Clinical trial NCT03779841
Conditions: Post-Operative Atrial Fibrillation
Sponsor: AbbVie
Start date: 2019-03-01; Completion date: 2023-03-06
Enrollment: 323 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Injections of 50 U were made into each 1 of 5 fat pads. The total injection volume into each fat pad was 1 mL. One-time treatment. arm 2: Injections of 25 U were made into each 1 of 5 fat pads. The total injection volume into each fat pad was 1 mL. One-time treatment. arm 3: Injections of placebo were made into each 1 of 5 fat pads. The total injection volume into each fat pad was 1 mL. One-time treatment.
Interventions: intervention 1: AGN-151607 intervention 2: Placebo
Intervention descriptions: intervention 1: Injections were made into each 1 of 5 fat pads. The total injection volume into each fat pad was 1 mL. One-time treatment. intervention 2: Injections of placebo were made into each 1 of 5 fat pads. The total injection volume into each fat pad was 1 mL. One-time treatment.

Protocol documents:
Prot_000.pdf: 


CONFIDENTIAL 
Protocol 1925-201-008 Amendment 1 
AGN-151607 
2 
Protocol Amendment Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
 
Amendment 1 
 
Amendment 1 (25 Sep 2020) 
Overall Rationale for the Amendment 
This summary includes changes made to Protocol 1925-201-008 Amendment 1 (dated 
25 Sep 2020). The purpose of this protocol amendment is to clarify specific points within the 
protocol based on clinical experience to date. These changes will not impact the safety 
assessment of botulinum toxin type A or alter the risk-benefit ratio for study participants. 
Administrative edits were also made, but not specifically noted (eg, corrected spelling, 
punctuation, grammar, abbreviations, and style errors) including global edits required for 
consistency (eg, “study drug”, “participants”, abbreviation use).  
Summary of Changes in Global Protocol Amendment 
Section No. and Name 
Description of Change 
Brief Rationale 
Global change 
• Text was revised throughout as needed regarding
time period ECG patch is to be worn post-surgery:
“for a full 30 days post-surgery”. This change may
not be universally reflected in text related to
statistical analyses where original text was more
often retained.
• To clarify that the ECG
patch should be worn for
a full 30 days
• Text was revised throughout as needed regarding
the 30-day cut-off post-discharge and 60-day
cut-off post-surgery.
• For clarification and 
consistency
• References were updated
• To include/update
references published after
original protocol was
finalized
Title page 
Study acronym was added 
For clarification 
Section 1.1, Synopsis 
Revised text as needed to align with in-text 
revisions 
For consistency 
Section 1.2, Schema 
Revised as needed to align with in-text revisions 
For consistency 
Section 1.3, Schedule of 
Activities 
All footnotes were sequentially renumbered 
For consistency and 
accuracy following 
addition and deletion of 
footnotes in the original 
protocol 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
3 
Section No. and Name 
Description of Change 
Brief Rationale 
• A new footnote ‘a’ was added to “Screening”: 
Screening and randomization activities can occur 
on the same day. If screening and randomization 
occur on the same day, all assessments for Visit 1 
and Visit 2 should be completed. Duplicate 
assessments (eg, laboratory assessments) do not 
have to be completed twice; please note a 12-lead 
ECG is required both before and after surgery. 
• To clarify that 
screening activities can 
take place on the same 
day as randomization 
• Current footnote ‘b’ was revised: These visits are 
optional and are only required if the participant is 
still hospitalized. Participants may remain in the 
hospital beyond Day 6, based on the recovery from 
surgery. The study visit procedures will have to be 
performed each day until discharge 
• For clarification 
• Current footnote ‘c’ was revised: In case of early 
discontinuation, attempts will be made to follow-up 
with the participant. for 3 months post dose. 
• To clarify that 
follow-up must occur as 
soon as possible after 
sponsor is notified of 
potential early 
discontinuation  
• Current footnote ‘d’ was revised: Day 367 must 
be at least 7 days and should be no more than 
14 days after Visit 13 (Day 360). 
• To clarify visit window 
• A new footnote ‘f’ was added to “Physical 
examination” Day 360: Physical examinations 
should be conducted where feasible. If the 
participant cannot attend the study visit, then the 
physical examination can be omitted, with sponsor 
approval. 
• To provide guidance 
regarding feasibility of 
study assessments being 
conducted 
• Current footnote ‘h’ was revised: Laboratory 
assessments (hematology, chemistry, coagulation 
and urinalysis) to be performed at screening, Day 1 
and day of discharge. The day of discharge can be 
from Day 3 onwards. Once discharged the 
participant does not have to return until Day 30 
(Visit 8). 
• To allow for remote 
assessments 
• A new footnote ‘i’ was added to “Laboratory 
assessments” Days 60, 90, and 360: Laboratory 
assessments should be conducted where feasible. 
If the participant cannot attend the study visit 
and/or an in-home assessment is not feasible, then 
the laboratory assessments can be omitted, after 
sponsor approval. 
• To provide guidance 
regarding feasibility of 
study assessments being 
conducted 
• Current footnote ‘j’ was revised: On Visit 2, 
Day 1, two 12-lead ECGs will be performed; 1 
before surgery and 1 after surgery. PFT should be 
performed after vital signs and ECG at a 
reasonable time apart from vital signs and ECG to 
avoid confounding ECG and vital signs data. 
• Clarified timing of 
when assessments should 
be conducted in relation 
to other assessments 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
4 
Section No. and Name 
Description of Change 
Brief Rationale 
• A new footnote ‘k’ was added to “12-lead ECG” 
at Days 60, 90, 180, 270, and 360: 12-lead ECGs 
should be conducted where feasible. If the 
participant cannot attend the study visit and/or an 
in-home assessment is not feasible, then the 
12-lead ECG can be omitted, after sponsor 
approval. 
• To provide guidance 
regarding feasibility of 
study assessments being 
conducted 
• A new footnote l was added to “ECG patch” 
Day 30: ECG patch must be worn for a full 
30 days post-surgery, even if Day 30 visit occurs 
prior to Day 30 due to window allowance. 
• To clarify that the ECG 
patch should be worn for 
a full 30 days 
• Current footnote ‘m’ was revised: ECG patch 
must be used for first 30 days after surgery and 
during the first 7 days following Day 60, Day 90, 
Day 180, Day 270 and Day 360 visits. 
• Clarified that footnote 
m was only regarding 
visits 9 to 13 
• Current footnote ‘n’ was revised: Vital signs 
taken after a participant has been in a resting 
position for a minimum of 5 minutes; include blood 
pressure, pulse, respiration rate, and body 
temperature. On Visit 2, Day 1, vital signs will be 
measured before and after surgery. PFT should be 
performed after vital signs and ECG. 
• Guidance regarding 
PFTs was moved to 
footnote i and r 
• Current footnote ‘r’ was revised: Pulmonary 
function to be assessed using a bedside spirometer 
and will include forced vital capacity (FVC) and 
the forced expiratory volume in 1 second (FEV1), 
3 seconds (FEV3) and 6 seconds (FEV6). Note, if 
local policies contraindicate or prohibit PFT 
assessments due to potential for viral spread or 
microbial precautions, then the PFT is not 
required after explicit approval from the sponsor. 
• To provide guidance 
regarding feasibility of 
study assessments being 
conducted 
• “EuroSCORE II” and corresponding footnote 
(footnote ‘t’) was added to the SoA: Impaired 
prognosis defined as EuroSCORE II > 7% 
perioperative mortality at screening is 
exclusionary. 
• Included guidance 
regarding EuroSCORE II 
in the SoA for 
consistency 
• A new footnote ‘u’ was added to “Serum 
sampling for immunogenicity assessment”: Serum 
collection should be conducted where feasible. If 
the participant cannot attend the study visit and/or 
an in-home assessment is not feasible, then the 
serum collection can be omitted, after sponsor 
approval. 
• To provide guidance 
regarding feasibility of 
study assessments being 
conducted 
 
 
 




CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
6 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 3, Objectives and 
Endpoints;  
Section 8.1.3.3 Clinically 
Important Tachycardia in 
Atrial Fibrillation;  
Section 9.4.1.4 Additional 
Efficacy Variables 
The following safety endpoint was revised: 
• Percentage of participants with clinically 
important tachycardia in AF (defined as heart rate 
≥ 100 bpm for at least 2 minutes) with or without 
systolic blood pressure < 100 mm Hg) 
Updated definition of 
safety endpoint  
Section 3, Objectives and 
Endpoints 
The following quality of life endpoints were 
added/deleted: 
• Healthcare resource utilization (eg, setting, 
provider, reason for visit)  
• Outpatient medical encounters and treatments 
(including physician or emergency room visits, 
tests and procedures, and medications) 
• Number and type of diagnostic and therapeutic 
tests and procedures 
For clarification 
Section 4.1, Overall Design 
The number of projected study sites was revised: It 
is projected that a total of approximately 20 to 30 
40 sites (North America and Europe) will enroll a 
total of approximately 330 participants for this 
Phase 2 study. 
For accuracy 
Section 5, Study 
Population; Rational for 
Inclusion and Exclusion 
Criteria 
Text was revised regarding IC 6.01: • Inclusion 
criterion 6.01 is to ensure participants have a 
regular sinus rhythm no detected arrhythmias in 
the 48 hours prior to surgery so that could impact 
study conduct. only POAF is measured  
To clarify inclusion 
criteria 6.01 
Section 5.1, Inclusion 
Criteria 
• Inclusion Criterion 2.01 was expanded:  
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. 
• To further clarify 
inclusionary valve 
repair/replacement 
procedures for primary 
surgery 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
7 
Section No. and Name 
Description of Change 
Brief Rationale 
 
• Inclusion Criterion 6.01 was revised: 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; surgery prior history of 
paroxysmal atrial fibrillation [AF] is acceptable). 
• To clarify inclusion 
criteria 6.01  
Section 5.2, Exclusion 
Criteria 
• Exclusion Criterion 1.07 was revised: Severe 
(> 55 mm left atrial diameter) left atrial 
enlargement 
• To clarify the 
measurement and atria 
• Exclusion Criterion 1.09 was revised: Presence 
or history of symptomatic atrioventricular block 
> 1st degree within the last 30 days (note: presence 
of a pacemaker is not exclusionary per se) 
• To clarify pacemaker is 
not exclusionary if other 
criteria are satisfied 
• Exclusion Criterion 1.10 was added:  
Exclusionary valve repair/replacement 
procedures include: 
• Combination of aortic and mitral valve 
repair/replacement  
• Isolated tricuspid valve repair/replacement 
• To further clarify 
exclusionary valve 
repair/replacement 
procedures for primary 
surgery 
• Exclusion Criterion 2.05 was revised: Prior 
open-chest, sternotomy cardiac surgery 
• To clarify which prior 
cardiac surgeries are 
excluded 
• Exclusion Criterion 4.02 was revised: Impaired 
prognosis defined as EuroSCORE II > 7% 
perioperative mortality at screening is 
exclusionary. 
• To clarify the timepoint 
of the assessment 
Section 6.1, Study 
Interventions; 
Table 6-1 Treatments 
Administered 
Text was added: 
Each of the 5 fat pads must be injected as part of 
the study procedure. However, in the event where 
1 fat pad is missing or is not accessible, the 
injection procedure can continue and only 4 mL 
of interventional product or placebo shall be 
injected. If, upon initial evaluation (ie, if 
injections have not yet occurred), 3 fat pads or 
fewer are accessible, the injection procedure 
should be aborted. If any injections of study 
intervention have already been made when the 
surgeon determines they are unable to inject 4 or 
more fat pads, the participant should remain in 
the study. 
 
