Botulinum Toxin Type A (AGN-151607) for the Prevention of Post-operative Atrial Fibrillation in Adult Participants Undergoing Open-chest Cardiac Surgery (NOVA)

A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy and Safety of Botulinum Toxin Type A (AGN-151607) Injections Into the Epicardial Fat Pads to Prevent Post-Operative Atrial Fibrillation in Patients Undergoing Open-Chest Cardiac Surgery

This is a multi-center, randomized, double-blind, placebo-controlled, parallel group, dose-ranging study to evaluate the efficacy and safety of botulinum toxin type A (AGN-151607) injections into the epicardial fat pads, foci of ganglionic plexi, to prevent Post-Operative Atrial Fibrillation (POAF) in patients undergoing open-chest cardiac surgery.

Study Overview

• Status: Completed
• Conditions: Post-Operative Atrial Fibrillation
• Intervention / Treatment: Drug: AGN-151607; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Wien
    • Vienna, Wien, Austria, 1090
      • Medizinische Universitaet Wien /ID# 238259
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute /ID# 236012
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital /ID# 237680
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Montreal Heart Insitute /ID# 234859
    • Montreal, Quebec, Canada, H2X 3E4
      • CHUM - Centre hospitalier de l'Universite de Montréal /ID# 238163
    • Montreal, Quebec, Canada, H4J 1C5
      • CIUSSS du Nord-de-l'ile-de-Montréal_Hopital du Sacré-Coeur de Montréal /ID# 234316
    • Québec, Quebec, Canada, G1V 4G5
      • Institut universitaire de cardiologie et de pneumologie de Québec - Université L /ID# 237166
• Germany
  • Hamburg, Germany, 21075
    • Asklepios Klinik Harburg-Hamburg /ID# 234855
• Italy
  • Brescia, Italy, 25123
    • ASST degli Spedali Civili di Brescia /ID# 234861
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum /ID# 237113
• Spain
  • Barcelona, Spain, 08039
    • Hospital Clínic. University of Barcelona /ID# 234853
• Sweden
  • Orebro Lan
    • Orebro, Orebro Lan, Sweden, 702 12
      • Orebro University Hospital Sweden /ID# 236047
• United Kingdom
  • Plymouth, United Kingdom, PL6 5FP
    • University Hospital Plymouth NHS Trust /ID# 234423
• United States
  • California
    • Stanford, California, United States, 94305-2200
      • Stanford University School of Med /ID# 236922
  • Connecticut
    • New Haven, Connecticut, United States, 06510-3206
      • Yale New Haven Hospital - Yale School of Medicine /ID# 238221
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-3017
      • Medstar Washington Hospital Center /ID# 234322
  • Georgia
    • Atlanta, Georgia, United States, 30342-1731
      • Emory Saint Joseph's Hospital /ID# 234334
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Lutheran Medical Group /ID# 237990
  • Louisiana
    • New Orleans, Louisiana, United States, 70121-2429
      • Ochsner Medical Center /ID# 238004
  • Maryland
    • Baltimore, Maryland, United States, 21201-1544
      • University of Maryland Medical Center /ID# 234352
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5000
      • University of Michigan /ID# 236228
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University-School of Medicine /ID# 238121
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center /ID# 237530
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai - The Mount Sinai Medical Center /ID# 234449
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital /ID# 237231
    • Durham, North Carolina, United States, 27705-4410
      • Duke University Medical Center /ID# 234314
    • Greenville, North Carolina, United States, 27858
      • East Carolina University /ID# 237820
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center /ID# 234408
  • South Carolina
    • Charleston, South Carolina, United States, 29425-0001
      • Medical University of South Carolina /ID# 236476
  • Texas
    • Plano, Texas, United States, 75093
      • Baylor Scott & White Research Institute /ID# 235937
  • Utah
    • Salt Lake City, Utah, United States, 84112-5500
      • University of Utah /ID# 237601
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia /ID# 237611

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Inclusion Criteria:

• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.
• Written informed consent from the participant has been obtained prior to any study-related procedures
• Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg. Written Authorization for Use and Release of Health and Research Study Information [US sites] and written Data Protection consent (European Union sites).
• Participants who are scheduled to undergo open-chest cardiac surgery. Includes: coronary artery bypass graft (CABG) and/or valve repair/replacement. Inclusionary valve repair/replacement procedures for the primary reason for surgery include: Aortic valve repair/replacement, Mitral valve repair/replacement, Combination of aortic and tricuspid valve repair/replacement, Combination of mitral and tricuspid valve repair/replacement CABG/valve combination procedures (when valvular procedure is one of the 4 sub-bulleted procedures immediately above), Left Atrial Appendage (LAA) procedures are allowed if CABG and/or valve repair or replacement is the qualifying surgical procedure, but is not a qualifying surgical procedure on its own.
• A male participant must agree to use contraception until Day 60 and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant (has a negative urine pregnancy result prior to randomization) not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP). A WOCBP who agrees to follow the contraceptive guidance until after Day 60.
• In sinus rhythm for the last 48 hours prior to randomization based on standard-of care assessments and study ECGs (note: continuous ECG monitoring for 48 hours is not required; prior history of paroxysmal AF is acceptable)
• Willing to wear an electrocardiogram (ECG) patch for a full 30 days post-surgery and for 7 days after each study visit
• Able, as assessed by the investigator, and willing to follow study instructions and likely to complete required study visit.

