New Formulations of Propafenone to Treat Atrial Fibrillation

Study Overview
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Brief Summary
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Propafenone is a currently used medicine to treat atrial fibrillation and is a mixture of two compounds, (R)-propafenone and (S)-propafenone. In this study, the investigators will randomize participants to (R)-propafenone, (S)-propafenone, or placebo.

Detailed Description
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Atrial fibrillation is a common cardiac arrhythmia that needs development of more effective medications. Propafenone is a medicine currently used to treat atrial fibrillation and is a mixture of two compounds, (R)-propafenone and (S)-propafenone. The investigators have discovered that purified (R)-propafenone may be more effective than (S)-propafenone for treatment of atrial fibrillation, and that (S)-propafenone reduces the efficacy of (R)-propafenone when administered as a mixture. This study will compare the ability of (R)-propafenone, (S)-propafenone, and placebo to suppress the induction of atrial fibrillation in participants undergoing an atrial fibrillation ablation procedure.

Official Title
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Comparison of (R) and (S) Propafenone for Prevention of Atrial Fibrillation Induction

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: (R)-propafenone
* Drug: (S)-Propafenone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion: History of atrial fibrillation Greater than or equal to 18 years of age Scheduled to undergo an atrial fibrillation ablation procedure Able to provide written informed consent Exclusion: Long-standing persistent atrial fibrillation at the time of ablation (greater than 1 year of a continuous atrial fibrillation episode) Is in atrial fibrillation or atrial flutter the morning of the ablation procedure The presence of any of the following in a patient without a permanent pacemaker for implantable cardiac defibrillator sick sinus syndrome indicated by the inability to previously tolerate an antiarrhythmic drug due to bradycardia sinus bradycardia with a heart rate less than 50 beats per minute at the time of study drug administration right bundle branch block, left bundle branch block, or bifascicular block PR-interval > 280ms, or history of 2nd or 3rd degree atrioventricular block Concomitant use of CYP3A4 and CYP2D6 inhibitors Previous surgical or catheter ablation for atrial fibrillation or Cox-Maze procedure Amiodarone use within 3 months prior to enrollment Antiarrhythmic drug (other than amiodarone) within 5 half-lives prior to atrial fibrillation ablation Expected life span < 1 year Creatinine clearance <30 mL/min Reversible cause of atrial fibrillation (ie. thyrotoxicosis) Unrevascularized coronary artery disease Canadian class IV angina Left ventricular ejection fraction <40% New York Heart Association Class III or IV symptoms Previous heart transplantation Planned heart transplantation or ventricular assist device Cardiac/thoracic surgery <6 months prior to enrollment Severe asthma or chronic obstructive pulmonary disease Breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (R)-propafenone<br>Single intravenous dose of (R)-propafenone (2mg/kg) infused over 10 minutes | Drug: (R)-propafenone<br> <br> |
| Active Comparator: (S)-Propafenone<br>Single intravenous dose of (S)-propafenone (2mg/kg) infused over 10 minutes | Drug: (S)-Propafenone<br> <br> |
| Placebo Comparator: Placebo<br>Placebo (normal saline) is infused over 10 minutes | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter | A rapid atrial pacing protocol was used to attempt to induce atrial fibrillation/atrial flutter. Twenty minutes after start of the study drug, participants underwent placement of a decapolar coronary sinus catheter. Pacing was performed from the proximal electrode at 20 milliamps and a pulse width of 2 ms. Bursts from the CS proximal electrode were induced to attempt atrial fibrillation. | Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol | Inducibility of atrial fibrillation (AF) or atrial flutter (AFL) expressed as an ordinal variable based on stage of the induction protocol. Stage 1 measured the AV block (Wenckebach) cycle length (AVBCL), AV node effective refractory period (AVN ERP) and atrial ERP (AERP). AVN ERP and AERP were measured at drive trains (S1) of 600 ms and 450 ms. Extrastimuli (S2) were introduced starting at a coupling interval of 500ms and decremented by 10ms with each pacing train. Stage 2 consisted of 15-beat bursts from the CS proximal electrode. The starting cycle length was 250ms, which was decremented by 10ms with each burst. A 10-second rest period was used between bursts. Step 2 was complete when 1:1 atrial capture was lost or a minimum cycle length of 180ms was reached. Stage 3 consisted of 15-second bursts. The cycle length used for the bursts was the fastest cycle length achieved during Step 2 that maintained 1:1 atrial conduction. | Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) | 
| Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter | A rapid atrial pacing protocol was used to attempt to induce atrial flutter. Twenty minutes after start of the study drug, participants underwent placement of a decapolar coronary sinus catheter. Pacing was performed from the proximal electrode at 20 milliamps and a pulse width of 2 ms. Bursts from the CS proximal electrode were induced to attempt atrial flutter. | Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ablation