Table footnote was deleted: a Each 1 of the 5 fat 
pads must be injected as part of the study 
procedure. However, in the event where 1 fat pad is 
missing or is not accessible, the injection procedure 
can continue and only 4 mL of interventional 
product or placebo shall be injected. If 3 fat pads or 
less are accessible, the injection procedure must be 
aborted. 
To clarify the decision to 
proceed (or not) based on 
initial inspection of 
accessible fat pads 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
8 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 6.2, 
Preparation/Handling/ 
Storage/Accountability 
Text was revised: All unused study intervention 
and used kits must should be returned to the 
sponsor or designee at the termination of the study. 
Unit counts will be performed when the study 
intervention is returned, and all study intervention 
must be accounted for. Accountability logs for 
destroyed materials should be maintained at the 
site to ensure all study intervention is accounted 
for. Study intervention may be destroyed on site if 
required by local/institutional policies after 
sponsor approval of destruction process and 
documentation. 
For improved accuracy 
Section 6.5.2, Permitted 
Interventions 
Text was revised: • Dosage information including 
dose, route of administration, and frequency 
For additional guidance 
Section 6.5.3, Rescue 
Medicine or Procedure 
• Text was added: Standard-of-care is allowable 
at any time during the study. The date and time of 
any medication administration, as well as the name, 
indication, and dosage regimen of the medication 
(ie, dose, route of administration, and frequency), 
should be recorded. 
• To provide guidance 
regarding all required 
information needed  
 
• Text was revised: An intervention to treat an A 
catheter based ablation for arrhythmia is allowed 
during follow-up as clinically warranted in the 
judgement of the treating physician and/or site-
based investigator physician. 
• For clarification 
Section 6.5.4, Prohibited 
Intervention During the 
Study 
Text was revised:  
Participants are prohibited from using 
aminoglycoside antibiotics or other medicinal 
products that interfere with neuromuscular 
transmission (eg, neuromuscular blocking agents) 
for 60 days post surgery.  
Please refer to Section 6.5.1 for prohibited 
interventions during the washout period prior to 
surgery. 
Administration of aminoglycosides or other 
agents interfering with neuromuscular 
transmission (eg, curare-like compounds) should 
only be performed with caution for 60 days 
post-surgery, as the effect of the toxin may be 
potentiated. 
To align with current 
guidance for available 
botulinum neurotoxins 
Section 7.2, Participant 
Discontinuation/Withdrawal 
from the Study 
The following bullet point was revised: • See the 
SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further 
evaluations that need to be completed. In case of 
early discontinuation, attempts will be made to 
follow-up with the participant for 3 months post
dose. 
For consistency 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
9 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 8, Study 
Assessments and 
Procedures 
• An additional bullet point was added: • Visits 4, 
5, 6, and 7 are optional and are only required if 
the participant is still hospitalized. Participants 
may remain in the hospital beyond Day 6, based 
on the recovery from surgery. The study visit 
procedures will have to be performed each day 
until discharge. 
• To clarify all 
procedures required prior 
to discharge for patients 
having extended hospital 
stay 
• An additional bullet point was added: • Study 
visits after the index surgery may be conducted at 
the participant’s home or other designated 
location in accordance with local ethics and/or 
IRB regulations, as well as with sponsor 
approval. 
• To include language 
regarding at home visits 
• Text was revised: • … However, testing of 
blood samples (including during unscheduled 
visits or samples for which local laboratory values 
are already available) must should be conducted 
by the central laboratory. 
• For clarification 
 
• Text was added: • Local laboratory results are 
required only in the event that the central 
laboratory results are not available in time for 
either study intervention administration and/or 
response evaluation. Local laboratory results 
collected at the screening visit can be used to 
determine participants’ eligibility if central 
laboratory results are not available. If a local 
sample is required, it is important that the sample 
for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are 
used to make either a study intervention decision 
or response evaluation, the results must be entered 
into the CRF. 
• For clarification and 
consistency 
Section 8.1.1, Occurrence of 
Post-Operative Atrial 
Fibrillation 
Text was added: The occurrence of POAF will be 
monitored through Day 30 and for 7 days after 
each of the following study visits: Day 60, Day 
90, Day 180, Day 270, and Day 360 by ECG 
patches placed on the upper left region of the 
chest (Table 8 1). 
For consistency 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
10 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 8.1.1, Occurrence of 
Post-Operative Atrial 
Fibrillation; Table 8-1 
• “Post-surgery” was added to text: Through Day 
367 (continuously through Day 30 post-surgery 
and during the first 7 days following Day 60, Day 
90, Day 180, Day 270 and Day 360 visits) 
• For clarification 
 
• Text was revised to include new timepoints  
Occurrence of POAF: 
7. Continuous AF ≥ 6 hours 
8.  Continuous AF ≥ 12 hours 
 
Time to first occurrence of POAF 
7. Continuous AF ≥ 6 hours 
8.  Continuous AF ≥ 12 hours 
• Endpoints expanded to 
include multiple 
definitions 
Section 8.1.3.2, 
Symptomatic Post-
Operative Atrial Fibrillation 
Text was revised: From Day 1 to Day 30 While 
the participant is wearing the ECG patch, if the 
symptoms of AF occur, the actual symptom will 
be documented by the participant in a symptom 
diary. Participants will be instructed by the site 
staff or designee on the appropriate completion of 
the symptom diary and instructions will be 
included with each diary. 
For clarification 
Section 8.1.3.2, 
Symptomatic Post-
Operative Atrial 
Fibrillation; Table 8-3 
• Text was revised: Through Day 30 and for 
7 days after each of the following study visits: 
Day 60, Day 90, Day 180, Say 270, and Day 360   
 
• For consistency 
 
• The following bullet point was deleted: 
• Symptoms will be assigned to the nearest AF 
within a 30 minute time window 
• For clarification 
Section 8.1.4.1, Need for 
Medical Intervention, 
Table 8-4 
Text was revised: Procedural intervention (ie, 
cardioversion, pacemaker implantation, ablation, 
additional cardiac surgery) 
For clarification and 
consistency 
Section 8.1.4.4, 
Re-hospitalization and Days 
Spent in Hospital, Table 8-7 
Text was added: 
• 
Binary measure (Y/N) of all-cause 
hospitalizations within 30 days post-discharge 
• 
Binary measure (Y/N) of non-arrhythmia 
cardiovascular hospitalizations within 30 days 
post-discharge 
• 
Binary measure (Y/N) of arrhythmia 
hospitalizations within 30 days post-discharge 
 
• 
Number of days spent in the hospital within 
60 days post-surgery for all cause hospitalizations 
• 
Number of days spent in the hospital within 
6  days post-surgery for non-arrhythmia 
cardiovascular hospitalizations 
• 
Number of days spent in the hospital within 
60  days post-surgery for arrythmia 
hospitalization 
• Binary measures were 
added for clarity; text was 
clarified regarding 
number of days spent in 
the hospital 60 days 
post-surgery 
 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
11 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 8.2.3, 
Electrocardiograms 
“Designee” was added: • Sites or designee shall 
transmit all study-required ECGs obtained to the 
ECG vendor. 
For clarification 
Section 8.2.5, Pulmonary 
Function Tests 
Text was added: Study participant pulmonary 
function will be assessed at the screening visit and 
Day 30 using forced procedures and compared 
across all 3 study groups (refer to study reference 
guide). Note, if local policies contraindicate or 
prohibit PFT assessments due to potential for 
viral spread or microbial precautions, then the 
PFT is not required after explicit approval from 
the sponsor. If PFT assessments are not 
prohibited by local regulations/policies, then the 
PFTs should be conducted. 
Updated for accuracy 
Section 8.2.7 
Immunogenicity 
Assessments 
Newly created section. Text was moved from 
Section 8.8 Biomarkers and Other Assessments to 
Section 8.2 Safety Assessments creating a new 
subsection 8.2.7 
Blood samples will be collected from all 
participants prior to dosing on Day 1 and at the 
Day 30 and Day 90 follow-up visits. A 2-tier 
assay approach will be used for the detection of 
binding and neutralizing antibodies to AGN-
151607 in human serum. In tier 1, serum 
samples will be screened using a validated 
enzyme-linked immunosorbent assay (ELISA). 
The positive samples will subsequently be 
immune depleted to confirm that the antibodies 
were specifically binding to AGN-151607 and 
then titered to assess the magnitude of antibodies 
present. In tier 2, only samples that are 
considered positive in the ELISA will be tested 
for neutralizing antibodies to AGN-151607 using 
a validated assay.  
Samples may be stored for a maximum of 2 years 
(or according to local regulations) following the 
last participant’s last visit for the study at a 
facility selected by the sponsor to enable further 
analysis of immune responses to AGN-151607. 
For improved consistency 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
12 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 8.3.1, Time Period 
and Frequency for 
Collecting Adverse Events 
and Serious Adverse Event 
Information 
Text was added: Assessment of causality to both 
the study intervention and the study procedures 
are required for reporting each SAE. For the 
purpose of causality assessment, “study 
procedure” on the SAE reporting form means the 
procedure of injecting the study intervention into 
the epicardial fat pads. It does not include any 
other study procedures (eg, the open-chest 
surgery and related procedures). Therefore, the 
check box on the SAE form titled “Causal 
Relationship to Study Procedure” should only be 
checked if, in the investigator’s judgement, the 
SAE was related to the injection procedure into 
the epicardial fat pads. The cardiac surgery 
procedure the study participant is undergoing 
(eg, CABG and/or valve repair/replacement) and 
any other procedures the participants may have 
during the study are NOT considered the study 
procedure for the purpose of SAE reporting 
causality assessment. 
For clarification 
Section 8.8.1 
Immunogenicity 
Assessments 
Blood samples will be collected from all 
participants prior to dosing on Day 1 and at the 
Day 30 and Day 90 follow up visits. A 2 tier assay 
approach will be used for the detection of binding 
and neutralizing antibodies to AGN 151607 in 
human serum. In tier 1, serum samples will be 
screened using a validated enzyme linked 
immunosorbent assay (ELISA). The positive 
samples will subsequently be immune depleted to 
confirm that the antibodies were specifically 
binding to AGN 151607 and then titered to assess 
the magnitude of antibodies present. In tier 2, only 
samples that are considered positive in the ELISA 
will be tested for neutralizing antibodies to AGN
151607 using a validated assay.  
Samples may be stored for a maximum of 2 years 
(or according to local regulations) following the 
last participant’s last visit for the study at a facility 
selected by the sponsor to enable further analysis of 
immune responses to AGN 151607. 
Section was moved to 
new subsection 8.2.7 for 
consistency 
 
 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
13 
Section No. and Name 
Description of Change 
Brief Rationale 
Section 8.9, Medical 
Resource Utilization and 
Health Economics 
Text was revised: Medical resource utilization and 
health economics data, associated with medical 
encounters, will be collected by the investigator 
and study-site personnel or designee for all 
participants throughout the study.  
 
