Evaluation of Standard vs. Reduced Dose Amiodarone Hydrochloride for Sinus Rhythm Maintenance Post-Cardioversion in Persistent Atrial Fibrillation

The primary objective of this multicenter randomized clinical trial is to compare the **efficacy** of maintaining sinus rhythm 12 months post electrical cardioversion between standard (200 mg/d) and reduced (100 mg/d) doses of amiodarone in patients with persistent atrial fibrillation. This is clinically relevant as it aims to optimize treatment regimens for maintaining sinus rhythm, potentially improving patient outcomes and reducing the risk of complications associated with atrial fibrillation.

Secondary objectives include:

• Comparing the adverse effects of standard and reduced doses of amiodarone over 12 months, focusing on major adverse events such as thyroid, liver, or lung toxicity.
• Evaluating the efficacy and safety of amiodarone based on polymorphisms in CYP2D6, CYP2C19, CYP1A2, CYP2C8, CYP3A4, and ABCB1.
• Correlating amiodarone plasma levels with the maintenance of sinus rhythm at 12 months post cardioversion.
• Correlating amiodarone plasma levels with polymorphisms in the aforementioned cytochrome P450 enzymes and ABCB1.

The clinical trial focuses on patients with **persistent atrial fibrillation**, aiming to evaluate the efficacy of different doses of amiodarone in maintaining sinus rhythm post electrical cardioversion. The study population includes both male and female participants aged 18 years and older. The trial does not involve a vulnerable population. Participants were selected based on documented persistent atrial fibrillation lasting seven days or more and were electively referred for electrical cardioversion under amiodarone treatment. All participants provided signed informed consent. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of two different dosing regimens of **amiodarone hydrochloride** in maintaining sinus rhythm following electrical cardioversion in patients with **persistent atrial fibrillation**. The trial will compare a standard dose of 200 mg per day with a reduced dose of 100 mg per day over a period of 12 months. The primary endpoint is the first recurrence of atrial fibrillation, confirmed by ECG, after randomization. Secondary endpoints include the assessment of adverse effects, study of genetic polymorphisms, plasma levels of amiodarone, and the correlation of these factors with safety and efficacy.

The trial is expected to commence recruitment on November 1, 2024, and conclude by June 1, 2028. Participants will be involved in the study for a maximum of 12 months. The study visits will include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participants' health status, medication adherence, and any adverse effects. The end-of-study visit will assess the final outcomes and collect data on the primary and secondary endpoints. Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the study protocol, or withdraw consent.

Inclusion criteria for the study are patients aged 18 years or older with documented persistent atrial fibrillation lasting at least seven days, who are electively referred for electrical cardioversion under amiodarone treatment, and who have provided signed informed consent. The study is categorized as a Phase IV trial, indicating it involves a drug that is already approved and used according to its marketing authorization, with minimal additional risk or burden compared to usual practice.

The clinical trial involves the administration of **Amiodarone hydrochloride** in the form of 200 mg tablets. The pharmaceutical form is a **TABLET**, and the active substance is **amiodarone hydrochloride**, a chemical compound. The medication is manufactured by Zentiva Pharma UK Limited. The trial aims to evaluate two different dosing regimens of amiodarone to maintain sinus rhythm after cardioversion in patients with persistent atrial fibrillation. The standard dosing regimen involves administering 200 mg per day, while the reduced dosing regimen involves 100 mg per day. The route of administration for both regimens is **ORAL**. The maximum treatment period for the trial is 12 months, with a maximum daily dose of 200 mg.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the efficacy of the two dosing regimens of amiodarone. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to compare the efficacy of maintaining sinus rhythm 12 months post-electrical cardioversion between the two dosing regimens in patients with persistent atrial fibrillation.

The efficacy of the clinical trial titled "Multicenter randomized clinical trial to evaluate two different amiodarone regimens to maintain sinus rhythm after cardioversion in persistent atrial fibrillation (PERIVERSION-2)" will be assessed by comparing the ability of two dosing regimens of **amiodarone hydrochloride** to maintain sinus rhythm 12 months post-electrical cardioversion in patients with persistent atrial fibrillation. The primary endpoint for efficacy evaluation is the first recurrence of atrial fibrillation (AF), which will be confirmed through an electrocardiogram (ECG) after randomization.

Secondary endpoints include the assessment of adverse effects, which will be determined by specific criteria such as thyroid-stimulating hormone (TSH) levels below 0.1 microUI/ml or exceeding 4.2 microUI/ml, a threefold increase in liver enzymes (AST, ALT, or GGT) compared to baseline levels, a QTc interval exceeding 500 ms, or any other adverse effects as per the drug's technical sheet. Additionally, the study will investigate polymorphisms in genes such as CYP2D6, CYP2C19, CYP1A2, CYP2C8, CYP3A4, and ABCB1, and correlate these with plasma levels of amiodarone, safety, and efficacy. Plasma levels of amiodarone will be monitored during follow-up to further assess the drug's efficacy and safety profile.