Evaluation of Prophylactic Treatment with Verapamil, Nebivolol, and Amiodarone Hydrochloride on Left Ventricular Function in Asymptomatic Patients with Frequent PVCs

The primary objective of the study is to demonstrate that **prophylactic treatment** of patients with asymptomatic frequent premature ventricular complexes (PVCs) is superior to a simple follow-up strategy with no therapy in preventing subsequent left ventricular (LV) dysfunction at 24 months. This is clinically relevant as it aims to prevent the progression of cardiac dysfunction in patients who are currently asymptomatic but at risk due to frequent PVCs. The prophylactic treatment involves the use of antiarrhythmic drugs, with the option of catheter ablation if the PVC burden remains above 10% after two lines of antiarrhythmic drug (AAD) treatment.

Secondary objectives include: - Evaluating the efficacy, safety, and feasibility of prophylactic PVC suppression using drugs with or without catheter ablation. - Prospectively assessing the impact of frequent PVCs on clinical, biological, and imaging endpoints to understand the chronological development of PVC-induced cardiomyopathy (PVC-iCMP) and identify early markers of the disease. - Identifying predictors of subsequent development of PVC-iCMP in healthy patients with PVCs to improve risk stratification in this population.

The clinical trial involves **asymptomatic patients** with frequent premature ventricular contractions (PVCs) and normal left ventricular ejection fraction (LVEF). The study population includes both male and female participants aged between 18 and 85 years. Participants are required to have a PVC burden of at least 10%, regardless of current or preexisting antiarrhythmic drug intake, and must maintain a normal LVEF of 55% or higher. Individuals with underlying cardiomyopathy are eligible as long as their left ventricular function remains preserved. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' lifestyle factors such as diet, physical activity, or habits are not specified. Key inclusion criteria include asymptomatic status and signed informed consent. The selection process ensures that participants meet these criteria to evaluate the efficacy of prophylactic treatment compared to a simple follow-up strategy in preventing subsequent left ventricular dysfunction over a 24-month period.

The clinical trial is designed to evaluate the efficacy of prophylactic treatment in **asymptomatic patients** with frequent premature ventricular contractions (PVCs) and normal left ventricular ejection fraction (LVEF). The study employs a randomized, double-blind, controlled design to compare the outcomes of patients receiving prophylactic treatment with those under a simple follow-up strategy without therapy. The trial is set to span a duration of 24 months, with the primary objective being to prevent the development of left ventricular dysfunction, defined as a 15% relative decrease in LVEF or an LVEF of less than 50% within two years following randomization.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 85 years), PVC burden (≥10%), asymptomatic status, and normal LVEF. Following randomization, participants will attend follow-up visits at 6, 12, 18, and 24 months (M6, M12, M18, and M24) to monitor PVC burden, LVEF, and other secondary endpoints such as global longitudinal strain (GLS) and exercise capacity. The end-of-study visit at M24 will assess the primary endpoint and overall treatment efficacy.

The expected length of participant involvement is 24 months, with conditions for early termination including the development of significant adverse events or a decision by the participant to withdraw consent. Safety endpoints will be closely monitored, including death from any cause, cardiovascular-related death, and hospitalization due to adverse events. The trial aims to provide comprehensive data on the prophylactic treatment's impact on preventing left ventricular dysfunction in the target patient population.

The clinical trial involves the administration of several **experimental medications**. **Verapamil** is provided in an oral pharmaceutical form, with a maximum daily dose of 360 mg and a total maximum dose of 262,800 mg over a 24-month period. The administration route is oral, and the medication is not a pediatric formulation. The active substance is chemically derived.

**Nebivolol** is also administered orally, with a maximum daily dose of 10 mg and a total maximum dose of 7,300 mg over the same treatment period. This medication is similarly not formulated for pediatric use and is chemically derived.

**Amiodarone Hydrochloride** is provided in an oral form, with a maximum daily dose of 200 mg and a total maximum dose of 94,000 mg over 24 months. The active substance is of chemical origin, and the formulation is not intended for pediatric patients.

**Propafenone Hydrochloride** is administered orally, with a maximum daily dose of 600 mg and a total maximum dose of 438,000 mg over the treatment period. The active substance is chemically derived, and the formulation is not pediatric.

**Bisoprolol Fumarate** combined with **Hydrochlorothiazide** is provided in an oral form, with a maximum daily dose of 10 mg and a total maximum dose of 7,300 mg over 24 months. Both active substances are of chemical origin, and the formulation is not intended for pediatric use.

**Cimetidine** is administered orally, with a maximum daily dose of 360 mg and a total maximum dose of 262,800 mg over the treatment period. The active substance is chemically derived, and the formulation is not pediatric.

**Flecainide** is provided in an oral form, with a maximum daily dose of 250 mg and a total maximum dose of 182,500 mg over 24 months. The active substance is of chemical origin, and the formulation is not intended for pediatric patients.

**Sotalol Hydrochloride** is administered orally, with a maximum daily dose of 320 mg and a total maximum dose of 233,600 mg over the treatment period. The active substance is chemically derived, and the formulation is not pediatric.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study aims to evaluate the efficacy of these medications in preventing left ventricular dysfunction in patients with asymptomatic frequent premature ventricular complexes.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the development of left ventricular (LV) dysfunction, specifically **PVC-iCMP**, defined as a 15% relative decrease in left ventricular ejection fraction (LVEF) and/or an LVEF of less than 50% within two years following randomization. This will be measured using cardiac magnetic resonance imaging (cMRI) or transthoracic echocardiography (TTE) when cMRI is not possible.

Secondary efficacy endpoints include the mean premature ventricular contraction (PVC) burden during the follow-up at months 6, 12, 18, and 24, and the percentage of patients achieving a PVC burden of less than 10% during the second year post-randomization. Additional measures include LVEF variation, LV volumes variation (end-diastolic and systolic volumes), and Global Longitudinal Strain (GLS) variation from baseline to month 24. The cumulative incidence of patients with a GLS decrease greater than 15% from baseline to month 24 will also be evaluated. Other parameters include the relative variation of Nt-ProBNP from baseline to month 24, exercise capacity on a treadmill (measured in Watts, Mets, MVO2), and NYHA classification at baseline and month 24. Quality of life will be assessed using the SF-36 scale at inclusion, month 12, and month 24.

Safety endpoints will also be monitored, including death from any cause, cardiovascular cause of death, hospitalization for adverse events, and the nature, frequency, severity, and outcome of adverse events and serious adverse events within the follow-up period. These may be linked or not to antiarrhythmic drugs or the ablation procedure.