptidase 9)	Quantification of fibrosis	at year 3
Secondary	Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)	Quantification of fibrosis	at year 1
Secondary	Dosage of TIMP1 (Tissue Inhibitory MetalloProtease 1)	Quantification of fibrosis	at year 3
Secondary	Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)	Quantification of fibrosis	at year 1
Secondary	Dosage of TIMP2 (Tissue Inhibitory MetalloProtease 2)	Quantification of fibrosis	at year 3
Secondary	Dosage of IL6 (Interleukin 6)	Quantification of inflammation	at year 1
Secondary	Dosage of IL6 (Interleukin 6)	Quantification of inflammation	at year 3
Secondary	Dosage of IL8 (Interleukin 8)	Quantification of inflammation	at year 1
Secondary	Dosage of IL8 (Interleukin 8)	Quantification of inflammation	at year 3