Clinical trial NCT05720572: Antazoline in Comparison to Propafenone in Pharmacological Cardioversion of Atrial Fibrillation.
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).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Atrial Fibrillation
Keywords: Antazoline
Antiarrhythmic drugs
Pharmacological cardioversion
Atrial fibrillation
Randomized controlled trial
Lead sponsor: Centre of Postgraduate Medical Education
Sponsor class: OTHER
First posted: 2023-02-09
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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

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.

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. Approval for the study was obtained from the local ethics committee (nr 85/PB/2019; July 10, 2019).

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

Eligibility criteria: 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.

Primary outcomes:
measure: Conversion of atrial fibrillation (AF) to sinus rhythm (SR)
timeFrame: 3 hours
Secondary outcomes:
measure: Time to conversion of atrial fibrillation to sinus rhythm
timeFrame: 3 hours
measure: Serious adverse event defined as every adverse event requiring hospitalization or prolonged observation
timeFrame: 3 hours
measure: Disturbances of atrioventricular conduction
timeFrame: 3 hours
measure: Hypotension < 90mmHg
timeFrame: 3 hours
measure: Pauses > 4s
timeFrame: 3 hours
measure: Tachycardia > 180bpm
timeFrame: 3 hours
measure: Nausea and/or vomiting
timeFrame: 3 hours
measure: Hot flush
timeFrame: 3 hours
measure: Drowsiness
timeFrame: 3 hours
measure: Headache
timeFrame: 3 hours
measure: Bitter/metallic taste
timeFrame: 3 hours
measure: Anxiety
timeFrame: 3 hours
measure: New complex ventricular arrhythmia
timeFrame: 3 hours
measure: Prolongation of QTc in ms (Bazett's formula) in comparison to baseline
timeFrame: 3 hours
Other outcomes:
Locations:
city: Warsaw
country: Poland
facility: Postgraduate Medical School
Study officials:
affiliation: Centre of Postgraduate Medical Education
name: Jarosław JK Karwowski, PhD
role: PRINCIPAL_INVESTIGATOR
References: