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Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF) (BOTAF)

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ClinicalTrials.gov Identifier: NCT04075981
Recruitment Status : Recruiting
First Posted : September 3, 2019
Last Update Posted : October 8, 2019
Sponsor:
Collaborators:
Merz Pharmaceuticals
Netherlands: Ministry of Health, Welfare and Sports
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Over the past few years, research has focused on the prevention of atrial fibrillation (AF) after cardiac surgery, but highly effective interventions are still missing. Postoperative AF remains the most common complication after cardiac surgery, with an incidence of 10 to 50%. This complication is usually a transient condition that resolves spontaneously but it has major adverse consequences for patients and the health care system, including increased rates of death, complications (strokes), and hospitalisations with inflated costs.

Recently, animal studies have demonstrated that neurotoxins such as botulinum toxin (BTX) injected into fat pads could suppress AF inducibility by parasympathetic activation. Botulinum toxin injection in fat pads has been studied in the dog's heart and could be associated with the reduction of atrial fibrillation in postoperative cardiac surgery. One pilot study has demonstrated the feasibility and safety of this technique in the human heart.

The investigators hypothesize that botulinum toxin injection may substantially reduce postoperative AF during the first postoperative month after cardiac surgery without any serious adverse events. By the suppression of ganglionic plexi (GP) activity in the epicardial fat pads, mild term antiarrhythmic effects can be achieved with fewer antiarrhythmic drugs and anticoagulant treatment.


Condition or disease Intervention/treatment Phase
Cardiac Surgery Drug: Botulinum Toxin Type A Injection [Xeomin] Other: Drug placebo Phase 3

Detailed Description:

Botulinium toxin use has been developed with success in wide-ranging fields (neurology, otorhinolaryngology, gynaecology, urology, plastic surgery, pain therapy), but not in cardiology.

In the cardio-vascular field, only one pilot study on man has shown its utility in the prevention of atrial fibrillation by blocking the triggering through the sympathic and parasympathic systems. The investigators need to assess its potential benefits to prevent postoperative atrial tachyarrhythmia in a randomised multicentre study, with an expected impact of approximately 30,000 patients per years in France undergoing these types of cardiac surgery.

The investigators hypothesize that botulinum toxin injection may substantially reduce postoperative AF during the first 3 weeks after cardiac surgery without any serious adverse events. By the suppression of ganglionic plexi (GP) activity in the epicardial fat pads, mild term antiarrhythmic effects can be achieved with fewer antiarrhythmic drugs and anticoagulant treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study is a double-blind multicenter randomized trial comparing treatment with botulinum toxin to normal saline (placebo) on top of usual treatment to prevent atrial fibrillation in patients undergoing cardiac surgery (coronary artery bypass graft surgery (CABG), aortic valve surgery, or ascending aorta surgery).
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Prevention of Post-operative Atrial Fibrillation by BOTulinum Toxin Injections Into Epicardial Fat Pads Around Pulmonary Veins in Patients Undergoing Cardiac Surgery"
Actual Study Start Date : September 30, 2019
Estimated Primary Completion Date : October 1, 2022
Estimated Study Completion Date : September 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Botulinum toxin

All patients from the experimental group will receive botulinum toxin (Xeomin®, incobotulinumtoxin A, Merz Pharma GmbH & Co KGaA, Germany; 200 U dissolved in 4 mL of 0.9% normal saline and 50 U/1 mL will be injected at each fat pad).

Botulinum toxin will be injected into the entire visible area of the 4 major epicardial fat pads, during extra corporal circulation and before aortic cross clamping in order to reduce the time of ischemia.

The whole estimated dosage would be therefore 200 units of incobotulinumtoxin A,

Drug: Botulinum Toxin Type A Injection [Xeomin]
Before the main stage of the surgery, botulinum toxin will be injected into the entire visible area of the 4 major epicardial fat pads, during extra corporal circulation and before aortic cross clamping in order to reduce the time of ischemia.
Other Name: Xeomin

Placebo Comparator: Placebo
All patients from the control group will receive placebo. Before the main stage of the surgery, during extra corporal circulation and before aortic cross clamping, the placebo dissolved in 4 mL of 0.9% normal saline will be injected into the entire visible area of the 4 major epicardial fat pads as follows (1 mL at each fat pad).
Other: Drug placebo
All patients from the control group will receive placebo. Before the main stage of the surgery, during extra corporal circulation and before aortic cross clamping, the placebo will be injected into the entire visible area of the 4 major epicardial fat pads as follows (1 mL at each fat pad).




Primary Outcome Measures :
  1. Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 weeks after cardiac surgery [ Time Frame: 3 weeks ]

    An episode of AF will be considered part of the primary outcome analyses if it last at least 30 seconds continuously within 21 days after cardiac surgery and is documented by any form of monitoring, regardless of symptoms. The definition of atrial fibrillation (at least 30 seconds continuously) results from recent publications and AF definition in the cardiovascular field64.

