Evaluation of Spironolactone on Right Ventricular Function and Arrhythmia in Arrhythmogenic Right Ventricular Dysplasia: A Double-Blind, Randomized Study

The primary objective of this study is to evaluate the benefit of **spironolactone** on the reduction of right ventricular deterioration and ventricular arrhythmia in patients with **arrhythmogenic right ventricular dysplasia** (ARVD) using echocardiography and 24-hour Holter-ECG. This is clinically relevant as it aims to determine the efficacy of spironolactone in managing ARVD, a condition characterized by the replacement of myocardial tissue with fibrofatty tissue, leading to arrhythmias and potential heart failure.

Secondary objectives include:

• Comparing the effect of spironolactone treatment versus placebo at 1 and 3 years of follow-up on arrhythmia onset using 24-hour Holter-ECG.
• Assessing the impact on functional status and symptoms at 1 and 3 years of follow-up.
• Evaluating changes in morphologic status using echocardiography at 1 and 3 years of follow-up.
• Determining whether the treatment effect varies according to genotype by comparing right ventricular function and arrhythmia burden at 1 and 3 years of follow-up.
• Investigating the association between fibrosis and inflammation markers and myocardial deterioration at 1 and 3 years of follow-up.

The clinical trial focuses on patients diagnosed with **arrhythmogenic right ventricular dysplasia** (ARVD). The study population includes both male and female adults aged 18 years and older. Participants are required to have a left ventricular ejection fraction (LVEF) greater than 40% and must be on optimized medical treatment, including beta-blockers. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include a diagnosis of ARVD based on Task Force criteria, with specific morphologic and rhythmic criteria established by the European Society of Cardiology/International Society and Federation of Cardiology. Participants must have signed written informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **spironolactone** in reducing right ventricular deterioration and ventricular arrhythmia in patients diagnosed with **arrhythmogenic right ventricular dysplasia** (ARVD). This study is a randomized, double-blind, controlled trial, conducted over a period of five years, with an estimated recruitment start date of September 2023 and an estimated end date of September 2028. Participants will be randomly assigned to receive either spironolactone 25mg tablets or a placebo, both administered orally. The trial will include adult patients aged 18 years or older, diagnosed with ARVD based on Task Force criteria, with a left ventricular ejection fraction (LVEF) greater than 40%, and who have provided signed written informed consent. Participants must be on optimized medical treatment, including beta-blockers, to be eligible for inclusion.

The sequence of study visits will begin with a screening visit to confirm eligibility based on the inclusion criteria. Following randomization, participants will undergo baseline assessments, including echocardiography and 24-hour Holter ECG monitoring, to establish initial measurements of right ventricular function and arrhythmia burden. Follow-up visits will occur at regular intervals, with key assessments repeated at one year and three years to evaluate changes in right ventricular function, arrhythmia burden, and other secondary endpoints such as functional status and fibrosis quantification. The end-of-study visit will occur at the conclusion of the five-year period, where final assessments will be conducted to determine the long-term effects of spironolactone on the primary and secondary endpoints.

Participant involvement is expected to last for the entire duration of the trial, approximately five years, unless early termination is warranted. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. The primary endpoint is defined by changes in right ventricular longitudinal strain and infundibulum diameter, as well as the number of ventricular extrasystoles, measured between baseline and one year. Secondary endpoints include additional measures of ventricular function, arrhythmia burden, and clinical outcomes over the one-year and three-year follow-up periods. The trial is categorized as a Phase 4 study, indicating its focus on post-marketing surveillance to further assess the therapeutic benefits and safety of spironolactone in this patient population.

The clinical trial involves the administration of **Spironolactone 25mg Tablets** as the experimental medication. Spironolactone is a **film-coated tablet** intended for **oral use**. Each tablet contains 25 milligrams of the active substance spironolactone, a chemical compound. The maximum daily dose is 25 mg, with a total maximum dose of 9125 mg over the course of the study. The treatment period is set for a maximum of 12 weeks. The tablets are manufactured by TEVA UK LIMITED and have undergone over-encapsulation for the purposes of the trial. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo consists of a **Lactose / 1% Magnesium Stearate blend**. The pharmaceutical form, dosage, and route of administration for the placebo are not specified. The placebo is designed to match the experimental treatment in appearance to maintain the double-blind nature of the trial. The placebo serves as a control to evaluate the efficacy of spironolactone in reducing right ventricular deterioration and ventricular arrhythmia in patients with arrhythmogenic right ventricular dysplasia (ARVD).

Efficacy in the clinical trial titled "BLOCKADE OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN PATIENTS WITH ARVD: A DOUBLE-BLIND MULTICENTRE PROSPECTIVE RANDOMIZED STUDY" will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of right ventricular deterioration and ventricular arrhythmia in patients with **Arrhythmogenic Right Ventricular Dysplasia (ARVD)**. Right ventricular deterioration is defined by a decrease in right ventricular longitudinal strain or an increase in right ventricular infundibulum diameter, measured by echocardiography, between baseline and one year of follow-up. Ventricular arrhythmia is assessed by the change in the number of occurrences of ventricular extrasystoles, greater than 500, during a 24-hour Holter ECG monitor test, also between baseline and one year of follow-up.

Secondary endpoints encompass a broader range of assessments, including the number of ventricular extrasystoles during a 24-hour Holter ECG monitor test, functional status indicators such as palpitations, ventricular tachycardia, dyspnea, syncope, sudden death, thoracic pain, major adverse cardiac events (MACE), and hospital admissions due to clinical deterioration over one and three years of follow-up. Additionally, left ventricular function, right ventricular size and function, and the evolution of QRS width and PR duration on ECG will be evaluated using echocardiography. The study will also quantify fibrosis and inflammation through the measurement of biomarkers such as MMP9, TIMP1, TIMP2, IL6, and IL8 at baseline and at one and three years of follow-up. These assessments will be conducted to determine the efficacy of spironolactone in reducing right ventricular deterioration and ventricular arrhythmia in patients with ARVD.