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Predictive Factors to Effectively Terminate Paroxysmal Atrial Fibrillation by Blocking Atrial Selective Ionic Currents (SELECTCARFAP)

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ClinicalTrials.gov Identifier: NCT03005366
Recruitment Status : Recruiting
First Posted : December 29, 2016
Last Update Posted : February 16, 2021
Sponsor:
Collaborator:
Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
Information provided by (Responsible Party):
David Filgueiras-Rama, Hospital San Carlos, Madrid

Brief Summary:
  • The main objective of this project is to study the efficacy and the mechanistic value of blocking both atrial specific and atria-preferential dynamics of ionic currents to terminate paroxysmal atrial fibrillation (AF).
  • The hypothesis is that a drug blocking atrial specific and atria-preferential dynamics of ionic currents (IK,ACh - acetylcholine sensitive K+ current - and INa - inward sodium current - , respectively) will be more effective to terminate paroxysmal AF episodes with fast atrial activation rates, than a classical INa blocker, which will be more effective to terminate AF episodes with slower activation rates.
  • The investigators will include patients without structural heart disease and short-lasting AF episodes (<48 h.). Double blind and single center study, in which patients will be randomly assigned to a cardioversion group using intravenous flecainide or to an atria-preferential and atrial-specific blockade group using intravenous vernakalant. Patients will be routinely monitored in the electrophysiology room to acquire both 12-lead digitized ECG signals and non-invasive body surface potential mapping. Atrial signals will be extracted from both the multisite body surface and ECG recordings to obtain temporal and spectral parameters, and measure organization and atrial rate in both groups. The results obtained in the clinical setting will be studied in mathematical models to understand their capability to terminate paroxysmal AF. The project expects to provide consistent, reliable and reproducible parameters that will assist clinicians to know what type of paroxysmal AF episodes will be more suitable to effectively terminate, upon administration of drugs with an atrial specific and atria-preferential profile.

Condition or disease Intervention/treatment Phase
Paroxysmal Atrial Fibrillation Drug: Vernakalant Drug: Flecainide Phase 4

Detailed Description:
  • Background: Different research strategies aim at understanding the mechanisms underlying the maintenance of atrial fibrillation (AF), while preventing ventricular pro-arrhythmia related to the use of anti-arrhythmic drugs to restore sinus rhythm. Such aims might be achieved by drugs that effectively terminate reentrant sources identified during AF, along with an atrial specific and atria-preferential blockade of ionic currents. The latter may be especially relevant in paroxysmal AF episodes with fast atrial activation rates, in which INa and IK,ACh are involved in the maintenance of fast atrial reentrant sources underlying AF.
  • Objective: The main objective of this project is to study the efficacy and the mechanistic value of blocking both atrial specific and atria-preferential dynamics of ionic currents to terminate paroxysmal AF.
  • The hypothesis is that a drug blocking atrial specific and atria-preferential dynamics of ionic currents (IK,ACh and INa, respectively) will be more effective to terminate paroxysmal AF episodes with fast atrial activation rates, than a classical INa blocker, which will be more effective to terminate AF episodes with slower activation rates.
  • Design: Double blind and single center study, in which patients will be randomly assigned to a cardioversion group using intravenous flecainide or to an atria-preferential and atrial-specific blockade group using intravenous vernakalant. Patients will be routinely monitored in the electrophysiology room for 90 minutes upon drug administration to acquire both 12-lead digitized ECG signals and non-invasive body surface potential mapping. Body surface recordings and conventional ECG signals will be exported to obtain temporal and spectral parameters of atrial activity during AF, and measure organization and atrial rate in both groups of patients undergoing pharmacological cardioversion. The success rate of cardioversion obtained in both groups will be correlated with the patterns of activation and spectral parameters obtained from the body surface, which will provide what type of paroxysmal AF episodes are suitable to terminate upon administration of anti-arrhythmic drugs with an atrial specific and atria-preferential profile.

Electrical cardioversion will be performed in subjects with unsuccessful pharmacological cardioversion within the first 24 h. after vernakalant or flecainide administration.

The results obtained in the clinical setting will be studied in realistic mathematical models to further understand the capability of both drugs to terminate paroxysmal AF.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Clinical Trial to Study Pharmacological Cardioversion of Paroxysmal Atrial Fibrillation by Vernakalant and Flecainide
Study Start Date : January 2017
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : October 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Flecainide
Conventional cardioversion group using intravenous flecainide.
Drug: Flecainide
2 mg /kg (max 150 mg) intravenously over 10 minutes.
Other Name: APOCARD

Active Comparator: Vernakalant
Atria-preferential and atrial-specific blockade group using intravenous vernakalant.
Drug: Vernakalant
Initial infusion: 3 mg/kg intravenously over a 10 minute period. For patients weighing ≥ 113 kg, the maximum initial dose will be 339 mg. If conversion to sinus rhythm does not occur within 15 minutes after the end of the initial infusion, a second 10 minute infusion of 2 mg/kg will be administered. For patients weighing ≥ 113 kg, the maximum second infusion will be 226 mg.
Other Name: BRINAVESS




Primary Outcome Measures :
  1. Electrocardiographic-based spectral parameters of atrial fibrillatory activity (Dominant frequency) associated with successful or unsuccessful cardioversion in both groups of patients. [ Time Frame: 18 months ]

    The investigators will quantify the difference in baseline dominant frequency values (Hz) of atrial fibrillatory activity between patients with successful cardioversion in the vernakalant and flecainide groups.

    The investigators will also quantify the difference in baseline dominant frequency values (Hz) of atrial fibrillatory activity between patients with successful and unsuccessful cardioversion within the vernakalant or flecainide group.