• Healthcare resource utilization (eg, setting, 
provider, reason for visit) 
• Number and type of diagnostic and therapeutic 
tests and procedures 
• Outpatient medical encounters and treatments 
(including physician or emergency room visits, 
tests and procedures, and medications). 
For clarification 
Section 9.1, Statistical 
Hypotheses 
Text was revised: Details regarding adjustment 
for multiple comparisons for other efficacy 
variables will be discussed in the SAP. There will 
be no adjustment for multiple comparisons for all 
other efficacy variables. 
For clarification and to 
refer readers to the SAP 
Section 9.3, Populations for 
Analyses  
Text was revised: • The modified intent-to-treat 
(mITT) population will consist of all randomized 
participants who received study intervention and 
had at least 1 post-dose ECG by Day 30 
post-surgery day of discharge. Analyses will be 
based on randomized intervention. 
For consistency 
Section 9.4.1, Efficacy 
Analysis 
Text was added to include new timepoints and text 
was revised to reflect the addition:  
The ECG measurements collected for AF episodes 
post-surgery will be used to provide 7 9 different 
definitions for POAF for use in statistical analyses, 
namely: 
7. At least 1 continuous AF episode ≥ 6 hours  
8. At least 1 continuous AF episode ≥ 12 hours 
Endpoints expanded to 
include multiple 
definitions 
Section 9.4.1.1, Primary 
Efficacy Variables 
Text was revised: For primary efficacy 
consideration, POAF will be defined as any 
continuous episode of AF lasting 30 seconds or 
more during the first 30 days post-surgery. The 
primary efficacy variable is the percentage of 
participants with at least 1 continuous AF episode 
≥ 30 seconds during the first 30 days post-surgery. 
AF will be defined as the detection of either AF or 
atrial flutter.  
For clarification 
Section 9.4.1.4, Additional 
Efficacy Variables 
Text was added: 
• 
Binary measure (Y/N) of all-cause 
hospitalizations within 30 days post-discharge 
• 
Binary measure (Y/N) of non-arrhythmia 
cardiovascular hospitalizations within 30 days 
post-discharge 
• 
Binary measure (Y/N) of arrhythmia 
hospitalizations within 30 days post-discharge 
For consistency 
 
 
 




CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
15 
Table of Contents 
Title Page ........................................................................................................................................1 
Protocol Amendment Summary of Changes ...............................................................................2 
Table of Contents .........................................................................................................................15 
List of Tables ................................................................................................................................18 
1. 
Protocol Summary ........................................................................................................19 
1.1. 
Synopsis ..........................................................................................................................19 
1.2. 
Schema ............................................................................................................................23 
1.3. 
Schedule of Activities (SoA) ..........................................................................................24 
2. 
Introduction ...................................................................................................................27 
2.1. 
Study Rationale ...............................................................................................................29 
2.2. 
Background .....................................................................................................................29 
2.3. 
Benefit/Risk Assessment ................................................................................................30 
3. 
Objectives and Endpoints ............................................................................................31 
4. 
Study Design ..................................................................................................................34 
4.1. 
Overall Design ................................................................................................................34 
4.1.1. 
Clinical Hypotheses ........................................................................................................35 
4.2. 
Scientific Rationale for Study Design ............................................................................35 
4.3. 
Justification for Dose ......................................................................................................35 
4.4. 
End of Study Definition ..................................................................................................35 
5. 
Study Population ...........................................................................................................36 
5.1. 
Inclusion Criteria ............................................................................................................36 
5.2. 
Exclusion Criteria ...........................................................................................................38 
Rationale for Inclusion and Exclusion Criteria ..............................................................................39 
5.3. 
Lifestyle Considerations .................................................................................................40 
5.4. 
Screen Failures ................................................................................................................40 
6. 
Study Intervention ........................................................................................................41 
6.1. 
Study Intervention Administered ....................................................................................41 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................42 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................42 
6.4. 
Study Intervention Compliance ......................................................................................43 
6.5. 
Concomitant Therapy .....................................................................................................43 
6.5.1. 
Prohibited Interventions and Washout Before the Study ................................................43 
6.5.2. 
Permitted Interventions ...................................................................................................44 
6.5.3. 
Rescue Medicine or Procedure .......................................................................................44 
6.5.4. 
Prohibited Interventions During the Study .....................................................................44 
6.5.5. 
Anticoagulation and Stroke Prevention ..........................................................................44 
6.6. 
Dose Modification ..........................................................................................................45 
6.7. 
Intervention after the End of the Study ...........................................................................45 


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Protocol 1925-201-008 Amendment 1 
AGN-151607 
16 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................46 
7.1. 
Discontinuation of Study Intervention ............................................................................46 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................46 
7.3. 
Lost to Follow-up............................................................................................................47 
8. 
Study Assessments and Procedures.............................................................................48 
8.1. 
Efficacy Assessments .....................................................................................................48 
8.1.1. 
Occurrence of Post-Operative Atrial Fibrillation ...........................................................48 
8.1.2. 
Primary Efficacy Assessments ........................................................................................49 
8.1.3. 
Secondary Efficacy Assessments ....................................................................................49 
8.1.4. 
Additional Efficacy Assessments ...................................................................................50 
8.1.5. 
Additional Endpoints ......................................................................................................53 
8.1.6. 
Exploratory Endpoints ....................................................................................................54 
8.2. 
Safety Assessments .........................................................................................................55 
8.2.1. 
Physical Examinations ....................................................................................................55 
8.2.2. 
Vital Signs .......................................................................................................................55 
8.2.3. 
Electrocardiograms .........................................................................................................55 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................56 
8.2.5. 
Pulmonary Function Testing ...........................................................................................56 
8.2.6. 
Suicidal Risk Monitoring ................................................................................................56 
8.2.7. 
Immunogenicity Assessments .........................................................................................57 
8.3. 
Adverse Events and Serious Adverse Events .................................................................57 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ................................................................................57 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse 
Events ..............................................................................................................................58 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................58 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................58 
8.3.5. 
Pregnancy ........................................................................................................................59 
8.3.6. 
Adverse Events of Special Interest .................................................................................59 
8.3.7. 
Medication Errors ...........................................................................................................59 
8.4. 
Treatment of Overdose ...................................................................................................59 
8.5. 
Pharmacokinetics ............................................................................................................60 
8.6. 
Pharmacodynamics .........................................................................................................60 
8.7. 
Genetics ..........................................................................................................................60 
8.8. 
Biomarkers and Other Assessments ...............................................................................60 
8.9. 
Medical Resource Utilization and Health Economics ....................................................60 
9. 
Statistical Considerations .............................................................................................61 
9.1. 
Statistical Hypotheses .....................................................................................................61 
9.2. 
Sample Size Determination ............................................................................................61 
9.3. 
Populations for Analyses ................................................................................................62 
9.4. 
Statistical Analyses .........................................................................................................62 
9.4.1. 
Efficacy Analyses ...........................................................................................................62 
9.4.2. 
Safety Analyses ...............................................................................................................65 


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Protocol 1925-201-008 Amendment 1 
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17 
9.4.3. 
Other Analyses ................................................................................................................67 
9.5. 
Interim Analyses .............................................................................................................67 
10. 
Supporting Documentation and Operational Considerations ..................................68 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................68 
10.1.1. Regulatory and Ethical Considerations ...........................................................................68 
10.1.2. Financial Disclosure........................................................................................................68 
10.1.3. Informed Consent Process ..............................................................................................69 
10.1.4. Data Protection................................................................................................................69 
10.1.5. Committees Structure......................................................................................................69 
10.1.6. Posting Clinical Study Data ............................................................................................69 
10.1.7. Data Quality Assurance ..................................................................................................70 
10.1.8. Source Documents ..........................................................................................................70 
10.1.9. Study and Site Closure ....................................................................................................71 
10.1.10. Publication Policy ...........................................................................................................71 
10.1.11. Compliance with Protocol...............................................................................................71 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................72 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................73 
10.4. 
Appendix 4: Abbreviations .............................................................................................78 
10.5. 
Appendix 5: Standard Discontinuation Criteria..............................................................81 
10.6. 
Appendix 6: Study Tabular Summary ............................................................................82 
10.7. 
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................84 
10.8. 
Appendix 8: Atrial Fibrillation Effect on QualiTy-of-life 
(AFEQT) Questionnaire .................................................................................................87 
10.9. 
Appendix 9: University of Toronto Atrial Fibrillation Severity 
Scale ................................................................................................................................89 
10.10. 
Appendix 10: Short Form-12 Health Survey ..................................................................92 
10.11. 
Appendix 11: EQ 5D-5L.................................................................................................95 
10.12. 
Appendix 12: Duke Activity Status Index ......................................................................98 
11. 
References ....................................................................................................................100 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
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18 
List of Tables 
Table 6-1 
Treatments Administered ......................................................................................... 41 
Table 6-2 
Prohibited Medications with Required Washout Period .......................................... 43 
Table 8-1 
Assessment of Post-Operative Atrial Fibrillation .................................................... 49 
Table 8-2 
Assessment of Atrial Fibrillation Burden ................................................................ 50 
Table 8-3 
Assessment of Symptomatic Post-operative Atrial Fibrillation ............................... 50 
Table 8-4 
Assessment of Pharmacologic Therapies and/or Medical Procedures ..................... 51 
Table 8-5 
Assessment of All-cause Length of Intensive Care Unit and Hospital Stay ............ 51 
Table 8-6 
Assessment of Length of Intensive Care Unit and Hospital Stay Based on Atrial 
Fibrillation Status ..................................................................................................... 52 
Table 8-7 
Assessment of Re-Hospitalizations Within 30 Days After Discharge ..................... 53 
Table 8-8 
Patient Reported Outcomes ...................................................................................... 54 
Table 10–1 Protocol-Required Safety Laboratory Assessments ................................................. 72 
Table 10–2 Highly Effective Contraceptive Methods................................................................. 85 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
19 
1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol 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 
Protocol Number: 1925-201-008 
Brief Title: Botulinum toxin type A (AGN-151607) for the prevention of post-operative atrial 
fibrillation in patients undergoing open-chest cardiac surgery 
Study Rationale: 
Post-operative atrial fibrillation (POAF) occurs at high rates despite standard-of-care therapies 
and is associated with problematic outcomes, eg, medical/procedural interventions, extended 
length of stay in the intensive care unit (ICU) and hospital, and rehospitalization. Nonclinical 
studies have demonstrated that injections of botulinum toxin type A into discrete regions of the 
heart can prevent atrial fibrillation (AF) and 2 clinical studies have demonstrated that botulinum 
toxin type A injections can prevent POAF with no noted safety issues.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Primary Efficacy 
• 
To compare the efficacy of AGN-151607 with 
placebo to prevent post-operative atrial fibrillation 
(POAF) in participants who are undergoing 
open-chest cardiac surgery 
• 
Percentage of participants with at least 
1 continuous atrial fibrillation (AF) episode 
≥ 30 seconds during the first 30 days post-surgery 
• 
To compare the efficacy of AGN-151607 with 
placebo to reduce AF burden in participants who 
are undergoing open-chest cardiac surgery 
• 
Percentage of time spent in AF (AF burden) during 
the first 30 days post-surgery  
• 
Percentage of participants with at least 1 event of 
symptomatic AF during the first 30 days 
post-surgery 
• 
Time to first occurrence of AF during the first 
30 days post-surgery 


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Protocol 1925-201-008 Amendment 1 
AGN-151607 
20 
Objectives 
Endpoints 
Secondary 
Secondary Efficacy 
• 
To compare the efficacy of AGN-151607 with 
placebo to prevent POAF using alternative 
definitions for AF in participants who are 
undergoing open-chest cardiac surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 2 minutes during the first 
30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 5 minutes during the first 
30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 30 minutes during the 
first 30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 1 hour during the first 
30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 4 hours during the first 
30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 6 hours during the first 
30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 12 hours during the first 
30 days post-surgery 
• 
Percentage of participants with at least 1 
continuous AF episode ≥ 24 hours during the first 
30 days post-surgery 
Safety 
Safety Assessments 
• 
To compare the safety of AGN-151607 with 
placebo in participants undergoing open-chest 
cardiac surgery 
• 
Adverse events (AEs), physical examination, 
clinical laboratory tests, vital signs, 
electrocardiogram (ECGs), pulmonary function  
• 
Potential immunogenicity response 
 
