AnProAF: Antazoline in Comparison to Propafenone in Pharmacological Cardioversion of Atrial Fibrillation.

Sponsor

Centre of Postgraduate Medical Education (Other)

Overall Status

Recruiting

CT.gov ID

NCT05720572

Collaborator

(none)

105

Enrollment

Location

Arms

Anticipated Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this randomized, double blind, non-inferiority clinical trial was to compare the clinical efficacy and safety of antazoline with propafenone in the rapid conversion of paroxysmal non-valvular atrial fibrillation to sinus rhythm in patients without heart failure

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Antazoline Drug: Propafenone	Phase 4

Detailed Description

Background

Atrial fibrillation (AF) is the most common type of arrhythmia, and occurs in approximately 3% of the population over 20 years of age and 9% of those over 80 years of age [1]. Restoration of sinus rhythm (SR) remains an integral part of the treatment for this type of arrhythmia. Early pharmacological (PCV) or electrical cardioversion (ECV) is necessary to improve symptoms, prevent the side effects of the prolonged crisis of arrhythmia, and avoid hospitalization. ECV requires general sedation and does not prevent from immediate AF recurrence. Therefore, the majority of patients are qualified for pharmacological attempts to terminate the arrhythmia. The early PCV of AF to SR may be achieved by administration of Class (Vaughan-Williams) IA, IC, and III antiarrhythmic drugs (AADs): flecainide, ibutilide, dofetilide, propafenone, amiodarone, or novel agent vernakalant. These AADs have limitations such as proarrhythmic side effects in patients with structural heart disease (IC), delayed onset of action (amiodarone), high cost, and low availability (vernakalant) [1].

An efficacious, well-tolerated, less expensive antiarrhythmic drug with rapid onset of action is necessary. Antazoline meslate is an antihistaminic agent with antiarrhythmic quinidine-like properties, which have been documented in 1960s [2,3]. Electrophysiologically, antazoline prolongs action potential duration and lowers its amplitude, prolongs phase-0 duration, reduces phase-4 of resting potential, and reduces excitability of cardiac tissue. Anticholinergic action of this drug leads to transient increase of heart rate, improving atrioventricular conduction and increasing the corrected QT-interval, left atrial refractory period, and inter-atrial conduction time [4-6]. In human healthy volunteers, the terminal elimination half-life of antazoline was 2.29 hours with a mean residence time of 3.45 hours [7]. In clinical practice, the drug can be administered intravenously in boluses of 50-100 mg every 3-5 minutes until successful cardioversion or up to a cumulative dose of 250-350 mg [8].

In Poland, it was registered for intravenous termination of supraventricular arrhythmias. Unfortunately, antazoline is not listed in any of the formal guidelines due to the lack of large randomized trials comparing this drug with other AADs in SR restoration. To the best of our knowledge, only one randomized clinical trial has been published that evaluated the antiarrhythmic effect of antazoline in comparison to placebo [9]. In antazoline group (38 patients), successful conversion of AF to SR was achieved in 72.2%, with a median duration of 16 minutes. Other published observational studies have shown high efficacy of antazoline, ranging between 50% and 80% and a rapid onset of action with cardioversion duration between 7 and 20 minutes [3,8,10-14]. The aim of this randomized, double blind, placebo-controlled, non-inferiority clinical trial is to assess clinical efficacy of antazoline in rapid conversion of atrial fibrillation to sinus rhythm in patients with paroxysmal atrial fibrillation without significant valvular disease or advanced heart failure.

Methods Study objectives The purpose of the study is to assess clinical efficacy of antazoline in rapid conversion of AF to SR in comparison to propafenone in patients with paroxysmal atrial fibrillation without significant valvular disease or advanced heart failure. Due to a presumed lack of statistical power, secondary end points and safety analysis will be considered exploratory.

The study protocol was approved by the local ethics committee and is in full compliance with the Declaration of Helsinki.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

105 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Study design This randomized, double-blind, placebo-controlled, non-inferiority clinical study is actually carried out at the Department of Heart Disease, Centre of Postgraduate Medical Education, Warsaw, Poland. The study will include 390 participants presenting with an episode of AF lasting less than 48 h. All participants must sign an informed consent form. The study protocol was approved by the local ethics committee and is in full compliance with the Declaration of Helsinki.Study design This randomized, double-blind, placebo-controlled, non-inferiority clinical study is actually carried out at the Department of Heart Disease, Centre of Postgraduate Medical Education, Warsaw, Poland. The study will include 390 participants presenting with an episode of AF lasting less than 48 h. All participants must sign an informed consent form. The study protocol was approved by the local ethics committee and is in full compliance with the Declaration of Helsinki.

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

After eligible patients provide informed consent, they are assigned a specific identifier. Neither the patient nor the researcher knows which group the subject will be assigned to. Patients are randomized according to the implemented random allocation sequence using numbered sealed envelopes, which are opened after inclusion of the patient for the study in a 1:1 ratio to treatment with antazoline or propafenone. After inclusion of the patient the study the nurse will open the numbered envelope and prepare three 10 cm3 syringes with study drugs according to randomization and pass them to the enrolling physician and nurse who will administer the drug. The patient, enrolling physician, nurse who administering the drug, and clinician reviewing the clinical outcomes will all be blinded to the treatment. The statistician, study nurse who prepares the syringes and clinician involved in safety control will be unblinded to the patient's assignment.

Primary Purpose:

Treatment

Official Title:

Clinical Efficacy and Safety of Antazoline in Comparison to Propafenone in Conversion of Paroxysmal Atrial Fibrillation to Sinus Rhythm - a Single Center, Randomized, Double-blinded Study (the AnProAF Study).

