Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF)

NCT04075981 | Recruiting Phase 3 DMC

• 2 other identifiers: P170912JPHRCN-17-0371
• Study Type: interventional
• Target: 220
• Locations: 1 country
• Sites: 9

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.

Conditions

Cardiac Surgery

Keywords

Xeomin®; Botox; Botulinum; Atrial Fibrillation; Cardiac surgery

Outcome Measures

Primary Outcomes (1)

• 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 both holter ECG Spiderflash-t recorder during the first 21 days post-op and ECG daily monitoring during the first 7 days after surgery.

  3 weeks

Secondary Outcomes (9)

• Death rate

  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

  3 months

• Number of patients presenting a cardiovascular event as conduction troubles, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events

  3 months

• Incidence of atrial tachyarrhythmia / Flutter

  3 months

• New onset of postoperative AF

  3 months

Study Arms (2)

Botulinum toxin

EXPERIMENTAL

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]

Placebo

PLACEBO COMPARATOR

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

Interventions

Botulinum Toxin Type A Injection [Xeomin] DRUG

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.

Also known as: Xeomin

Botulinum toxin

Drug placebo OTHER

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).

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Merz Pharmaceuticals: collaborator
• Ministry of Health, France: collaborator

Study Sites (9)

Corentin Celton

Issy-les-Moulineaux, France, France

ACTIVE NOT RECRUITING

Hôpital Marie Lannelongue

Le Plessis-Robinson, France, France

ACTIVE NOT RECRUITING

CHU Limoges

Limoges, France, France

ACTIVE NOT RECRUITING

Hôpital Saint-Joseph

Marseille, Provence-Alpes-Côte d'Azur Region, 13008, France

ACTIVE NOT RECRUITING

Clinique Ambroise Paré

Neuilly-sur-Seine, Île-de-France Region, 92200, France

ACTIVE NOT RECRUITING

Institut Mutualiste Montsouris

Paris, Île-de-France Region, 75014, France

RECRUITING

Hôpital Européen Georges Pompidou

Paris, Île-de-France Region, 75015, France

RECRUITING

Hôpital Bichat

Paris, Île-de-France Region, 75877, France

WITHDRAWN

Centre Cardiologique du Nord

Saint-Denis, Île-de-France Region, 93200, France

WITHDRAWN

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Botulinum Toxins, Type A; incobotulinumtoxinA

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloproteases; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Bacterial Toxins; Toxins, Biological; Biological Factors

Study Officials

• FLORENS Emmanuelle, MD

  Assistance Publique Hopitaux de Paris (APHP)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emmanuelle FLORENS, MD

CONTACT

+33(0)1 56 09 31 55; emmanuelle.florens@aphp.fr

Laura LE MAO, MSc

CONTACT

+33(0)1 56 09 54 97; laura.le-mao@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: August 19, 2019
• First Posted: September 3, 2019
• Study Start: September 30, 2019
• Primary Completion: October 30, 2025
• Study Completion (Estimated): September 30, 2026
• Last Updated: May 16, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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

Locations

FR (9)