Overall Study Design: 
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 POAF in participants 
undergoing open-chest cardiac surgery.  
Key inclusion criteria:  
• 55 to 90 years of age, inclusive, at the time of signing the informed consent  
• 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 or 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 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
21 
above]; left atrial appendage [LAA] procedures are allowed if CABG and/or valve 
repair/replacement is the qualifying surgical procedure, but is not a qualifying surgical 
procedure on its own). 
• 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  
Key exclusion criteria:  
• 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 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 (> 55mm 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) 
• Exclusionary valve repair/replacement procedures include combination of aortic and 
mitral valve repair/replacement; isolated tricuspid valve repair/replacement. 
• Prior or concomitant therapy with 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 
• Impaired prognosis defined as EuroSCORE II > 7% perioperative mortality at screening 
is exclusionary 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
22 
The use of any concomitant medication, prescription or over-the-counter, including vitamins, 
and/or herbal supplements, is to be recorded in the participant’s records at each visit along with 
the reason the medication is taken.  
Screening may occur up to 28 days before randomization on Day 1, Visit 2. 
An independent data safety monitoring board (DSMB) will meet throughout the course of this 
study.  
Study visits after the index surgery may be conducted at the participant’s home or other 
designated location in accordance with local ethics and/or IRB regulations, as well as with 
sponsor approval. 
Number of Participants: 
Approximately 400 participants will be screened to achieve approximately 330 randomly 
assigned to study intervention, in order to have an estimated 300 participants complete all the 
efficacy assessments up to Day 60 (100 participants per intervention group; Section 9.2).  
Number of Sites: 
It is projected that a total of approximately 20 to 40 sites (North America and Europe) will enroll 
participants. 
Intervention Groups and Study Duration: 
This Phase 2, placebo-controlled study will evaluate the efficacy and safety of one-time 
injections of AGN-151607 125 U (25 U per fat pad) and 250 U (50 U per fat pad) distributed 
across each of the 5 major epicardial fat pads for the prevention of POAF in participants 
undergoing open-chest cardiac surgery. Injections will be administered during the open-chest 
cardiac surgery. Primary and secondary efficacy will be assessed for 30 days post-surgery; 
participants will be followed for additional efficacy and safety through Day 367 post-surgery. 
Prior to the database lock, an interim analysis of all efficacy data will be performed when all 
randomized participants have completed the Day 60 visit, or exited the study earlier. 
Data Monitoring Committee: No 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
23 
1.2. 
Schema 
 
D = study day; TC = telephone call; U = units; V = Visit 
a Hospital discharge could take more than 6 days. 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
24 
1.3. 
Schedule of Activities (SoA) 
Study Period 
Screeninga 
Days 1 to 60 
Day 61 through Day 360 
Early 
Discc 
Visit Number 
V1 
V2 
V3 
V4b 
V5b 
V6b 
V7b 
TC1 
V8 
V9 
V10 
V11 
V12 
V13 
TC2 
Day Number 
(up to 
28 days) 
D1 
D2 
D3 
D4 
D5 
D6 
D14 
D30 
D60 
D90 
D180 
D270 
D360 
D367d 
Visit Windows 
- 
- 
- 
- 
- 
- 
- 
± 3d 
± 3d 
± 3d 
± 7d 
± 7d 
± 7d 
± 7d 
V13 + 
7d 
(+ 7d) 
- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
Xe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Xf 
 
X 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for 
women of childbearing 
potential)e,g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessmentse,h 
X 
X 
 
 
 
 
X 
 
X 
Xi 
Xi 
 
 
Xi 
 
X 
Sample collection for biomarker 
assessmente 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGj  
X 
X 
X 
X 
X 
X 
X 
 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
 
X 
ECG patch 
 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xm 
Xm 
Xm 
Xm 
Xm 
X 
 
Vital signse,n 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and abdominal 
circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense AF symptom diary and 
train participant on proper useo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AF symptom diary reviewo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study interventionp 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of fat pads and 
injection procedure 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE reviewq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PFTr 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medication and 
concurrent procedure reviewe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
25 
Study Period 
Screeninga 
Days 1 to 60 
Day 61 through Day 360 
Early 
Discc 
Visit Number 
V1 
V2 
V3 
V4b 
V5b 
V6b 
V7b 
TC1 
V8 
V9 
V10 
V11 
V12 
V13 
TC2 
Day Number 
(up to 
28 days) 
D1 
D2 
D3 
D4 
D5 
D6 
D14 
D30 
D60 
D90 
D180 
D270 
D360 
D367d 
Visit Windows 
- 
- 
- 
- 
- 
- 
- 
± 3d 
± 3d 
± 3d 
± 7d 
± 7d 
± 7d 
± 7d 
V13 + 
7d 
(+ 7d) 
- 
AFEQT 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
AFSS 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
DASI 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
EuroSCORE IIt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-12v2 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
EQ-5D-5L 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
Record discharge from ICU 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Record discharge from hospital 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Record any additional healthcare 
resource utilization 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum sampling for 
immunogenicity assessmentu 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
AE = adverse event; AF = atrial fibrillation; AFEQT = Atrial Fibrillation Effect on Quality-of-life Questionnaire; AFSS = University of Toronto Atrial Fibrillation Severity Scale; 
D(d) = day; DASI = Duke Activity Status Index; Disc = discontinuation; ECG = electrocardiogram; EQ-5D-5L = A measure of health-related quality of life developed by the 
EuroQol Group; FU = follow-up; ICU = intensive care unit; PFT = pulmonary function test; SAE = serious adverse event; SF-12v2 = Short Form-12 Health Survey, version 2; 
TC = telephone call; V = visit 
a Screening and randomization activities can occur on the same day. If screening and randomization occur on the same day, all assessments for Visit 1 and Visit 2 should be 
completed. Duplicate assessments (eg, laboratory assessments) do not have to be completed twice; please note a 12-lead ECG is required both before and after surgery. 
b These visits are optional and are only required if the participant is still hospitalized. Participants may remain in the hospital beyond Day 6, based on the recovery from surgery. 
The study visit procedures will have to be performed each day until discharge.  
c In case of early discontinuation, attempts will be made to follow-up with the participant. 
d Day 367 must be at least 7 days and should be no more than 14 days after Visit 13 (Day 360). 
e On Day 1, assessments to be performed prior to surgery.  
f Physical examinations should be conducted where feasible. If the participant cannot attend the study visit, then the physical examination can be omitted, after sponsor approval. 
g Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.  
h Laboratory assessments (hematology, chemistry, coagulation and urinalysis) to be performed at screening, Day 1 and day of discharge. The day of discharge can be from Day 3 
onwards.  
i Laboratory assessments should be conducted where feasible. If the participant cannot attend the study visit and/or an in-home assessment is not feasible, then the laboratory 
assessments can be omitted, after sponsor approval. 
j On Visit 2, Day 1, two 12-lead ECGs will be performed; 1 before surgery and 1 after surgery. PFT should be performed at a reasonable time apart from vital signs and ECG to 
avoid confounding ECG and vital signs data.  
k 12-lead ECGs should be conducted where feasible. If the participant cannot attend the study visit and/or an in-home assessment is not feasible, then the 12-lead ECG can be 
omitted, after sponsor approval. 
l ECG patch must be worn for a full 30 days post-surgery, even if Day 30 visit occurs prior to Day 30 due to window allowance. 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
26 
m ECG patch must be used during the first 7 days following Day 60, Day 90, Day 180, Day 270 and Day 360 visits.  
n Vital signs taken after a participant has been in a resting position for a minimum of 5 minutes; include blood pressure, pulse, respiration rate, and body temperature. On Visit 2, 
Day 1, vital signs will be measured before and after surgery.  
o AF symptom diary must be used for first 30 days after surgery (or until early discontinuation if before Day 30) and during the first 7 days following Day 60, Day 90, Day 180, 
Day 270 and Day 360 visits. The diary should be returned to the site and be part of the medical records. 
p Unblinded site pharmacist or designee will prepare drug; injected by investigator who is blinded to study intervention.  
q Method of detecting AEs and SAEs: care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and nonleading verbal questioning of the participant 
is the preferred method to inquire about AE occurrences. 
r Pulmonary function to be assessed using a spirometer and will include forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1), 3 seconds (FEV3) and 
6 seconds (FEV6). Note, if local policies contraindicate or prohibit PFT assessments due to potential for viral spread or microbial precautions, then the PFT is not required after 
explicit approval from the sponsor. 
s If participant withdraws after Day 180, these early discontinuation procedures will not be performed. 
t Impaired prognosis defined as EuroSCORE II > 7% perioperative mortality at screening is exclusionary. 
u Serum collection should be conducted where feasible. If the participant cannot attend the study visit and/or an in-home assessment is not feasible, then the serum collection can 
be omitted, after sponsor approval. 
 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
27 
2. 
Introduction 
Allergan has developed a botulinum toxin type A neurotoxin complex, AGN-151607, for the 
prevention of post-operative atrial fibrillation (POAF) in patients undergoing cardiac surgery. 
AGN-151607 will be injected intraoperatively into discrete targets of the heart, namely the 
epicardial fat pads near the pulmonary veins and atria. The administration of AGN-151607 is 
intended to neuromodulate the ganglionic plexi in these regions, thus lowering the risk of 
developing POAF. 
Atrial fibrillation (AF) is a supraventricular tachyarrhythmia with uncoordinated atrial activation 
and, consequently, ineffective atrial contraction (January 2014). Characteristics on an 
electrocardiogram (ECG) include:  
1) 
Irregular R-R intervals  
2) 
Absence of distinct P waves  
3) 
Irregular atrial activity  
AF is a common complication of cardiac surgery, occurring post-operatively in 30% to 60% of 
patients undergoing coronary artery bypass and/or cardiac valve surgical procedures, with an 
unchanged incidence over past decades (Mostafa 2012). 
POAF is associated with recurrent AF, longer hospital stays (including in intensive-care 
settings), increased healthcare costs (in-hospital and post-discharge), higher risk of stroke, and 
increased mortality (Arsenault 2013; Kertai 2014; LaPar 2014; Mathew 2004); all of which 
reflect an increased clinical burden due to POAF, including the need for medical/procedural 
interventions.  
Cardiac surgery via median sternotomy (open-chest or “open-heart” surgery) yields access to the 
epicardial fat pads, ie, the cardiac autonomic ganglionic plexi, which contain a rich network of 
nerves. These autonomic nerves have been targeted in several, customarily used ablative 
procedures to attenuate AF, both post-operative and more broadly. Surgical and catheter-based 
interventions (eg, ablations, surgical excisions of tissue) of the autonomic nervous tissue near the 
left atrial ostia of the pulmonary veins, including the epicardial fat pads, have demonstrated 
positive results in the prevention of recurrent AF (Katritsis 2011; Katritsis 2013; 
Pokushalov 2013; Gillinov 2016). 
Based on 1) the effectiveness of ablative and surgical intervention on cardiac autonomic nerve 
foci, 2) the general safety of these procedures involving tissue disruption, and 3) a goal to avoid 
permanent destruction of cardiac tissue, temporary neuromodulation has been hypothesized to be 
an effective approach as preventative therapy of POAF in cardiac surgery patients. Pursuant to 
this hypothesis, several recent nonclinical and clinical studies were performed, showing that 
neuromodulation with botulinum toxin type A, injected into discrete epicardial fat pads at the 
time of open-chest surgery, reduces the incidence of POAF (Tsuboi 2002; Oh 2010; Oh 2011; 
Pokushalov 2015; Lo 2016; Waldron 2019). Nonclinical proof‐of-concept studies have shown 
that injections of botulinum toxin type A into the epicardial fat pads of dogs in an open-chest 
cardiac surgical procedure, and using a rapid atrial pacing model of atrial arrhythmia, led to 






CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
AGN-151607 
30 
2.3. 
Benefit/Risk Assessment 
Patients undergoing cardiac surgery are at a high risk of developing POAF. POAF is associated 
with a number of negative outcomes, such as need for medical/procedural interventions, 
extended length of stay in the ICU and hospital, and rehospitalization. Treatment with one-time 
injections of AGN-151607 may prevent the occurrence of POAF in these cardiac-surgery 
patients and thus represents a distinct potential for benefit. In addition, the injection of botulinum 
toxin type A into discrete epicardial fat pads has been shown to be safe and tolerable in cardiac 
surgery patients during 2 separate clinical trials, with up to 3 years of follow-up reported 
(Pokushalov 2015; Waldron 2019; Romanov 2019). Injections of AGN-151607 will be 
administered in addition to standard-of-care therapies, such as beta-blockers, as needed.  
The AE profile of AGN-151607 has not yet been fully characterized in humans. However, 
extensive safety data are available from clinical studies and post-marketing experience with 
BOTOX. BOTOX experience is considered relevant to the current program, having a similar 
dose range and other similarities with AGN-151607, as outlined in the IB.  
More detailed information about the known and expected benefits and risks and expected AEs of 
AGN-151607 may be found in the IB. 


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Protocol 1925-201-008 Amendment 1 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Primary efficacy 
• 
To compare the efficacy of AGN-151607 
with placebo to prevent post-operative atrial 
fibrillation (POAF) in participants who are 
undergoing open-chest cardiac surgery 
• 
Percentage of participants with at least 1 continuous 
atrial fibrillation (AF) episode ≥ 30 seconds during the 
first 30 days post-surgery 
Secondary 
Secondary efficacy 
• 
To compare the efficacy of AGN-151607 
with placebo to reduce AF burden in 
participants who are undergoing open-chest 
cardiac surgery  
• 
Percentage of time spent in AF (AF burden) during the 
first 30 days post-surgery  
• 
Percentage of participants with at least 1 event of 
symptomatic AF during the first 30 days post-surgery 
• 
Time to first occurrence of AF during the first 30 days 
post-surgery 
• 
To compare the efficacy of AGN-151607 
with placebo to prevent POAF using 
alternative definitions for AF in participants 
who are undergoing open-chest cardiac 
surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 2 minutes during the first 30 days post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 5 minutes during the first 30 days post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 30 minutes during the first 30 days 
post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 1 hour during the first 30 days post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 4 hours during the first 30 days post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 6 hours during the first 30 days post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 12 hours during the first 30 days post-surgery 
• 
Percentage of participants with at least 1 continuous AF 
episode ≥ 24 hours during the first 30 days post-surgery 
Safety 
Safety assessments 
• 
To compare the safety of AGN-151607 with 
placebo in participants undergoing open-
chest cardiac surgery 
• 
AEs, physical examination, clinical laboratory tests, vital 
signs, ECGs, pulmonary function 
• 
Potential immunogenicity response 


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Objectives 
Endpoints 
Additional 
Additional efficacy 
• 
To compare the clinical benefit of 
AGN-151607 with placebo in participants 
who are undergoing open-chest cardiac 
surgery 
• 
Percentage of participants with clinically important 
tachycardia in AF (defined as heart rate ≥ 100 bpm for at 
least 2 minutes)  
• 
Percentage of participants needing pharmacologic 
intervention (ie, anticoagulation, antiarrhythmic drugs) 
during the first 30 days post-surgery due to AF 
• 
Percentage of participants needing pharmacologic 
intervention (ie, anticoagulation, antiarrhythmic drugs) 
from Day 31 to Day 360 post-surgery due to AF 
• 
Percentage of participants needing procedural 
intervention (ie, cardioversion, ablation, additional 
surgery) during the first 30 days post-surgery due to AF 
• 
Percentage of participants needing procedural 
intervention (ie, cardioversion, ablation, additional 
surgery) from Day 31 to Day 360 post-surgery due to AF 
• 
Time to first prescription of pharmacologic intervention 
due to POAF during the first 30 days post-surgery and 
length of time that prescription is taken 
• 
Time of POAF resolution from first dose of prescription 
of pharmacologic intervention 
• 
Time to first procedural intervention due to POAF 
during the first 30 days post-surgery 
• 
Time of POAF resolution from first procedural 
intervention due to AF 
• 
Length of stay in the ICU and reason 
• 
Length of stay in hospital and reason 
• 
Number of all-cause re-hospitalizations within 30 days 
post-discharge 
• 
Number of non-arrhythmia cardiovascular 
re-hospitalizations within 30 days post-discharge 
• 
Number of arrhythmia re-hospitalizations within 30 days 
post-discharge 
• 
Number of days spent in the hospital: within 30 days 
post-discharge and within 60 days post-surgery 
• 
Percentage of participants with any occurrence of AF as 
defined in the primary and secondary endpoints during 
the first 7 days following Day 60, Day 90, Day 180, 
Day 270 and Day 360 visits 
• 
Percentage of time spent in AF (AF burden) during the 
first 7 days following Day 60, Day 90, Day 180, 
Day 270 and Day 360 visits 
• 
Percentage of participants with at least 1 event of 
symptomatic AF during the first 7 days following 
Day 60, Day 90, Day 180, Day 270 and Day 360 visits 
 


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Objectives 
Endpoints 
Tertiary/Exploratory 
 




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An independent data safety monitoring board (DSMB) will meet throughout the course of this 
study. 
4.1.1. 
Clinical Hypotheses 
Injection of AGN-151607 into epicardial fat pads near the pulmonary veins and atria will prevent 
the occurrence of POAF, reduce the incidence of negative outcomes known to be associated with 
POAF, favorably impact health care resources utilization, and be well-tolerated and safe in 
patients undergoing open-chest cardiac surgery.  
4.2. 
Scientific Rationale for Study Design 
This is a randomized, double-blind, placebo-controlled, dose-ranging study to assess the efficacy 
and safety of a one-time injection of AGN-151607 in open-chest cardiac surgery participants. 
The use of placebo is justified as all participants will receive standard-of-care therapies, such as 
beta-blockers. Participants who experience POAF during the trial will be treated as per 
investigator judgement and local standards of care. All medications and procedures will be 
recorded. AF symptoms and quality of life outcomes will be collected through patient reported 
assessments.  
4.3. 
Justification for Dose 
There are 2 doses of AGN-151607 which will be tested: 250 U and 125 U.  
The highest dose planned for this study is 250 U (50 U per epicardial fat pad) of AGN-151607. 
The dose was selected based on prior clinical experience. There have been 2 clinical trials 
conducted by external investigators which have injected 50 U per fat pad of botulinum toxin type 
A (non-AGN-151607) in cardiac-surgery participants. One of these trials injected a total of 
250 U of BOTOX (50 U into 5 epicardial fat pads; Waldron 2019) and the other injected a total 
of 200 U of Xeomin (50 U into 4 epicardial fat pads; Pokushalov 2015; Romanov 2019). In both 
studies, these doses were found to be safe and well-tolerated. 
The lower dose planned for this study is 125 U (25 U per epicardial fat pad) of AGN-151607. 
This dose was selected to determine whether a lower dose would provide a similar efficacy and 
safety profile as the higher dose.  
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the schedule of activities (SoA, Section 1.3) for the last 
participant in the study globally. A participant is considered to have completed the primary and 
secondary efficacy part of the study if he/she has completed the Day 60 (Visit 9). A participant is 
considered to have completed the full study if he/she has completed the Day 367. 


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5. 
Study Population 
The study population consists of participants undergoing open-chest cardiac surgery who have 
given informed consent to participate. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Age 
1.01 
Participants must be 55 to 90 years of age, inclusive, at the time of signing the 
informed consent. 
2. 
Type of Participant and Surgical Characteristics 
2.01 
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. 
3. 
Sex 
3.01 
Male or female 


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4. 
Contraceptives 
4.01 
Male participants willing to minimize the risk of inducing pregnancy up to Day 60. 
 
A male participant must agree to use contraception as detailed in Appendix 7, 
Section 10.7 of this protocol until Day 60 and refrain from donating sperm during 
this period. 
4.02 
Female participants willing to minimize the risk of inducing pregnancy up to 
Day 60.  
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: 
a. 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 7, 
Section 10.7 
OR 
b. 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 7, 
Section 10.7 of this protocol until after Day 60.  
5. 
Informed Consent 
5.01 
Capable of giving signed informed consent as described in Appendix 1, 
Section 10.1, which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol. 
5.02 
Written informed consent from the participant has been obtained prior to any 
study-related procedures.  
5.03 
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 [EU] sites). 
6. 
Other 
6.01 
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). 
6.02 
Willing to wear an ECG patch for a full 30 days post-surgery and for 7 days after 
each study visit 
6.03 
Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete required study visit. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. 
Medical Conditions 
1.01 
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. 
1.02 
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. 
1.03 
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. 
1.04 
Permanent/persistent AF  
1.05 
Has a known allergy or sensitivity to any botulinum toxin type A preparation 
1.06 
Has a known allergy or sensitivity to medical adhesive (eg, ECG patch adhesive; 
hydrogel-based adhesive) 
1.07 
Severe (> 55 mm left atrial diameter) left atrial enlargement  
1.08 
Left ventricular ejection fraction (LVEF) < 25% 
1.09 
Presence or history of symptomatic atrioventricular block > 1st degree within the last 
30 days (note: presence of a pacemaker is not exclusionary per se) 
1.10 
Exclusionary valve repair/replacement procedures include: 
• Combination of aortic and mitral valve repair/replacement  
• Isolated tricuspid valve repair/replacement 
2. 
Prior/Concomitant Therapy 
2.01 
Class I or III antiarrhythmic drugs unless proper washout was documented 
(Section 6.5.1) 


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2.02 
Botulinum toxin type A (of any serotype) use within 6 months of randomization 
2.03 
Has been immunized for any botulinum toxin type A serotype as determined by 
participant medical history 
2.04 
Preoperative need for inotropes/vasopressors or intra-aortic balloon pump 
2.05 
Prior open-chest, sternotomy cardiac surgery 
2.06 
History of ablation for AF 
2.07 
Planned ablation procedure for AF at the time of surgery 
2.08 
Emergency surgery 
3. 
Prior/Concurrent Clinical Study Experience 
3.01 
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of entry into this study 
4. 
Diagnostic Assessments 
4.01 
Participants have diagnostic assessments which in the opinion of the investigator prevent 
participation in the study. 
4.02 
Impaired prognosis defined as EuroSCORE II > 7% perioperative mortality at screening 
is exclusionary. 
5. 
Other 
5.01 
Females who are pregnant, nursing, or planning a pregnancy during the study  
5.02 
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. 
 
Rationale for Inclusion and Exclusion Criteria 
• Inclusion criterion 1.01 is to ensure appropriate age of the study population since 
increased age is associated with higher occurrence of POAF. 
• Inclusion criterion 2.01 is to ensure that fat pads are accessible as part of the standard 
surgical procedure. 
• Inclusion criterion 3.01 is to ensure that the study population is representative of the 
target population which comprises male and female participants. 