    This endpoint will be measured through ECG recorder during the first 21 days post-op (Spiderflash-t).



Secondary Outcome Measures :
  1. Death rate [ Time Frame: 12 months ]
    Death rate at 12 months

  2. Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 monthes after cardiac surgery [ Time Frame: 3 months ]
    Incidence of rhythm disorders of postoperative AF in patients undergoing cardiac surgery at 3 months defined as atrial arrhythmia during at least 30 seconds continuously.

  3. Number of patients presenting a cardiovascular event as conduction troubles, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events [ Time Frame: 3 months ]
    conduction troubles such as atrioventricular block or the need for transient or permanent placement of a pacemaker, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events.cardiac surgery at 3 months defined as atrial arrhythmia during at least 30 seconds continuously.

  4. Incidence of atrial tachyarrhythmia / Flutter [ Time Frame: 3 months ]
    Incidence of all atrial tachyarrhythmia including atrial fibrillation, but also atrial flutter and atrial tachycardia 3 months, and each arrhythmia taken individually between the two parallel groups.cardiac surgery at 3 months defined as atrial arrhythmia during at least 30 seconds continuously.

  5. New onset of postoperative AF [ Time Frame: 3 months ]
    Incidence of new onset of postoperative AF depending on the following subgroups: age, gender, heart failure, left atrial enlargement, Euro SCORE 2, renal function, type of surgery

  6. End of surgery until discharge (intervals from end of surgery to extubation, in hours) [ Time Frame: 10 days ]
    Mechanical ventilation duration and postoperative length of stay in intensive care unit and in hospital

  7. Readmission rate [ Time Frame: 3 and 12 months ]
    Unplanned readmission rate at 3 months and 12 months for cardiovascular cause or haemorrhage.

  8. Antiarrhythmic drugs [ Time Frame: 3 months ]
    Number of antiarrhythmic drugs and curative anticoagulation within 3 months following cardiac surgery.

  9. total hospital cost [ Time Frame: twelve months ]
    Initial admission and readmissions for cardiovascular cause, and Incremental cost effectiveness ratio (additional cost per additional survival, additional QALY or per additional adverse event recognised).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Indication for cardiac surgery (CABG, aortic valve repair or aortic valve replacement excluding the sutureless valve, ascending aorta surgery), according to the European Heart Association guidelines.
  • Patients in hemodynamically stable condition.
  • Sinus rhythm at moment of randomisation (ECG).
  • Age: ≥18 to ≤80 years old.
  • Negative serum or urinary β-hCG for women of child-bearing potential.
  • Patients able to attend several consultations at the centre.
  • Informed consent signed.
  • Affiliation to French social security regime.

Exclusion Criteria:

  • Previous cardiac surgery.
  • Preoperative history of persistent AF or atrial tachycardia.
  • Planned maze procedure or pulmonary vein (PV) isolation.
  • Use of class I or III antiarrhythmic drugs within 5 elimination half-life of the drug (for amiodarone: one year).
  • Mitral or tricuspid valve surgery.
  • Congenital cardiomyopathy.
  • Neuro-muscular disease.
  • Protected populations e.g. minor patient, breastfeeding women, patients under legal guardianship, curatorship or legal protection. .
  • Participation in another interventional trial.
  • Unwillingness to participate.
  • Contraindications to botulinum toxin under investigation or to the excipients: known hypersensitivity.
  • Patient with active endocarditis Minimal invasive surgery (ministernotomy)

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): NCT04075981


Contacts
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Contact: Emmanuelle FLORENS, MD +33(0)1 56 09 31 55 emmanuelle.florens@aphp.fr
Contact: Hakima MANSEUR, MSc +33(0)1 56 09 59 71 hakima.manseur@aphp.fr

Locations
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France
Hôpital Européen Georges Pompidou Recruiting
Paris, Ile De France, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Merz Pharmaceuticals
Netherlands: Ministry of Health, Welfare and Sports
Investigators
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Principal Investigator: FLORENS Emmanuelle, MD Assistance Publique Hopitaux de Paris (APHP)
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04075981    
Other Study ID Numbers: P170912J
PHRCN-17-0371 ( Other Identifier: Ministry of health )
First Posted: September 3, 2019    Key Record Dates
Last Update Posted: October 8, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individuel participant data that underlie results in publication could be shared Individuel participant data detailed in meta analysis protocol could be shared
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: one year after the last publication
Access Criteria:

Data sharing must be accepted by the sponsor and the PI based on scientific project and scientific involvement of the PI team.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Xeomin®
Botox
Botulinum
Atrial Fibrillation
Cardiac surgery
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Botulinum Toxins
Botulinum Toxins, Type A
abobotulinumtoxinA
incobotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents