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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Post-Operative Atrial Fibrillation

Intervention / Treatment
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* Drug: AGN-151607
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGN-151607 (250 U)<br>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<br>* 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.<br>|
| Experimental: AGN-151607 (125 U)<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 |