Blockade of the Renin-Angiotensin-Aldosterone System in Patients with Arvd.brave

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospices Civils De Lyon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

20 Dec 2024 → ongoing

Decision date (initial)

2023-08-24

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Direction générale de la santé

External identifiers

EU CT number

2023-505048-20-00

ClinicalTrials.gov

NCT03593317

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Evaluate the benefit of spironoclatone on the reduction of right ventricular deterioration and ventricular arrhythmia in patients with ARVD using echocardiography and 24h Holter-ECG.

Secondary objectives 10

1. Compare the effect of spironolactone treatment versus placebo at 1 year of follow-up on arrhythmia onset using 24h Holter-ECG
2. Compare the effect of spironolactone treatment versus placebo at 1 year follow-up on functional status.
3. Compare the effect of spironolactone treatment versus placebo at 1 year of follow-up on morphologic status using echocardiography.
4. Evaluate whether the treatment effect varies according to the genotype: Comparison of RV function using echocardiography and arrhythmia burden using 24h Holter-ECG at 1 year of follow-up according to the genotype (No mutation versus, at least, one mutation on desmosome genes).
5. Evaluate the association between fibrosis and inflammation markers and myocardial deterioration at 1 year of follow-up.
6. Compare the effect of spironolactone treatment versus placebo at 3 years of follow-up on arrhythmia onset using 24h Holter-ECG.
7. Compare the effect of spironolactone treatment versus placebo at 3 years follow-up on symptoms and functional status
8. Compare the effect of spironolactone treatment versus placebo at 3 years of follow-up on morphologic status.
9. Evaluate whether the treatment effect varies according to the genotype: Comparison of RV function using echocardiography and arrhythmia burden using 24h Holter-ECG at 3 years of follow-up according to the genotype
10. Evaluate the association between fibrosis and inflammation markers and myocardial deterioration at 3 years of follow-up.

Conditions and MedDRA coding

Arrhythmogenic right ventricular dysplasia

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Adult patient≥ 18 years
2. 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
3. LVEF >40%
4. Signed written informed consent
5. Patient on optimised medical treatment, including beta-blockers.

Exclusion criteria 13

1. Patients under judicial protection
2. 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.
3. No health insurance
4. Right heart failure patient (RV volume>150ml)
5. Spironolactone contraindication
6. Mandatory indication for a combination of ACE inhibitor and sartan or renin inhibitor (each authorized separately)
7. Acute phase of systemic disease
8. Uncompensated hypothyroidism
9. Acute hyperthyroidism
10. Normal right ventricular volume
11. Heart transplantation
12. Swallowing disorders
13. Participation in any other interventional clinical investigation that may have an impact on our study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Right ventricular deterioration is defined by a decrease in RV longitudinal strain or/and increase of RV infundibulum diameter between baseline and 1 year of follow-up measured by echography. Ventricular arrhythmia is defined by the change in arrhythmia, defined as a number of occurrences of ventricular extrasystoles > 500 during a 24h-Holter ECG monitor test, between baseline and 1 year of follow-up

Secondary endpoints 10

1. Ventricular arrhythmia is defined by number of ventricular extrasystoles during a 24h-Holter ECG monitor test, between baseline and 1 year of follow-up.
2. Functional status is defined by presence/absence and number of palpitations, ventricular tachycardia, dyspnea, syncope, sudden death, thoracic pain, MACE, and hospital admissions owing to clinical deterioration during the 1 year of follow-up
3. LV function (LV diameters, LV volumes, LVEF, LVGLS, presence of aneurism, % of dyskinesia), size of RV (LVOT diameters - PLAX and SAX, end-diastolique area, end-systolique area, 3D volumes), RV function (fractional shortening, presence of aneurism , % dyskinesia, TAPSE, tissue Doppler velocity, 3D RVEF, lateral longitudinal strain, global longitudinal strain) on echography between baseline and 1 year , and evolution of QRS width and PR duration on ECG between baseline and 1 year
4. RV function (fractional shortening, presence of aneurism , % dyskinesia, TAPSE, tissue Doppler velocity, 3D RVEF, lateral longitudinal strain, global longitudinal strain) using echocardiography and arrhythmia burden using 24h Holter-ECG at 1 year of follow-up according to the genotype (No mutation versus, at least, one mutation on desmosome genes).
5. Quantification of fibrosis and inflammation (measured at baseline and 1-year of follow-up) by dosage of MMP9, TIMP1, TIMP2, IL6 and IL8
6. Ventricular arrhythmia is defined by number of ventricular extrasystoles during a 24h-Holter ECG monitor test, between baseline and 3 years of follow-up
7. Functional status is defined by presence/absence and number of palpitations, ventricular tachycardia, dyspnea, syncope, sudden death, thoracic pain, MACE, and hospital admissions owing to clinical deterioration during the 3 years of follow-up.
8. Left Ventricle (LV) function (LV diameters, LV volumes, LVEF, LVGLS, presence of aneurism, % of dyskinesia), size of RV (LVOT diameters - PLAX and SAX, end-diastolique area, end-systolique area, 3D volumes), RV function (fractional shortening, presence of aneurism , % dyskinesia, TAPSE, tissue Doppler velocity, 3D RVEF, lateral longitudinal strain, global longitudinal strain) on echography between baseline and 3 years, and evolution of QRS width and PR duration on ECG between baseline and 3 year
9. RV function (fractional shortening, presence of aneurism , % dyskinesia, TAPSE, tissue Doppler velocity, 3D RVEF, lateral longitudinal strain, global longitudinal strain) using echocardiography and arrhythmia burden using 24h Holter-ECG at 3 years of follow-up according to the genotype (No mutation versus, at least, one mutation on desmosome genes).
10. Quantification of fibrosis and inflammation (measured at baseline and 3 years of follow-up) by dosage of MMP9, TIMP1, TIMP2, IL6 and IL8.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospices Civils De Lyon

Sponsor organisation

Hospices Civils De Lyon

Address

3 Quai Des Celestins, Bp 2251 Bp 2251

City

Lyon Cedex 02

Postcode

69229

Country

France

Scientific contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr Chevalier

Public contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr Chevalier

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications