Evaluation of Sacubitril/Valsartan in Preventing Disease Progression in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy: A Multicenter Randomized Trial

The primary objective of the ARNI-ARVC multicentre randomized trial is to evaluate the **anti-fibrotic** and antiremodeling effects of sacubitril/valsartan in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). This is clinically relevant as ARVC is a progressive condition characterized by fibrofatty replacement of the myocardium, leading to arrhythmias and heart failure. The potential anti-fibrotic and antiremodeling properties of sacubitril/valsartan could offer a therapeutic benefit in slowing disease progression and improving patient outcomes.

The clinical trial involves participants diagnosed with **arrhythmogenic right ventricular cardiomyopathy (ARVC)**, a condition characterized by fibrotic and remodeling changes in the heart. The study population includes both male and female subjects, aged 18 years and older, with a left ventricular ejection fraction (LVEF) of 40% or greater as assessed by cardiac magnetic resonance imaging (CMR). The trial does not include a vulnerable population. Participants were selected based on a confirmed diagnosis of ARVC according to the 2010 International Task Force Criteria (ITFC). The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits have not been specified. Key inclusion criteria include the ability to provide written informed consent. The trial aims to evaluate the anti-fibrotic and antiremodeling effects of sacubitril/valsartan in individuals with ARVC.

The clinical trial is designed to evaluate the **anti-fibrotic** and antiremodeling effects of **sacubitril/valsartan** in patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC). This is a multicenter, randomized, double-blind, controlled trial. The trial is expected to span from September 2022 to April 2029, with participant involvement lasting up to 48 weeks. The study will utilize **Entresto** film-coated tablets, administered orally, with varying dosages of 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg, depending on the treatment phase.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the 2010 International Task Force Criteria for ARVC, age over 18 years, and a left ventricular ejection fraction (LVEF) of at least 40% as assessed by cardiac magnetic resonance (CMR). Following the screening, participants will be randomized into treatment groups. Regular follow-up visits will be scheduled to monitor the primary endpoints, which include the degree of fibrosis of the left ventricular muscle and LVEF in CMR, as well as the load of ventricular arrhythmias. Secondary endpoints will assess NT-proBNP concentration, fibrosis markers, morphological and functional criteria via echocardiography and CMR, ECG parameters, arrhythmias, physical capacity, hospitalization for heart failure symptoms, and sudden cardiac death.

The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with the study protocol, or withdraw consent. The trial aims to provide comprehensive data on the efficacy of sacubitril/valsartan in preventing disease progression in ARVC, contributing valuable insights into the management of this condition.

The clinical trial involves the administration of **Entresto** in three different dosages, each formulated as film-coated tablets. The first experimental medication is Entresto 24 mg/26 mg film-coated tablets, containing the active substances **valsartan** and **sacubitril**. These tablets are administered orally. The maximum daily dose is 24 mg of valsartan and 26 mg of sacubitril, with a total maximum dose of 48 mg per day. The treatment period is set for a maximum of 48 weeks. The medication functions as an angiotensin II receptor antagonist and neprilysin inhibitor, and it is not a pediatric formulation.

The second experimental medication is Entresto 49 mg/51 mg film-coated tablets, also containing valsartan and sacubitril. These tablets are administered orally, with a maximum daily dose of 49 mg of valsartan and 51 mg of sacubitril, and a total maximum dose of 98 mg per day. The treatment duration is up to 48 weeks. This formulation also acts as an angiotensin II receptor antagonist and neprilysin inhibitor and is not intended for pediatric use.

The third experimental medication is Entresto 97 mg/103 mg film-coated tablets, containing the same active substances, valsartan and sacubitril. These tablets are administered orally, with a maximum daily dose of 97 mg of valsartan and 103 mg of sacubitril, and a total maximum dose of 194 mg per day. The treatment period is limited to 48 weeks. Similar to the other formulations, this medication serves as an angiotensin II receptor antagonist and neprilysin inhibitor and is not a pediatric formulation.

All three formulations are produced by Novartis Europharm Limited and are chemically derived. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial titled "Sacubitril/valsartan in the prevention of disease progression in patients with an ancient arrhythmogenic service - ARNI-ARVC multicentre randomized trial" will be assessed using both primary and secondary endpoints. The primary endpoints include the degree of fibrosis of the left ventricular muscle as measured by cardiac magnetic resonance (CMR) examination, **left ventricular ejection fraction (LVEF)** in CMR, and ventricular arrhythmias load. These parameters will provide insights into the anti-fibrotic and antiremodeling effects of sacubitril/valsartan in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).

Secondary endpoints will encompass a range of biomarkers and clinical assessments. These include NT-proBNP concentration and two fibrosis markers: sST2 and Gal-3. Morphological and functional criteria will be evaluated using echocardiography (ECHO) and CMR, focusing on the size of the left and right ventricles and contractility disorders. Electrocardiogram (ECG) parameters such as terminal activation delay (TAD) and the extent of negative T waves in precordial leads will also be assessed. Additional evaluations will include arrhythmias in ECG, 24-hour Holter ECG recording, ergospirometry, and implantable cardioverter-defibrillator (ICD) readings. Physical capacity will be measured through peak oxygen consumption (pVO2) in ergospirometric tests. Hospitalization for heart failure symptoms and sudden cardiac death will also be monitored as part of the secondary endpoints.