Exclusion Criteria:

• Any uncontrolled clinically significant medical condition other than the one under study that, in the investigator's opinion, would put the participant at an unacceptable risk with exposure to botulinum toxin type A.
• Exclusionary valve repair/replacement procedures include: Combination of aortic and mitral valve repair/replacement, Isolated tricuspid valve repair/replacement.
• Any medical condition that may put the participant at increased risk with exposure to botulinum toxin type A, including diagnosed muscular dystrophy (eg, Duchenne's muscular dystrophy), myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, mitochondrial disease, or any other significant disease which might interfere with neuromuscular function.
• Participants with presence or history of any of the following within 3 months prior to the Day 1 visit that may indicate a vulnerable respiratory state per the investigator's clinical judgment: aspiration pneumonia, lower respiratory tract infections, uncontrolled asthma, severe chronic obstructive pulmonary disease, or otherwise compromised respiratory function.
• Permanent/persistent atrial fibrillation (AF)
• Has a known allergy or sensitivity to any botulinum toxin type A preparation. - Has a known allergy or sensitivity to medical adhesive (eg, ECG patch adhesive; hydrogel-based adhesive).
• Severe (> 55 mm left atrial diameter) left atrial enlargement
• Left ventricular ejection fraction (LVEF) < 25%
• Presence or history of symptomatic atrioventricular block > 1st degree within the last 30 days (note: presence of a pacemaker is not exclusionary per se) - Class I or III antiarrhythmic drugs unless proper washout was documented
• Botulinum toxin type A (of any serotype) use within 6 months of randomization
• Has been immunized for any botulinum toxin type A serotype as determined by participant medical history
• Preoperative need for inotropes/vasopressors or intra-aortic balloon pump
• Prior open-chest, sternotomy cardiac surgery - History of ablation for AF
• Planned ablation procedure for AF at the time of surgery
• Emergency surgery
• Current enrollment in an investigational drug or device study or participation in such a study within 30 days of entry into this study
• Participants have diagnostic assessments which in the opinion of the investigator prevent participation in the study
• Impaired prognosis defined as EuroSCORE II > 7% perioperative mortality at screening is exclusionary.
• Females who are pregnant, nursing, or planning a pregnancy during the study
• The participant has a condition or is in a situation which, in the investigator's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with the participant's participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AGN-151607 (250 U); Injections of 50 U will be made into each 1 of 5 fat pads. The total injection volume into each fat pad will be 1 mL. One-time treatment.	Drug: AGN-151607; Injections will be made into each 1 of 5 fat pads. The total injection volume into each fat pad will be 1 mL. One-time treatment.
Experimental: AGN-151607 (125 U); Injections of 25 U will be made into each 1 of 5 fat pads. The total injection volume into each fat pad will be 1 mL. One-time treatment.	Drug: AGN-151607; Injections will be made into each 1 of 5 fat pads. The total injection volume into each fat pad will be 1 mL. One-time treatment.
Placebo Comparator: Placebo; Injections of placebo will be made into each 1 of 5 fat pads. The total injection volume into each fat pad will be 1 mL. One-time treatment.	Drug: Placebo; Injections of placebo will be made into each 1 of 5 fat pads. The total injection volume into each fat pad will be 1 mL. One-time treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of participants with at least 1 continuous atrial fibrillation (AF) episode ≥ 30 seconds during the first 30 days post-surgery.	30 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of time spent in AF (AF burden) during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 event of symptomatic AF during the first 30 days post-surgery	30 days
Time to first occurrence of AF during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 2 minutes during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 5 minutes during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 30 minutes during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 1 hour during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 4 hours during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 24 hours during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 6 hours during the first 30 days post-surgery	30 days
Percentage of participants with at least 1 continuous AF episode ≥ 12 hours during the first 30 days post-surgery	30 days

Collaborators and Investigators

• Sponsor: AbbVie
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• Piccini JP, Ahlsson A, Dorian P, Gillinov MA, Kowey PR, Mack MJ, Milano CA, Perrault LP, Steinberg JS, Waldron NH, Adams LM, Bharucha DB, Brin MF, Ferguson WG, Benussi S. Design and Rationale of a Phase 2 Study of NeurOtoxin (Botulinum Toxin Type A) for the PreVention of Post-Operative Atrial Fibrillation - The NOVA Study. Am Heart J. 2022 Mar;245:51-59. doi: 10.1016/j.ahj.2021.10.114. Epub 2021 Oct 20.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): March 24, 2022
• Study Completion (Actual): March 2, 2023

Study Registration Dates

• First Submitted: December 17, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: 1925-201-008; 2017-004399-68 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• IPD Sharing Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• IPD Sharing Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No