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

Primary Purpose

Cardiac Surgery

Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Botulinum Toxin Type A Injection [Xeomin]
Drug placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiac Surgery focused on measuring Xeomin®, Botox, Botulinum, Atrial Fibrillation, Cardiac surgery

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.
  • 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 (including disorders of pre-operative swallowing).
  • 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)

Sites / Locations

  • Clinique Ambroise ParéRecruiting
  • Institut Mutualiste MontsourisRecruiting
  • Hôpital Européen Georges PompidouRecruiting
  • Hôpital Bichat
  • Centre Cardiologique du Nord
  • Hôpital Saint-JosephRecruiting
  • Corentin Celton
  • Hôpital Marie LannelongueRecruiting
  • CHU LimogesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Botulinum toxin

Placebo

Arm Description

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,

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).

Outcomes

Primary Outcome Measures

Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 weeks after cardiac surgery
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

Death rate
Death rate at 12 months
Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 monthes after cardiac surgery
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.
Number of patients presenting a cardiovascular event as conduction troubles, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events
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.
Incidence of atrial tachyarrhythmia / Flutter
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.
New onset of postoperative AF
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
End of surgery until discharge (intervals from end of surgery to extubation, in hours)
Mechanical ventilation duration and postoperative length of stay in intensive care unit and in hospital
Readmission rate
Unplanned readmission rate at 3 months and 12 months for cardiovascular cause or haemorrhage.
Antiarrhythmic drugs
Number of antiarrhythmic drugs and curative anticoagulation within 3 months following cardiac surgery.
total hospital cost
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).

Full Information

First Posted
August 19, 2019
Last Updated
November 15, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Merz Pharmaceuticals, Ministry of Health, France
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1. Study Identification

Unique Protocol Identification Number
NCT04075981
Brief Title
Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF)
Acronym
BOTAF
Official Title
Prevention of Post-operative Atrial Fibrillation by BOTulinum Toxin Injections Into Epicardial Fat Pads Around Pulmonary Veins in Patients Undergoing Cardiac Surgery"
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Recruiting
Study Start Date
September 30, 2019 (Actual)
Primary Completion Date
October 1, 2022 (Anticipated)
Study Completion Date
September 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Merz Pharmaceuticals, Ministry of Health, France

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiac Surgery
Keywords
Xeomin®, Botox, Botulinum, Atrial Fibrillation, Cardiac surgery

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Botulinum toxin
Arm Type
Experimental
Arm Description
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,
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Botulinum Toxin Type A Injection [Xeomin]
Other Intervention Name(s)
Xeomin
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Drug placebo
Intervention Description
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 Measure Information:
Title
Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 weeks after cardiac surgery
Description
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).
Time Frame
3 weeks
Secondary Outcome Measure Information:
Title
Death rate
Description
Death rate at 12 months
Time Frame
12 months
Title
Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 monthes after cardiac surgery
Description
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.
Time Frame
3 months
Title
Number of patients presenting a cardiovascular event as conduction troubles, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events
Description
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.
Time Frame
3 months
Title
Incidence of atrial tachyarrhythmia / Flutter
Description
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.
Time Frame
3 months
Title
New onset of postoperative AF
Description
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
Time Frame
3 months
Title
End of surgery until discharge (intervals from end of surgery to extubation, in hours)
Description
Mechanical ventilation duration and postoperative length of stay in intensive care unit and in hospital
Time Frame
10 days
Title
Readmission rate
Description
Unplanned readmission rate at 3 months and 12 months for cardiovascular cause or haemorrhage.
Time Frame
3 and 12 months
Title
Antiarrhythmic drugs
Description
Number of antiarrhythmic drugs and curative anticoagulation within 3 months following cardiac surgery.
Time Frame
3 months
Title
total hospital cost
Description
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).
Time Frame
twelve months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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. 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 (including disorders of pre-operative swallowing). 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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Emmanuelle FLORENS, MD
Phone
+33(0)1 56 09 31 55
Email
emmanuelle.florens@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Laura LE MAO, MSc
Phone
+33(0)1 56 09 54 97
Email
laura.le-mao@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
FLORENS Emmanuelle, MD
Organizational Affiliation
Assistance Publique Hopitaux de Paris (APHP)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Clinique Ambroise Paré
City
Neuilly-sur-Seine
State/Province
Ile-de-France
ZIP/Postal Code
92200
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pierre SQUARA
Email
pierre.squara@orange.fr
Facility Name
Institut Mutualiste Montsouris
City
Paris
State/Province
Ile-de-France
ZIP/Postal Code
75014
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Milena NOGHIN
Email
milena.noghin-gulivati@imm.fr
Facility Name
Hôpital Européen Georges Pompidou
City
Paris
State/Province
Ile-de-France
ZIP/Postal Code
75015
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emmanuelle FLORENS
Email
emmanuelle.florens@aphp.fr
Facility Name
Hôpital Bichat
City
Paris
State/Province
Ile-de-France
ZIP/Postal Code
75877
Country
France
Individual Site Status
Withdrawn
Facility Name
Centre Cardiologique du Nord
City
Saint-Denis
State/Province
Ile-de-France
ZIP/Postal Code
93200
Country
France
Individual Site Status
Withdrawn
Facility Name
Hôpital Saint-Joseph
City
Marseille
State/Province
Provence-Alpes-Côte d'Azur
ZIP/Postal Code
13008
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yvan LE DOLLEY
Email
yledolley@hopital-saint-joseph.fr
Facility Name
Corentin Celton
City
Issy-les-Moulineaux
Country
France
Individual Site Status
Active, not recruiting
Facility Name
Hôpital Marie Lannelongue
City
Le Plessis-Robinson
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marion GAILLARD, MD
Email
m.gaillard@ghpsj.fr
Facility Name
CHU Limoges
City
Limoges
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eline LAHOZ, MD
Email
eline.lahoz@chu-limoges.fr

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individuel participant data that underlie results in publication could be shared Individuel participant data detailed in meta analysis protocol could be shared
IPD Sharing Time Frame
one year after the last publication
IPD Sharing 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

Learn more about this trial

Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF)

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