Oral Amiodarone for Acute Cardioversion of Atrial Fibrillation Study (AAA)

The investigators will seek to determine the safety and efficacy of high-dose amiodarone (2000mg), given as a single uniform oral dose, for the treatment of acute atrial fibrillation in both a hospital inpatient and ambulatory outpatient setting. The investigators will conduct a placebo-controlled randomized trial, with outcome ascertainment at 48h.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Amiodarone Hydrochloride; Drug: Placebo

Detailed Description

Background: Atrial fibrillation (AF) is estimated to affect over 33 million people worldwide and is often associated with significant co-morbidities such as myocardial infarction, heart failure, dementia, and embolic stroke. Consequently, AF poses a significant burden to the healthcare system, in both direct and indirect costs of disease.

The management of AF in the acute setting is complex, especially for patients who suffer from persistent AF, defined as sustained AF for > 7 days. While one possible treatment strategy involves allowing AF to continue whilst controlling the ventricular rate (i.e. rate control), in certain cases, it is preferable to terminate the AF and restore normal sinus rhythm (i.e. rhythm control) for relief of intolerable symptoms associated with AF.

There are several methods currently in use for rhythm control, including observation without intervention, use of oral and/or intravenous anti-arrhythmic drugs for pharmacological cardioversion, and electrical cardioversion. However, each of these strategies come with significant limitations. Amiodarone was originally developed for treatment of angina, but is now widely recognized for its anti-arrhythmic properties. Current American College of Cardiology/American Heart Association/European Society of Cardiology guidelines recommend the use of amiodarone as a cardioversion agent in both intravenous and oral administration. Furthermore, the use of oral amiodarone is considered the standard of care for rhythm management in AF. Prior studies have demonstrated that the administration of a single, oral converting dose of amiodarone has similar rates of sinus rhythm conversion at 24 hours post-intervention compared to Vaughan-Williams Class 1C anti-arrhythmic medications. The use of amiodarone as a first-line therapy for AF is appealing when considering its safety profile.

Objectives: To determine the safety and efficacy of high-dose amiodarone, given as a single uniform oral dose, for the treatment of acute AF in a hospital inpatient setting and acute persistent AF in an outpatient ambulatory clinic.

Methods: This study will be a double-blind randomized controlled trial in patients with symptomatic AF. Amiodarone and placebo capsules will be prepared in single dose packs. A single dose pack will consist of either 2000 mg of amiodarone hydrochloride crushed and placed in 10 gel capsules of 200 mg each, or 10 gel capsules of crushed placebo. Individual dose packs will then be randomly assigned to participants with a unique research number.

Candidate inpatients will be identified through emergency room presentation, outpatient clinic admissions, or inpatient consultation. Once participants have been consented and allocated a study number, they will be randomly assigned a dose pack. Participants will be required to ingest the entire 10 capsule dose pack in one sitting with food witnessed by one of the study investigators or a designated study nurse. Following drug administration, participants will have cardiac monitoring and regular vital sign measurements for up to 48 hours. The investigators will provide the participants with a diary to record any potential adverse side effect symptoms, and the participant will be given the phone number of a study team member to contact if they are concerned about any adverse effects. After the 48 hour period, a study team member will contact the participant and ask specifically about potential adverse events.

Candidate outpatients will be identified through emergency room presentation or outpatient clinics not requiring hospital admission. Once participants have been consented and allocated a study number, they will be assigned a dose pack. Participants will be required to ingest the entire 10 capsule dose pack in one sitting with food. The time of capsule ingestion will be recorded. Following drug administration, participants will be provided with a portable cardiac monitor to wear for 48 hours. History taking of potential adverse side effect symptoms will be performed on a daily basis, or more frequently if required. After the 48 hour period, a 12-lead electrocardiogram with be performed to confirm of successful reversion to sinus rhythm, continuing AF, or other heart rhythm. The portable cardiac monitor will be retrieved and analyzed for evidence of time to successful reversion to sinus rhythm.

The investigators plan to enrol 42 AF patients, with 21 patients randomized to oral amiodarone and 21 patients randomized to placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Satish R Raj, MD MSCI; Phone Number: 4032106152; Email: autonomic.research@ucalgary.ca
• Study Contact Backup: Name: Rasha Hamzeh, RN; Email: rasha.hamzeh1@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Recruiting
      • University of Calgary
      • Contact: Satish R Raj, MD, MSCI; Phone Number: 403-210-6152; Email: autonomic.research@ucalgary.ca
      • Contact: Robert S Sheldon, MD, PhD; Phone Number: 403-220-8191; Email: autonomic.research@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Acute persistent or paroxysmal atrial fibrillation or atrial flutter with duration < 14 days (continuous with no spontaneous conversions), confirmed by ECG or cardiac telemetry
• History of symptoms associated with atrial fibrillation
• Appropriate anticoagulation (warfarin with an international normalized ratio (INR) > 2.0 or direct oral anticoagulant)

Exclusion Criteria:

• Received > 10 g of amiodarone in the prior 6 months, or other Class III anti-arrhythmic agents in the prior 3 months
• previous severe adverse event following a cardioversion for atrial fibrillation
• Hypothyroid and not on thyroid replacement therapy
• Recent myocardial infarction (within 2 weeks)
• Acute pulmonary oedema requiring hospital admission or New York Heart Association (NYHA) class IV heart failure
• Severe left ventricular dysfunction or left ventricular ejection fraction < 36%, as determined by cardiac imaging
• Sick sinus syndrome, high grade atrioventricular block, ventricular rate < 50 beats per minute in the absence of a mechanical pacemaker
• Severe renal or hepatic disease
• Known congenital long QT syndrome
• Hypotension with systolic blood pressure < 90 mmHg
• Pregnant or breast-feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Oral placebo	Drug: Placebo; Oral placebo to be given as a 10-capsule dose pack and ingested in a single sitting with food; Other Names: Sugar Pill
Experimental: Oral Amiodarone; Amiodarone hydrochloride 2000 mg	Drug: Amiodarone Hydrochloride; Amiodarone hydrochloride 2000 mg PO to be given as a 10-capsule dose pack and ingested in a single sitting with food; Other Names: Cordarone; Nexterone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Successful Reversion to Sinus Rhythm	Time to successful reversion to sinus rhythm (continuous variable), as documented by continuous cardiac monitoring	48 hours of intervention administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conversion Rate to Sinus Rhythm	Conversion rate to sinus rhythm (dichotomous variable), as documented by continuous cardiac monitoring	48 hours of intervention administration
Early Recurrence of Atrial Fibrillation After Initial Reversion to Sinus Rhythm	Early recurrence of atrial fibrillation (lasting > 6 minutes) after initial reversion to sinus rhythm (dichotomous variable), as documented by continuous cardiac monitoring	48 hours of intervention administration

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: Satish R Raj, MD MSCI, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2022
• Primary Completion (Anticipated): December 31, 2025
• Study Completion (Anticipated): December 31, 2026

Study Registration Dates

• First Submitted: October 13, 2020
• First Submitted That Met QC Criteria: October 19, 2020
• First Posted (Actual): October 20, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Amiodarone
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: REB20-1555

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No