Actual Study Start Date :

Sep 1, 2019

Anticipated Primary Completion Date :

Sep 1, 2025

Anticipated Study Completion Date :

Jan 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Antazoline Any patient fulfilling the inclusion criteria will be prepared to pharmacological cardioversion in a standard way comprising of standard baseline 12-lead ECG, continuous ECG monitoring, periodic noninvasive blood pressure monitoring (BP) and iv line. After drug administration the patient will be observed for 3 hours after the first dose with exit ECG and BP measure taken at the end of observation. Further treatment of the patient depends on clinical state and follows appropriate clinical guidelines.	Drug: Antazoline Participants assigned to the antazoline group will be administered antazoline in boluses in boluses of 100 mg diluted to 20 cm3 every 10 minutes up to a total dose of 300 mg diluted to 60 cm3 or conversion of AF to SR. Drug administration will also be stopped in case of an adverse event or conversion of AF to a different supraventricular arrhythmia. BP will be measured before every injection.
Active Comparator: Propafenone Any patient fulfilling the inclusion criteria will be prepared to pharmacological cardioversion in a standard way comprising of standard baseline 12-lead ECG, continuous ECG monitoring, periodic noninvasive blood pressure monitoring (BP) and iv line. After drug administration the patient will be observed for 3 hours after the first dose with exit ECG and BP measure taken at the end of observation. Further treatment of the patient depends on clinical state and follows appropriate clinical guidelines.	Drug: Propafenone Patients assigned to the propafenone group were administered three 20-cm3 boluses every 10 minutes up to 60 cm3 or conversion of AF to SR. Each of the first two boluses included 70 mg propafenone (total dose 140 mg), and the third bolus contained only 20-cm3 0.9% NaCl. Drug administration will be stopped in case of an adverse event or conversion of AF to a different supraventricular arrhythmia. BP will be measured before every injection.

Arm

Intervention/Treatment

Experimental: Antazoline

Any patient fulfilling the inclusion criteria will be prepared to pharmacological cardioversion in a standard way comprising of standard baseline 12-lead ECG, continuous ECG monitoring, periodic noninvasive blood pressure monitoring (BP) and iv line. After drug administration the patient will be observed for 3 hours after the first dose with exit ECG and BP measure taken at the end of observation. Further treatment of the patient depends on clinical state and follows appropriate clinical guidelines.

Drug: Antazoline

Participants assigned to the antazoline group will be administered antazoline in boluses in boluses of 100 mg diluted to 20 cm3 every 10 minutes up to a total dose of 300 mg diluted to 60 cm3 or conversion of AF to SR. Drug administration will also be stopped in case of an adverse event or conversion of AF to a different supraventricular arrhythmia. BP will be measured before every injection.

Active Comparator: Propafenone

Drug: Propafenone

Patients assigned to the propafenone group were administered three 20-cm3 boluses every 10 minutes up to 60 cm3 or conversion of AF to SR. Each of the first two boluses included 70 mg propafenone (total dose 140 mg), and the third bolus contained only 20-cm3 0.9% NaCl. Drug administration will be stopped in case of an adverse event or conversion of AF to a different supraventricular arrhythmia. BP will be measured before every injection.

Outcome Measures

Primary Outcome Measures

Conversion of atrial fibrillation (AF) to sinus rhythm (SR) [3 hours]
Conversion of AF to SR confirmed in standard 12-lead ECG during the observation period

Secondary Outcome Measures

Time to conversion of atrial fibrillation to sinus rhythm [3 hours]
Serious adverse event defined as every adverse event requiring hospitalization or prolonged observation [3 hours]
Disturbances of atrioventricular conduction [3 hours]
Hypotension < 90mmHg [3 hours]
Pauses > 4s [3 hours]
Pauses in heart beat
Tachycardia > 180bpm [3 hours]
Nausea and/or vomiting [3 hours]
Hot flush [3 hours]
Drowsiness [3 hours]
Headache [3 hours]
Bitter/metallic taste [3 hours]
Anxiety [3 hours]
New complex ventricular arrhythmia [3 hours]
Prolongation of QTc in ms (Bazett's formula) in comparison to baseline [3 hours]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent for participating in the study and written standard version of informed consent for cardioversion accepted at the Department of Heart Disease, Warsaw, Poland
Age 18 to 90years
AF lasting < 48 hours
Stable cardio-pulmonary state on enrollment
In case of unclear history of heart failure or suspicion of left ventricle damage echocardiographyis indicated prior to enrollment

Exclusion Criteria:

Lack of written informed consent
Allergy to antazoline or propafenone
Intolerance of anatzoline or propafenone
AF related to significant valvular disease
Clinically significant heart failure or ejection fraction <50%
Systolic blood pressure (BP) <100 mmHg
History of significant bradyarrhythmia not treatedwith permanent pacemaker
Resting ventricular rate of < 80 bpm without pacemaker backup
Heart rate > 140 bpm
Tachycardia >160'
Advanced liver or kidney failure
Acute coronary syndrome, coronary artery by-passgraft, stroke or transient ischemic attack within 30 days before enrollment
Preexcitation in ECG not treated by radiofrequency ablation of accessory pathway
Signs and symptoms of ischemia related to AF
An investigational drug used within 30 days before enrollment
Advanced liver or kidney failure
QT prolongation over 440 ms or QTc (Bazett's formula) over the population norm
Pregnancy or breast feeding
Background therapy of any oral AADs.