Efficacy of Flecainide Monotherapy Versus Flecainide with Beta-Blockers or Calcium Channel Blockers in Andersen-Tawil Syndrome and MEPPC Patients

The primary objective of this study is to evaluate the **efficacy** of **flecainide** monotherapy compared to combination therapy with **beta-blockers** or **calcium channel blockers** in patients diagnosed with **Andersen-Tawil syndrome** (ATS) and **Multifocal Ectopic Purkinje-related Premature Contractions** (MEPPC). This investigation is clinically relevant as it aims to optimize drug therapy for the suppression of ventricular arrhythmias, which are critical in managing these conditions. Additionally, for patients with MEPPC, the study will compare the efficacy of **quinidine** with flecainide monotherapy in a subsequent phase. The outcomes of this study could significantly impact therapeutic strategies and improve patient management in these specific cardiac conditions.

The clinical trial involves participants diagnosed with **Andersen-Tawil syndrome** (ATS) or **Multifocal Ectopic Purkinje-related Premature Contractions** (MEPPC). The study population includes both male and female subjects aged 18 years and older. Participants are required to have a clinical diagnosis of ATS or MEPPC, with a demonstrated disease phenotype including ventricular arrhythmia burden, and must currently be on a stable dose of flecainide for at least three months. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria focus on individuals with specific diagnostic and treatment backgrounds, ensuring a targeted study group for evaluating the efficacy of flecainide monotherapy compared to combination therapies. Lifestyle factors such as diet and physical activity are not specified as considerations for this trial.

The clinical trial is designed to evaluate the efficacy of **flecainide** monotherapy compared to combination therapy with **beta-blockers** or **calcium channel blockers** in patients diagnosed with **Andersen-Tawil syndrome** (ATS) and **Multifocal Ectopic Purkinje-related Premature Contractions** (MEPPC). The study employs a randomized, double-blind, controlled design to ensure unbiased results. The trial is expected to commence on April 1, 2024, and conclude by May 1, 2025, with a total duration of approximately 13 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a clinical diagnosis of ATS or MEPPC, demonstrated ventricular arrhythmia burden, and stable treatment with flecainide for at least three months. The study will include follow-up visits to monitor the primary endpoint, which is the ventricular ectopy burden per 24-hour period. These visits will involve standard 12-lead electrocardiograms and 24-hour electrocardiographic monitoring using an ECG patch, aligning with routine clinical practice and posing no additional risk to participants.

The expected length of participant involvement is up to 10 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is categorized as a low-intervention clinical trial, as the investigational medicinal products (IMPs) are authorized and indicated for use in these conditions, and the procedures involved are standard clinical practices. The study aims to provide valuable insights into optimizing drug therapy for the suppression of ventricular arrhythmias in the specified patient population.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in treating ventricular arrhythmias in Andersen-Tawil syndrome and multifocal ectopic Purkinje-related premature contractions. The first medication is a combination of **bisoprolol fumarate** and **hydrochlorothiazide**, administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 350 mg over a treatment period of 5 days. The pharmaceutical form is coded as PHF00082MIG.

**Metoprolol succinate** is another experimental medication used in the trial. It is administered orally with a maximum daily dose of 250 mg and a total maximum dose of 8750 mg over 5 days. The pharmaceutical form is PHF00212MIG.

**Nebivolol** is also included in the study, administered orally with a maximum daily dose of 10 mg and a total maximum dose of 350 mg over 5 days. The pharmaceutical form is PHF00245MIG.

**Verapamil** is used as a comparator treatment, administered orally with a maximum daily dose of 480 mg and a total maximum dose of 16800 mg over 5 days. The pharmaceutical form is PHF00209MIG.

**Quinidine** is another comparator treatment, administered orally with a maximum daily dose of 1200 mg and a total maximum dose of 42000 mg over 5 days. The pharmaceutical form is PHF00209MIG.

**Propranolol hydrochloride** is administered orally with a maximum daily dose of 160 mg and a total maximum dose of 5600 mg over 5 days. The pharmaceutical form is PHF00231MIG.

**Flecainide** is a key experimental medication in the trial, administered orally with a maximum daily dose of 250 mg and a total maximum dose of 17500 mg over 10 days. The pharmaceutical form is PHF00209MIG.

Lastly, **atenolol** combined with **chlortalidone** is administered orally with a maximum daily dose of 100 mg and a total maximum dose of 3500 mg over 5 days. The pharmaceutical form is PHF00009MIG.

All medications are administered orally, and participant compliance is monitored throughout the trial. The study aims to compare the efficacy of these medications, particularly focusing on the use of flecainide monotherapy versus combination therapies involving beta-blockers or calcium channel blockers.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the **ventricular ectopy burden** per 24-hour period. This parameter will be measured using a standard 12-lead electrocardiogram and 24-hour electrocardiographic monitoring with an ECG patch. These tools are employed to ensure accurate and reliable data collection, reflecting routine clinical practice for patients with Andersen-Tawil syndrome (ATS) and multifocal ectopic Purkinje-related premature contractions (MEPPC). The trial will compare the efficacy of **flecainide** monotherapy against combination therapy with beta-blockers or calcium channel blockers in patients with ATS, and against **quinidine** in MEPPC patients during phase 2. The study is designed as a low-intervention clinical trial, utilizing authorized medicinal products in accordance with their marketing authorization, thereby minimizing additional risks to participants. The trial is expected to conclude by May 2025, with recruitment starting in April 2024.