New Formulations of Propafenone to Treat Atrial Fibrillation

• ClinicalTrials.gov Identifier: NCT02710669
• Recruitment Status: Terminated
• First Posted: March 17, 2016
• Results First Posted: May 14, 2021
• Last Update Posted: June 3, 2022
• Sponsor: Vanderbilt University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Bjorn Knollmann, Vanderbilt University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Atrial Fibrillation	Drug: (R)-propafenone; Drug: (S)-Propafenone; Drug: Placebo	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 193 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Comparison of (R) and (S) Propafenone for Prevention of Atrial Fibrillation Induction
• Study Start Date: October 2016
• Actual Primary Completion Date: March 11, 2020
• Actual Study Completion Date: April 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: (R)-propafenone; Single intravenous dose of (R)-propafenone (2mg/kg) infused over 10 minutes	Drug: (R)-propafenone
Active Comparator: (S)-Propafenone; Single intravenous dose of (S)-propafenone (2mg/kg) infused over 10 minutes	Drug: (S)-Propafenone
Placebo Comparator: Placebo; Placebo (normal saline) is infused over 10 minutes	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter [ Time Frame: Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) ]
   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.

Secondary Outcome Measures :

1. Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol [ Time Frame: Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) ]

   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.

2. Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter [ Time Frame: Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes) ]
   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.

Eligibility Criteria

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

Criteria

Inclusion:

1. History of atrial fibrillation
2. Greater than or equal to 18 years of age
3. Scheduled to undergo an atrial fibrillation ablation procedure
4. Able to provide written informed consent

Exclusion:

1. Long-standing persistent atrial fibrillation at the time of ablation (greater than 1 year of a continuous atrial fibrillation episode)
2. Is in atrial fibrillation or atrial flutter the morning of the ablation procedure

3. The presence of any of the following in a patient without a permanent pacemaker for implantable cardiac defibrillator

   1. sick sinus syndrome indicated by the inability to previously tolerate an antiarrhythmic drug due to bradycardia
   2. sinus bradycardia with a heart rate less than 50 beats per minute at the time of study drug administration
   3. right bundle branch block, left bundle branch block, or bifascicular block
   4. PR-interval > 280ms, or history of 2nd or 3rd degree atrioventricular block
4. Concomitant use of CYP3A4 and CYP2D6 inhibitors
5. Previous surgical or catheter ablation for atrial fibrillation or Cox-Maze procedure
6. Amiodarone use within 3 months prior to enrollment
7. Antiarrhythmic drug (other than amiodarone) within 5 half-lives prior to atrial fibrillation ablation
8. Expected life span < 1 year
9. Creatinine clearance <30 mL/min
10. Reversible cause of atrial fibrillation (ie. thyrotoxicosis)
11. Unrevascularized coronary artery disease
12. Canadian class IV angina
13. Left ventricular ejection fraction <40%
14. New York Heart Association Class III or IV symptoms
15. Previous heart transplantation
16. Planned heart transplantation or ventricular assist device
17. Cardiac/thoracic surgery <6 months prior to enrollment
18. Severe asthma or chronic obstructive pulmonary disease
19. Breastfeeding

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Bjorn Knollmann, MD/PhD; Vanderbilt University
• Study Director: Ben Shoemaker, MD; Vanderbilt University

  Study Documents (Full-Text)

Documents provided by Bjorn Knollmann, Vanderbilt University:

Study Protocol and Statistical Analysis Plan  [PDF] October 3, 2019

Informed Consent Form  [PDF] October 23, 2019

More Information

Publications:

Faggioni M, Savio-Galimberti E, Venkataraman R, Hwang HS, Kannankeril PJ, Darbar D, Knollmann BC. Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts. Circ Arrhythm Electrophysiol. 2014 Apr;7(2):313-20. doi: 10.1161/CIRCEP.113.000994. Epub 2014 Feb 3.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shoemaker MB, Yoneda ZT, Crawford DM, Akers WS, Richardson T, Montgomery JA, Phillips S, Shyr Y, Saavedra P, Estrada JC, Kanagasundram A, Shen ST, Michaud GF, Crossley G, Ellis CR, Knollmann BC. A Mechanistic Clinical Trial Using (R)- Versus (S)-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the Prevention of Atrial Fibrillation Induction. Circ Arrhythm Electrophysiol. 2022 Oct;15(10):e010713. doi: 10.1161/CIRCEP.121.010713. Epub 2022 Sep 27.

• Responsible Party: Bjorn Knollmann, Professor of Medicine and Pharmacology, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT02710669
• Other Study ID Numbers: 151952; 1R01HL124935-01A1 ( U.S. NIH Grant/Contract )
• First Posted: March 17, 2016
• Results First Posted: May 14, 2021
• Last Update Posted: June 3, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Bjorn Knollmann, Vanderbilt University:

ablation

Additional relevant MeSH terms:

Atrial Fibrillation; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Propafenone; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action