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• Inclusion criteria 4.01 and 4.02 are to minimize risk of pregnancy during the first 60 days 
of the study. Regarding 4.02 and female participants, the risk of pregnancy will be also 
minimized by the age criteria. 
• Inclusion criteria 5.01 to 5.03 are to ensure protection of the study participants through 
the informed consent process. 
• Inclusion criterion 6.01 is to ensure participants have no detected arrhythmias in the 
48 hours prior to surgery that could impact study conduct.  
• Inclusion criteria 6.02 and 6.03 is to ensure quality of the study data. 
• Exclusion criteria 1.01 to 1.09 are necessary to prevent participants with medical 
conditions that could increase the risk of AEs with exposure to botulinum toxin type A 
preparation or have conditions that could confound the results of the study in the analysis 
of efficacy.  
• Exclusion criterion 2.01 is necessary to avoid antiarrhythmic medications so any efficacy 
the study intervention may have is not reduced.  
• Exclusion criteria 2.02 and 2.03 are necessary to avoid any effects of prior botulinum 
toxin type A or prior surgical procedures influencing the results.  
• Exclusion criteria 2.04 to 2.08 are to ensure absence of prior cardiac procedures that may 
influence POAF and confound the study results. 
• Exclusion criterion 3.01 is customary in clinical trials and is necessary to prevent 
interactions with other investigation products. 
• Exclusion criteria 4.01 and 5.02 are necessary to ensure the protection and well-being of 
the study participants. 
• Exclusion criterion 4.02 is to ensure that the perioperative risk of death is compatible 
with the intended study follow-up duration. 
• Exclusion criterion 5.01 is to ensure protection of the fetus and mother during pregnancy.  
5.3. 
Lifestyle Considerations 
The ECG-acquisition patch cannot be submerged in water and participants should comply with 
all other restrictions necessary, ie, those customarily required of patients undergoing open-chest 
cardiac surgery. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any AE. 
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened unless authorized by the sponsor.  


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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
AGN-151607 is not currently authorized or licensed in any country worldwide. 
6.1. 
Study Intervention Administered 
Each of the 5 fat pads must be injected as part of the study procedure. However, in the event 
where 1 fat pad is missing or is not accessible, the injection procedure can continue and only 
4 mL of interventional product or placebo shall be injected. If, upon initial evaluation 
(ie, injections have not yet occurred), 3 fat pads or fewer are accessible, the injection procedure 
should be aborted. If any injections of study intervention have already been made when the 
surgeon determines they are unable to inject 4 or more fat pads, the participant should remain in 
the study. 
Table 6-1 
Treatments Administered 
Study Intervention Name 
AGN-151607 
Placebo 
Dosage Formulation 
Unit Dose Strength(s) 
250 U, 125 U 
Not applicable 
Route of Administration  
Injection into epicardial fat pads 
Injection into epicardial fat pads 
Dosing Instructionsa 
Injections of 25 U or 50 U will be 
made into each 1 of 5 fat pads as 
described in Section 6.3. 
The total injection volume in to 
each fat pad will be 1 mL.  
Injections of placebo will be made into 
each 1 of 5 fat pads as described in 
Section 6.3. 
The total injection volume in to each fat 
pad will be 1 mL.  
Packaging and Labeling 
Study intervention will be 
provided in a blinded carton 
container containing 3 
AGN-151607 (50 U or 200 U) 
vials. Each vial will be labeled as 
required per country requirement. 
Placebo will be provided in a blinded 
carton container containing 3 vials 
visually identical to the study 
intervention. Each vial will be labeled as 
required per country requirement. 
 


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6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).  
4. Further guidance and information for the pre- and intra-operative handling of study 
interventions, and for the final disposition of unused study interventions, will be provided by 
the sponsor. 
All unused study intervention and used kits should be returned to the sponsor or designee at the 
termination of the study. Unit counts will be performed when the study intervention is returned, 
and all study intervention must be accounted for. Accountability logs for destroyed materials 
should be maintained at the site to ensure all study intervention is accounted for. Study 
intervention may be destroyed on site if required by local/institutional policies after sponsor 
approval of destruction process and documentation. 
Details on the reconstitution and handling of AGN-151607 can be found in the Pharmacy 
Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
At screening, each participant who provides informed consent will be assigned a number that 
will serve as the participant identification number on all study documents.  
An automated Interactive Web Response System (IWRS) assigns the participant’s identification 
number and this will be used to manage the randomization and intervention assignment based on 
a centralized randomization list prepared by Allergan Biostatistics. The randomization will be 
stratified by age (< 65, ≥ 65 years) and type of surgery (presence/absence of valve surgery). 
Within each stratification group, participants will be randomly assigned to one of the 
intervention groups in a 1:1:1 ratio. Before the study is initiated, the log-in information and 
instructions for the IWRS will be provided to each site. 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study.  
At each study site, a designated staff member will serve as the independent drug 
reconstitutor (IDR). This person will be responsible for study intervention preparation. 
The IDR will prepare the study intervention as described in the Pharmacy Manual. The 
investigator will inject the reconstituted study intervention according to the study intervention 


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administration instructions. Administration instructions are further detailed in the Surgical 
Manual. 
The injection volume and intervention administration will be identical for each participant 
whether they are assigned to the 250 U dose, 125 U dose, or the placebo group.  
To maintain data integrity for the study while it is still ongoing, sponsor personnel responsible 
for performing the interim analysis will be different from the project team personnel who 
manage and maintain the study conduct activities, including data collection, data clarification, 
analysis development, safety monitoring, and investigational site monitoring and management. 
The project team personnel will be prohibited from accessing the unmasked interim results.  
Blinding is critical to the integrity of the clinical trial. The IWRS will be programmed with 
blind-breaking instructions. In case of an emergency, the investigator has the sole responsibility 
for determining if unblinding of a participant’s study intervention assignment is warranted. 
Participant safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a participant’s study intervention assignment unless this 
could delay emergency treatment of the participant. If a participant’s study intervention 
assignment is unblinded, the sponsor must be notified within 24 hours after breaking the blind. 
The date and reason that the blind was broken must be recorded in the source documentation. 
6.4. 
Study Intervention Compliance 
Participants will receive a single dose of AGN-151607 under the direct supervision of study site 
personnel.  
The study site will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration. 
6.5. 
Concomitant Therapy 
The use of any concomitant medication, prescription or over-the-counter, including vitamins, 
and/or herbal supplements, is to be recorded in the participant’s records at each visit along with 
the reason the medication is taken. 
6.5.1. 
Prohibited Interventions and Washout Before the Study 
Participants must discontinue any of the medications listed in Table 6-2 for the specified period 
prior to surgery. Other medications being used at screening may be continued. 
Table 6-2 
Prohibited Medications with Required Washout Period 
Drug Class/Treatment 
Washout Required Prior to Surgery 
Class I or Class III antiarrhythmic drugs 
(eg, amiodarone) 
At least 5 half-lives or 5 days, whichever is the longest. 
In the case of amiodarone, 90 days washout is required.  
All types of botulinum toxins 
At least 6 months since last treatment with any 
botulinum toxin 


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6.5.2. 
Permitted Interventions 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Indication 
• Dates of administration including start and end dates 
• Dosage information including dose, route of administration, and frequency 
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor. 
The sponsor or designee should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.3. 
Rescue Medicine or Procedure 
There will be no rescue medication provided by the sponsor for the study.  
Standard-of-care will be used at investigator discretion. The study site will supply medications 
that will be obtained locally, eg, antiarrhythmics drugs, anticoagulants (eg, anti-vitamin 
K agents, heparin) and rate-control medication (eg, esmolol, metoprolol, diltiazem). 
Standard-of-care is allowable at any time during the study. The date and time of any medication 
administration, as well as the name, indication, and dosage regimen of the medication (ie, dose, 
route of administration, and frequency), should be recorded. 
An intervention to treat an arrhythmia is allowed during follow-up as clinically warranted in the 
judgement of the treating physician and/or site-based investigator physician. 
6.5.4. 
Prohibited Interventions During the Study 
Please refer to Section 6.5.1 for prohibited interventions during the washout period prior to 
surgery. 
Administration of aminoglycosides or other agents interfering with neuromuscular transmission 
(eg, curare-like compounds) should only be performed with caution for 60 days post-surgery, as 
the effect of the toxin may be potentiated. 
6.5.5. 
Anticoagulation and Stroke Prevention 
For participants for whom anticoagulation is indicated, treatment should be provided according 
to local or organization standards with the goal of achieving at least one of the following 
outcomes prior to discharge: 
1) If treated with warfarin, participant must have achieved a target International Normalized 
Ratio (INR) of 2.0 to 3.0 
2) If “bridged” with low molecular weight heparin, participant can be discharged with an 
INR of less than 2.0 


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3) If treated with non-vitamin K antagonist oral anticoagulants (NOACs), international 
guidelines do not mandate routine coagulation testing nor recommend target INR. The 
investigator should refer to the drug prescribing information for more precise guidance in 
situation when assessment of the anticoagulation effect is useful.  
4) If they are deemed by the site principal investigator to be stable for discharge from an 
anti-coagulation standpoint 
6.6. 
Dose Modification 
Not applicable. 
6.7. 
Intervention after the End of the Study 
There will be no intervention following the end of the study. 


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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
A premature discontinuation will occur if a participant who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the 
protocol-defined study procedures. 
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented. 
The sponsor should be consulted in advance of withdrawal whenever possible. Every effort 
should be made to retain participants in the study until completion as much as possible. 
Participants who are withdrawn from the study may not be re-enrolled but will be asked to 
undergo all early withdrawal activities. Definitions of the standard terms are provided in 
Appendix 5, Section 10.5. 
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms: 
Commonly Used Terms 
Other Acceptable Terms 
Adverse event 
Death 
Lost to follow-up 
 
Other 
 
Physician decision 
 
Pregnancy 
 
Protocol deviation 
 
Site terminated by sponsor 
 
Study terminated by sponsor 
 
Withdrawal by subject 
 
 
7.1. 
Discontinuation of Study Intervention 
Not applicable for a one-time intervention. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. The 
investigator should follow-up with the sponsor so that any samples can be destroyed.  


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• See the SoA for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed. In case of early discontinuation, 
attempts will be made to follow-up with the participant. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts will be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Section 1.3). 
• Visits 4, 5, 6, and 7 are optional and are only required if the participant is still hospitalized. 
Participants may remain in the hospital beyond Day 6, based on the recovery from surgery. 
The study visit procedures will have to be performed each day until discharge. 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue in the study.  
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.  
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. 
• Study visits after the index surgery may be conducted at the participant’s home or other 
designated location in accordance with local ethics and/or IRB regulations, as well as with 
sponsor approval.  
• Procedures conducted as part of the participant’s routine clinical management (eg, chest 
X-ray or echocardiography) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified criteria and 
were performed within the time frame defined in the SoA. However, testing of blood samples 
(including during unscheduled visits or samples for which local laboratory values are already 
available) should be conducted by the central laboratory.  
• Local laboratory results are required only in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response evaluation. 
Local laboratory results collected at the screening visit can be used to determine participant’s 
eligibility if central laboratory results are not available. If a local sample is required, it is 
important that the sample for central analysis is obtained at the same time. Additionally, if 
the local laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be entered into the eCRF. 
8.1. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
For the primary, secondary, and additional endpoints, AGN-151607 intervention arms will be 
compared with placebo. These comparisons are further described in Section 9.4.1. 
8.1.1. 
Occurrence of Post-Operative Atrial Fibrillation 
The occurrence of POAF will be monitored through Day 30 and for 7 days after each of the 
following study visits: Day 60, Day 90, Day 180, Day 270, and Day 360 by ECG patches placed 
on the upper left region of the chest (Table 8-1).  


