Clinical trial NCT03779841: Botulinum Toxin Type A (AGN-151607) for the Prevention of Post-operative Atrial Fibrillation in Adult Participants Undergoing Open-chest Cardiac Surgery (NOVA)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Post-Operative Atrial Fibrillation
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2018-12-19
Enrollment: 323
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 30 Seconds During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial intensive care unit (ICU) admission date after open-chest cardiac surgery.
Secondary outcomes:
measure: Percentage of Time Spent in Atrial Fibrillation or Atrial Flutter (AF Burden) During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Event of Symptomatic AF (Atrial Fibrillation or Atrial Flutter) During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Time to First Occurrence of AF (Atrial Fibrillation or Atrial Flutter) During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 2 Minutes During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 5 Minutes During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 6 Minutes During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 30 Minutes During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 1 Hour During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 4 Hours During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 6 Hours During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 12 Hours During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous AF (Atrial Fibrillation or Atrial Flutter) Episode ≥ 24 Hours During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous Atrial Fibrillation (Excluding Atrial Flutter) Episode ≥ 30 Seconds During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous Atrial Flutter Episode ≥ 30 Seconds During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous Atrial Tachycardia Episode (Defined as the Duration of the Longest Supraventricular Tachycardia [SVT] Run) ≥ 30 Seconds During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
measure: Percentage of Participants With at Least 1 Continuous Episode of Either Atrial Fibrillation or Atrial Flutter or Atrial Tachycardia ≥ 30 Seconds During the First 30 Days Post-surgery
timeFrame: First 30 days following the initial ICU admission date after open-chest cardiac surgery.
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Med /ID# 236922
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital - Yale School of Medicine /ID# 238221
state: Connecticut
city: Washington
country: United States
facility: Medstar Washington Hospital Center /ID# 234322
state: District of Columbia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital /ID# 234334
state: Georgia
city: Fort Wayne
country: United States
facility: Lutheran Medical Group /ID# 237990
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Medical Center /ID# 238004
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center /ID# 234352
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan /ID# 236228
state: Michigan
city: Saint Louis
country: United States
facility: Washington University-School of Medicine /ID# 238121
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center /ID# 237530
state: New Hampshire
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai - The Mount Sinai Medical Center /ID# 234449
state: New York
city: Asheville
country: United States
facility: Mission Hospital /ID# 237231
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center /ID# 234314
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University /ID# 237820
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Medical Center /ID# 234408
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina /ID# 236476
state: South Carolina
city: Plano
country: United States
facility: Baylor Scott & White Research Institute /ID# 235937
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah /ID# 237601
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia /ID# 237611
state: Virginia
city: Vienna
country: Austria
facility: Medizinische Universitaet Wien /ID# 238259
state: Wien
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute /ID# 236012
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital /ID# 237680
state: Ontario
city: Montreal
country: Canada
facility: Montreal Heart Insitute /ID# 234859
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Centre hospitalier de l'Universite de Montréal /ID# 238163
state: Quebec
city: Montreal
country: Canada
facility: CIUSSS du Nord-de-l'ile-de-Montréal_Hopital du Sacré-Coeur de Montréal /ID# 234316
state: Quebec
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec - Université L /ID# 237166
state: Quebec
city: Hamburg
country: Germany
facility: Asklepios Klinik Harburg-Hamburg /ID# 234855
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia /ID# 234861
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum /ID# 237113
city: Barcelona
country: Spain
facility: Hospital Clínic. University of Barcelona /ID# 234853
city: Orebro
country: Sweden
facility: Orebro University Hospital Sweden /ID# 236047
state: Orebro Lan
city: Plymouth
country: United Kingdom
facility: University Hospital Plymouth NHS Trust /ID# 234423
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: 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.