Secondary Outcome Measures :
  1. Cardioversion success (yes/no) in patients with paroxysmal atrial fibrillation episodes lasting < 24 hours or ≥24 hours. [ Time Frame: 18 months ]
  2. Electrocardiographic-based spectral parameters of atrial fibrillatory activity (Dominant frequency) in patients with episodes lasting < 24 hours or ≥24 hours. [ Time Frame: 18 months ]
    The investigators will quantify the difference in baseline dominant frequency values (Hz) of atrial fibrillatory activity between patients with episodes lasting < 24 hours or ≥24 hours.

  3. Spectral parameters of atrial fibrillatory activity (Dominant frequency) recorded by non-invasive body surface potential mapping associated with successful or unsuccessful cardioversion in both groups of patients. [ Time Frame: 24 months ]

    The investigators will quantify the difference in baseline dominant frequency values (Hz) of atrial fibrillatory activity between patients with successful cardioversion in the vernakalant and flecainide groups.

    The investigators will also quantify the difference in baseline dominant frequency values (Hz) of atrial fibrillatory activity between patients with successful and unsuccessful cardioversion within the vernakalant or flecainide group.


  4. Effects on reentrant-based atrial fibrillation (dominant frequency decrease, rotor meandering) in 2D models of fast and low atrial activation rates under the effect of vernakalant or flecainide. [ Time Frame: 24 months ]
    The investigators will quantify dominant frequency changes (Hz) and rotor meandering (mm) under the effect of vernakalant or flecainide in 2D computational models.

  5. Atrial Fibrillation Quality of Life questionnaire (AF-QOL). [ Time Frame: 24 months ]

Other Outcome Measures:
  1. Patient's perception during cardioversion. The investigators will used a custom-designed five-question questionnaire as follows: [ Time Frame: 24 months ]

    i) Do you recall something from the cardioversion attempt? yes/no. ii) If (1) is yes, was it uncomfortable? yes/no. iii) Did you feel any pain during the cardioversion attempt? yes/no. iv) Please, provide an score from '0' to '10' to evaluate your general perception of the cardioversion attempt.

    v) If necessary, would you undergo another cardioversion attempt using the same strategy? yes/no.




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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients ≥ 20 and ≤65 year-olds.
  2. Patients with paroxysmal AF lasting <48 hours, in whom pharmacological cardioversion may be indicated.
  3. Hemodynamically stable patients (systolic blood pressure > 100 mm Hg and < 160 mm Hg. Diastolic blood pressure <95 mm Hg).
  4. Weight of 45-136 kg .
  5. Appropriate anticoagulation therapy according to the clinical practice guidelines of the European Society of Cardiology in paroxysmal AF episodes lasting < 48 hours.
  6. Signed informed consent.

Exclusion Criteria:

  1. Corrected QT interval> 440 milliseconds, long QT family or history of 'Torsades de Pointes' syndrome.
  2. Symptomatic bradycardia or ventricular rate <50 bpm without a pacemaker, or QRS interval> 140 milliseconds.
  3. Patients with heart failure regardless of the classification of the New York Heart Association (NYHA).
  4. Second or third degree atrioventricular block, or right bundle branch block associated with partial left bundle branch block (bifascicular block).
  5. Cardiogenic or septic shock, chronic myocardial infarction, acute coronary syndrome, or heart surgery in the previous 30 days before inclusion.
  6. Valvular stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis.
  7. Previous unsuccessful electrical cardioversion or longstanding atrial fibrillation (no attempt to convert to sinus rhythm).
  8. Treatment with other investigational drug within 60 days before enrollment.
  9. Previous treatment with vernakalant.
  10. Secondary causes of atrial fibrillation, hyperthyroidism, uncorrected electrolyte imbalance, or digoxin toxicity.
  11. IV / oral treatment with Class I or III antiarrhythmics (except amiodarone) in the previous 48 hours.
  12. Renal failure with glomerular filtration rate <35 ml / min.
  13. Intravenous / oral amiodarone within the previous 3 months.
  14. Pregnant or nursing women.
  15. Intolerance or allergy to any of the two drugs being studied.
  16. Refusal to sign the informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03005366


Contacts
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Contact: David Filgueiras, MD, PhD +34913303000 ext 7045 david.filgueiras@salud.madrid.org
Contact: María-Jesús García-Torrent, PharmD, PhD +34913303000 ext 7510 mgtorrent@salud.madrid.org

Locations
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Spain
Hospital Clínico Universitario San Carlos Recruiting
Madrid, Madrid/Madrid, Spain, 28040
Contact: Asunción Conde, PharmaD    +34913303000 ext 7510    asunconde66@gmail.com   
Contact: María-Jesús García-Torrent, PharmaD, PhD    +34913303000 ext 7510    mgtorrent@salud.madrid.org   
Sponsors and Collaborators
David Filgueiras-Rama
Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
Investigators
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Study Chair: Nicasio Pérez-Castellano, MD, PhD Hospital Clínico San Carlos
Study Chair: Asunción Conde, PharmD Hospital Clínico San Carlos
Study Chair: María-Jesús García-Torrent, PharmD, PhD Hospital Clínico San Carlos
Publications:

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Responsible Party: David Filgueiras-Rama, MD PhD, Hospital San Carlos, Madrid
ClinicalTrials.gov Identifier: NCT03005366    
Other Study ID Numbers: SELECTI-CARFAP
First Posted: December 29, 2016    Key Record Dates
Last Update Posted: February 16, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by David Filgueiras-Rama, Hospital San Carlos, Madrid:
Atrial fibrillation
vernakalant
flecainide
cardioversion
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Flecainide
Anti-Arrhythmia Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action