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Table 8-1 
Assessment of Post-Operative Atrial Fibrillation 
Assessment 
Timing 
Criteria 
Occurrence of POAFa 
Through Day 367 
(continuously through 
Day 30 post-surgery and 
during the first 7 days 
following Day 60, 
Day 90, Day 180, 
Day 270 and Day 360 
visits) 
As measured by ECG:  
1. Continuous AF ≥ 30 secondsb 
2. Continuous AF ≥ 2 minutes 
3. Continuous AF ≥ 5 minutes 
4. Continuous AF ≥ 30 minutes 
5. Continuous AF ≥ 1 hour 
6. Continuous AF ≥ 4 hours 
7. Continuous AF ≥ 6 hours 
8. Continuous AF ≥ 12 hours 
9. Continuous AF ≥ 24 hours 
Time to first occurrence of POAF 
Through Day 367 
(continuously through 
Day 30 post-surgery and 
during the first 7 days 
following Day 60, 
Day 90, Day 180, 
Day 270 and Day 360 
visits) 
As measured by ECG:  
1. Continuous AF ≥ 30 seconds 
2. Continuous AF ≥ 2 minutes 
3. Continuous AF ≥ 5 minutes 
4. Continuous AF ≥ 30 minutes 
5. Continuous AF ≥ 1 hour 
6. Continuous AF ≥ 4 hours 
7. Continuous AF ≥ 6 hours 
8. Continuous AF ≥ 12 hours 
9. Continuous AF ≥ 24 hours  
AF = atrial fibrillation; ECG = electrocardiogram; POAF = post-operative atrial fibrillation 
a Multiple AF events may occur within 30 days 
b Continuous AF ≥ 30 seconds is the primary endpoint 
c Follow-up through Day 30 will be the primary endpoint and 7-day follow-up periods will be part of the 
exploratory endpoints 
 
8.1.2. 
Primary Efficacy Assessments 
The primary efficacy assessment will measure the occurrence of POAF (ie, 30-second cutoff for 
continuous AF) during the first 30 days post-surgery (Table 8-1). 
8.1.3. 
Secondary Efficacy Assessments 
Secondary endpoints will include assessments of the occurrence of POAF according to different 
definitions of AF (ie, different timing cutoffs for continuous AF), time to first occurrence of 
POAF, percentage of time spent in AF (AF burden), and percentage of participants with at least 
1 event of symptomatic AF, during the first 30 days post-surgery. 
8.1.3.1. 
Percentage of Time Spent in Atrial Fibrillation 
ECG patches will continuously monitor for all occurrences and durations of AF through Day 30 
(Table 8-2). Based on this information, an analysis will measure the total time spent in AF 
divided by the time spent in the study. The resulting calculation will represent the percent of time 
each participant has spent in AF during the first 30 days post-surgery (AF burden). 


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Table 8-2 
Assessment of Atrial Fibrillation Burden 
Assessment 
Timing 
Measurement 
Percentage of time spent in AF 
Through Day 30  
• 
Continuous ECG monitoring will allow for 
determining total time spent in AF. This 
will then be divided by the time spent in the 
study. 
AF = atrial fibrillation; ECG = electrocardiogram  
 
8.1.3.2. 
Symptomatic Post-operative Atrial Fibrillation 
The occurrence of POAF is often associated with the onset of particular symptoms, such as 
dizziness, palpitations, and fatigue. All participants will be wearing ECG patches with the ability 
to mark the date and time that a symptom is experienced by simply pressing a button on the ECG 
patch itself (Table 8-3). While the participant is wearing the ECG patch, if symptoms of AF 
occur, the actual symptom will be documented by the participant in a symptom diary. 
Participants will be instructed by the site staff or designee on the appropriate completion of the 
symptom diary and instructions will be included with each diary.  
Table 8-3 
Assessment of Symptomatic Post-operative Atrial Fibrillation 
Assessment 
Timing 
Measurement 
Occurrence of symptomatic POAF 
Through Day 30 and 
for 7 days after each of 
the following study 
visits: Day 60, Day 90, 
Day 180, Say 270, and 
Day 360  
• 
Participants will press their ECG patch 
when they experience a symptom and then 
log the symptom in a diary. The information 
will be used to identify cases of 
symptomatic POAF. 
AF = atrial fibrillation; ECG = electrocardiogram; POAF = post-operative atrial fibrillation  
 
8.1.3.3. 
Clinically Important Tachycardia in Atrial Fibrillation 
Clinically important tachycardia in AF is defined as heart rate ≥ 100 bpm for at least 2 minutes. 
The occurrence of clinically important tachycardia in AF is often associated with the need for 
pharmacologic or procedural interventions and is therefore likely to be associated with higher 
resources utilization. Evidence for clinically important tachycardia in AF will be acquired using 
ECG patches and/or hospital monitoring. 
8.1.4. 
Additional Efficacy Assessments 
Additional efficacy endpoints will include assessments of the occurrence of POAF, time to first 
occurrence of POAF, percentage of time spent in AF (AF burden), and percentage of participants 
with at least one event of symptomatic AF, based on continuous monitoring of all occurrences of 
AF during the first 7 days following Day 60, Day 90, Day 180, Day 270 and Day 360 visits, as 
described in Section 8.1.1, and Section 8.1.3.  


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8.1.4.1. 
Need for Medical Intervention 
If POAF occurs in cardiac-surgery participants, it is at the discretion of the investigator whether 
to intervene with customary, accepted treatments of pharmacologic therapies and/or medical 
procedures (Table 8-4). Such interventions will be captured as additional endpoints, and will 
support assessing the potential burden caused by the occurrence of POAF. 
Table 8-4 
Assessment of Pharmacologic Therapies and/or Medical Procedures 
Assessment 
Timing 
Measurement 
Pharmacologic intervention (ie, 
anticoagulation, antiarrhythmic drugs) 
Through Day 367 
• 
Timing of prescription and whether it was 
prescribed due to occurrence of POAF 
• 
Length of prescription 
• 
Timing of AF resolution, if available 
Procedural intervention (ie, cardioversion, 
pacemaker implantation, ablation, 
additional cardiac surgery) 
Through Day 367 
• 
Timing of procedure and whether it was 
assigned due to the occurrence of POAF 
• 
Timing of AF resolution, if available 
AF = atrial fibrillation; POAF = post-operative atrial fibrillation  
A composite endpoint composed of pharmacologic and procedural interventions will also be analyzed. 
 
8.1.4.2. 
All-cause Length of Stay in the Intensive Care Unit and Hospital 
All participants will be in-hospital for the CABG and/or valve surgery. The all-cause length of 
stay in ICU and discharge to a regular ward and the all-cause length of stay in hospital will be 
recorded. 
Table 8-5 
Assessment of All-cause Length of Intensive Care Unit and Hospital Stay 
Assessment 
Timing 
Measurement 
Length of stay in the ICU 
Through hospital 
stay 
• 
Time of discharge from ICU to a regular 
ward  
• 
If participant remains in the ICU, reasons 
must be documented 
Length of stay in hospital 
Through hospital 
stay 
• 
Time of discharge from hospital 
• 
If participant remains in the hospital, 
reasons must be documented 
ICU = intensive care unit 
 
8.1.4.3. 
Length of Stay in the Intensive Care Unit and Hospital based on Atrial 
Fibrillation Status 
The length of ICU and hospital stay are dependent on a number of factors, one of which is the 
occurrence of POAF (Table 8-6). Length of stay in ICU and reason for ICU stay will be 
recorded. Recommendation for successful anticoagulation therapy if indicated is available in 
Section 6.5.5. 


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Table 8-6 
Assessment of Length of Intensive Care Unit and Hospital Stay Based on Atrial Fibrillation 
Status 
Assessment 
Timing 
Measurement 
Length of stay in the ICU  
Through hospital 
stay 
• 
Time of discharge from ICU to a regular 
ward 
• 
Reason for ICU stay must be 
documented, including if it was 
AF-related 
Length of stay in hospital  
Through hospital 
stay 
• 
Time of discharge from hospital 
• 
Reason for hospital stay must be 
documented, including if it was 
AF-related 
AF = atrial fibrillation; ICU = intensive care unit; POAF = post-operative atrial fibrillation  
 
8.1.4.4. 
Re-hospitalization and Days Spent in Hospital 
Re-hospitalizations within 30 days after discharge will be logged with the reason(s) for the 
re-hospitalization (Table 8-7). In addition, all days spent in the hospital within 60 days after the 
surgery will be logged with the reason(s) for the re-hospitalization. 


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Table 8-7 
Assessment of Re-Hospitalizations Within 30 Days After Discharge 
Assessment 
Timing 
Measurement 
30-day re-hospitalization 
Through Day 30 
post-discharge 
• 
Number of all-cause hospitalizations 
within 30 days post-discharge 
• 
Number of non-arrhythmia cardiovascular 
hospitalizations within 30 days 
post-discharge 
• 
Number of arrhythmia hospitalizations 
within 30 days post-discharge 
• 
Binary measure (Y/N) of all-cause 
hospitalizations within 30 days 
post-discharge 
• 
Binary measure (Y/N) of non-arrhythmia 
cardiovascular hospitalizations within 
30 days post-discharge 
• 
Binary measure (Y/N) of arrhythmia 
hospitalizations within 30 days 
post-discharge 
Days in hospital 60 days after surgery 
Through Day 60 
post-surgery 
• 
Number of days spent in the hospital 
within 60 days post-surgery for all-cause 
hospitalizations 
• 
Number of days spent in the hospital 
within 60 days post-surgery for 
non-arrhythmia cardiovascular 
hospitalizations 
• 
Number of days spent in the hospital 
within 60 days post-surgery for arrythmia 
hospitalization 
 
8.1.5. 
Additional Endpoints 
8.1.5.1. 
Patient Reported Outcomes 
Planned timepoints for all patient reported outcomes (PROs) assessments are provided in the 
SoA (Section 1.3). 
Several PROs will be utilized during this study (Table 8-8) to evaluate the impact of intervention 
on AF symptoms, activities of daily living, and health-related quality of life.  


