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New Formulations of Propafenone to Treat Atrial Fibrillation

Primary Purpose

Atrial Fibrillation

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
(R)-propafenone
(S)-Propafenone
Placebo
Sponsored by
Vanderbilt University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atrial Fibrillation focused on measuring ablation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Vanderbilt University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

(R)-propafenone

(S)-Propafenone

Placebo

Arm Description

Single intravenous dose of (R)-propafenone (2mg/kg) infused over 10 minutes

Single intravenous dose of (S)-propafenone (2mg/kg) infused over 10 minutes

Placebo (normal saline) is infused over 10 minutes

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
March 12, 2016
Last Updated
June 1, 2022
Sponsor
Vanderbilt University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02710669
Brief Title
New Formulations of Propafenone to Treat Atrial Fibrillation
Official Title
Comparison of (R) and (S) Propafenone for Prevention of Atrial Fibrillation Induction
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Terminated
Why Stopped
Study halted/terminated prematurely due to COVID.
Study Start Date
October 2016 (undefined)
Primary Completion Date
March 11, 2020 (Actual)
Study Completion Date
April 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atrial Fibrillation
Keywords
ablation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
193 (Actual)

8. Arms, Groups, and Interventions

Arm Title
(R)-propafenone
Arm Type
Experimental
Arm Description
Single intravenous dose of (R)-propafenone (2mg/kg) infused over 10 minutes
Arm Title
(S)-Propafenone
Arm Type
Active Comparator
Arm Description
Single intravenous dose of (S)-propafenone (2mg/kg) infused over 10 minutes
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo (normal saline) is infused over 10 minutes
Intervention Type
Drug
Intervention Name(s)
(R)-propafenone
Intervention Type
Drug
Intervention Name(s)
(S)-Propafenone
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Number of Participants With Successful Induction of 30 Seconds of Atrial Fibrillation/Atrial Flutter
Description
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.
Time Frame
Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes)
Secondary Outcome Measure Information:
Title
Number of Participants With Successful Inducibility of Atrial Fibrillation/Atrial Flutter Expressed as an Ordinal Variable Based on Stage of the Induction Protocol
Description
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.
Time Frame
Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes)
Title
Number of Participants With Successful Induction of 30 Seconds of Atrial Flutter
Description
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.
Time Frame
Twenty minutes post-dosage to end of induction protocol (approximately 10 minutes)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bjorn Knollmann, MD/PhD
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ben Shoemaker, MD
Organizational Affiliation
Vanderbilt University
Official's Role
Study Director
Facility Information:
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
24493699
Citation
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.
Results Reference
background
PubMed Identifier
36166682
Citation
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.
Results Reference
derived

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New Formulations of Propafenone to Treat Atrial Fibrillation

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