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Table 8-8 
Patient Reported Outcomes 
Assessment 
Timing 
Measurement 
AFEQT 
Screening, Day 30, 
Day 90, Day 180, (or 
early discontinuation if 
necessarya) 
• 
A questionnaire to assess Health Related Quality of Life (HRQoL) 
in patients with AF. AFEQT evaluates QoL across 3 domains: 
symptoms, daily activities and treatment concerns.  
The questionnaire uses 20 questions on a 7-point Likert scale to 
measure the overall AFEQT score and treatment satisfaction.  
• 
The estimated time to complete the AFEQT questionnaire is 
approximately 5 to 10 minutes. 
AFSS 
Screening, Day 30, 
Day 90, Day 180, (or 
early discontinuation if 
necessarya)  
• 
A self-reported, disease-specific quality of life instrument used to 
capture subjective and objective ratings of disease burden in 
patients with AF. The AFSS consists of 19 items. It contains a 
visual analogue scale, 4 items on AF frequency, duration and 
severity that are used to calculate AF burden, 4 items on health care 
utilization, and 7 items regarding the severity of specific symptoms.  
• 
The estimated time to complete the AFSS is 5 to 10 minutes. 
DASI 
Screening, Day 30, 
Day 90, Day 180, (or 
early discontinuation if 
necessarya) 
• 
A 12-item, self-administered questionnaire which provides a 
standardized assessment of functional status that uses the patient’s 
ability to perform a set of common activities of daily living to gauge 
functional capacity. 
• 
The estimated time to complete the DASI questionnaire is 
approximately 5 minutes. 
EQ-5D-5L 
Screening, Day 30, 
Day 90, Day 180, (or 
early discontinuation if 
necessarya) 
• 
A standardized measure of health-related quality of life comprised 
of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The scores on these 
5 dimensions can be converted to a single summary index number 
(utility) reflecting preferability compared to other health profiles. 
• 
The estimated time to complete the EQ-5D-5L questionnaire is 
approximately 5 minutes. 
SF-12v2 
Screening, Day 30, 
Day 90, Day 180, (or 
early discontinuation if 
necessarya) 
• 
A 12-item, self-administered health survey standardized across age, 
disease, and treatment group to measure. Eight health domain scales 
contribute to the scoring of both the Physical and Mental 
Component Summary measures.  
• 
The estimated time to complete the SF-12v2 questionnaire is 
approximately 5 to 10 minutes. 
AF = atrial fibrillation; AFEQT = Atrial Fibrillation Effect on Quality-of-life Questionnaire; AFSS = University of Toronto 
Atrial Fibrillation Severity Scale; DASI = Duke Activity Status Index; EQ-5D-5L = A measure of health-related quality of life 
developed by the EuroQol Group; SF-12v2 = Short Form-12 Health Survey, version 2 
a If participant withdraws after Day 180, these early discontinuation procedures will not be performed 
8.1.6. 
Exploratory Endpoints 


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8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• A physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal and neurological systems. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
• BP and pulse measurements will be assessed in a resting position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• BP and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs will be measured after 5 minutes of rest and will include temperature, systolic and 
diastolic BP, pulse, and respiratory rate. Three readings of BP and pulse will be taken. The 
first reading should be rejected. The second and third readings should be averaged to give the 
measurement to be recorded in the eCRF. 
8.2.3. 
Electrocardiograms 
• Sites or designee shall transmit all study-required ECGs obtained to the ECG vendor. If 
multiple ECGs have been obtained for the same participant on the same date, the first 
readable ECG shall be entered as the visit ECG, and all others shall be entered as 
unscheduled. All readable ECGs received by the vendor shall be sent for ECG vendor, 
cardiologist over-read. The sponsor will receive all ECG data, including vendor cardiologist 
assessments, in the data transfer, including those ECGs that could not be evaluated. 
• On Visit 2, Day 1, two 12-lead ECGs will be performed; 1 before surgery and 1 after surgery. 
• A 12-lead ECG will be obtained in the supine or semi-recumbent position as outlined in the 
SoA (see Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.  
• The X-axis speed will be a standard 25 mm per second; the ECG tracing will be kept at the 
study site. Measurements will be recorded for the following parameters in lead II or lead III: 
heart rate, PR interval, QRS duration, QT interval, and QTc. All ECGs will be clinically 
interpreted by the investigator or sub-investigator. 


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8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2, Section 10.2, for the list of clinical laboratory tests to be performed and the 
SoA for the timing and frequency. 
o The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
• All laboratory tests with values considered clinically significant during participation in the 
study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator. 
o If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, Section 10.2, 
must be conducted in accordance with the laboratory manual and the SoA. 
o If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
8.2.5. 
Pulmonary Function Testing 
Study participant pulmonary function will be assessed at the screening visit and Day 30 using 
forced procedures and compared across all 3 study groups (refer to study reference guide). Note, 
if local policies contraindicate or prohibit PFT assessments due to potential for viral spread or 
microbial precautions, then the PFT is not required after explicit approval from the sponsor. If 
PFT assessments are not prohibited by local regulations/policies, then the PFTs should be 
conducted. 
Spirometry testing will be conducted by a pulmonologist, pulmonary technician, respiratory 
therapist, nurse, and/or other appropriate personnel trained in this procedure, following the 
American Thoracic Society (ATS) Standardization of Spirometry guidelines (Miller, 2005). To 
demonstrate reproducibility of results, participants will be required to perform at least 3 
acceptable spirometry maneuvers up to a maximum of 8 attempts. The results of all respiratory 
measures will be reviewed for clinically significant findings. 
The assessments will include the following: 
1. Forced vital capacity (FVC) measured from a maximal forced exhalation 
2. Forced expiratory volume (FEV) in 1 second (FEV1), 3 seconds (FEV3) and 6 seconds 
(FEV6) 
8.2.6. 
Suicidal Risk Monitoring 
Not applicable. 


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8.2.7. 
Immunogenicity Assessments 
Blood samples will be collected from all participants prior to dosing on Day 1 and at the Day 30 
and Day 90 follow-up visits. A 2-tier assay approach will be used for the detection of binding 
and neutralizing antibodies to AGN-151607 in human serum. In tier 1, serum samples will be 
screened using a validated enzyme-linked immunosorbent assay (ELISA). The positive samples 
will subsequently be immune depleted to confirm that the antibodies were specifically binding to 
AGN-151607 and then titered to assess the magnitude of antibodies present. In tier 2, only 
samples that are considered positive in the ELISA will be tested for neutralizing antibodies to 
AGN-151607 using a validated assay. 
Samples may be stored for a maximum of 2 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the sponsor to enable further 
analysis of immune responses to AGN-151607. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3, Section 10.3. 
AEs will be reported by the participant or, when appropriate, by a caregiver. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All AEs/SAEs from the signing of the ICF until the Day 367 follow-up visit/early 
discontinuation visit will be collected at the timepoints specified in the SoA (Section 1.3), and as 
observed or reported spontaneously by study participants. 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent, will be recorded as an AE.  
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3, Section 10.3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3, 
Section 10.3. Assessment of causality to both the study intervention and the study procedures are 
required for reporting each SAE. For the purpose of causality assessment, “study procedure” on 
the SAE reporting form means the procedure of injecting the study intervention into the 


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epicardial fat pads. It does not include any other study procedures (eg, the open-chest surgery 
and related procedures). Therefore, the check box on the SAE form titled “Causal Relationship to 
Study Procedure” should only be checked if, in the investigator’s judgement, the SAE was 
related to the injection procedure into the epicardial fat pads. The cardiac surgery procedure that 
the study participant is undergoing (eg, CABG and/or valve repair/replacement) and any other 
procedures the participants may have during the study are NOT considered the study procedure 
for the purpose of SAE reporting causality assessment. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs and non-serious AEs of special interest (as defined 
in Section 8.3.6)] will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings, if done, including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)s/independent ethics 
committees (IECs), and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 


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• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until Day 60. 
• If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7, 
Section 10.7. 
• Abnormal pregnancy outcomes (eg, spontaneous or elective abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Adverse Events of Special Interest 
An AE of special interest (AESI) for botulinum toxin type A, is possible distant spread of toxin 
(PDSOT). See Section 9.4.2.1 for further details.  
8.3.7. 
Medication Errors 
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows: 
• Wrong study drug 
• Wrong dose (including dosing regimen, strength, form, concentration, amount) 
• Wrong route of administration 
• Wrong participant (ie, not administered to the intended participant) 
Medication errors include occurrences of overdose and underdose of the study intervention. 
Overdose: Unintentional administration of a quantity of the study intervention AGN-151607 
given per administration that is above the maximum recommended dose according to the 
protocol for the study intervention. An overdose for this study will be any dose of AGN-151607 
exceeding the higher assigned dose specified in the protocol (ie, more than 250 U) 
Underdose: Unintentional administration of a quantity of the study intervention AGN-151607 
given per administration that is under the minimum recommended dose according to the 
protocol. An underdose for this study will be any dose of AGN-151607 less than the lower 
assigned dose specified in the protocol (ie, less than 125 U). 
8.4. 
Treatment of Overdose 
For this study, any dose of AGN-151607 greater than an assigned dose specified in the protocol 
will be considered an overdose. 
Sponsor does not recommend specific intervention for an overdose. 


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In the event of an overdose, the investigator/treating physician should: 
1. Contact the sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
8.5. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
PD parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers and Other Assessments 
Collection of samples for biomarker research is also part of this study. Blood samples will be 
collected from all participants in this study as specified in the SoA (Section 1.3). These samples 
will be used to test for immunogenicity and will also include biomarkers involved in the 
inflammatory process and in the autonomic nervous system. The biomarkers to be analyzed will 
be listed in the SAP. 
• Samples will be tested for assessment of biomarkers to evaluate their association with the 
observed clinical responses to study intervention. 
Samples may be stored for a maximum of 2 years (or according to local regulations) following 
the last participant’s last visit for the study at a facility selected by the sponsor to enable further 
analysis of biomarker responses to AGN-151607. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are evaluated in this study 
(Section 8.1.3 and Section 8.1.5). 
Medical resource utilization and health economics data, associated with medical encounters, will 
be collected by the investigator and study-site personnel or designee for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.  
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient) 
• Duration of hospitalization (total days or length of stay, including duration by wards 
[eg, ICU]) 
• Healthcare resource utilization (eg, setting, provider, reason for visit) 


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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
In general, continuous variables will be summarized by descriptive statistics and will include 
sample size, mean, standard deviation, median, minimum, and maximum. Nominal variables will 
be summarized by frequency and percentage. Continuous variables will be analyzed using 
2-sample t-test or analysis of variance (ANOVA) techniques for comparisons between treatment 
groups, and paired t-tests for within-group comparisons. Ordinal variables will be analyzed using 
Wilcoxon rank-sum or Cochran-Mantel-Haenszel (CMH) tests for pairwise comparisons 
between groups, and Wilcoxon signed-rank tests for within-group comparisons. Time-to-event 
data will be analyzed using Cox proportional hazards models or the Kaplan-Meier nonparametric 
model. Nominal variables will be analyzed using Pearson's chi-square test or, if 25% or more of 
the cells have expected counts less than 5, Fisher's exact test. 
The analyses will include 3 treatment groups: Placebo, 125 U, and 250 U of AGN-151607. Each 
dose level of AGN-151607 (125 U and 250 U) will be separately compared to placebo. All 
treatment comparisons will be made at the α = 0.05 level (2-sided). To control for multiplicity in 
comparing 2 doses of AGN-151607 with placebo, the primary efficacy variable will be tested 
sequentially by first comparing the high dose to placebo. The low dose will be compared to 
placebo only if the comparison to the high dose is found to be statistically significant. Details 
regarding adjustment for multiple comparisons for other efficacy variables will be discussed in 
the SAP.  
9.2. 
Sample Size Determination 
A sample size of 100 randomized participants per intervention group will provide approximately 
80% power to detect the treatment difference between each of the AGN-151607 doses (assumed 
equally effective) and placebo for the primary efficacy endpoint. The power calculations are 
based on the following assumptions: 
• The expected incidence of early postoperative AF within 30 days post-surgery will be 47.8% 
in the placebo group and 27.8% in each of the AGN-151607 groups. This assumption is 
based on the results observed in the Pokushalov study (Pokushalov 2015) and the Duke 
University Medical Center clinical trial discussed in Section 2 (Waldron 2019).  
• Two-sided Mantel-Haenszel test statistic and a significance level of 0.05 for the test. 
Calculations will be performed using commercial software PASS 2008 (Hintze 2008).  
Assuming that approximately 10% in each intervention group will drop out early from the study, 
a total of approximately 330 participants will be randomly assigned to study intervention, in 
order to have approximately 300 participants complete all the efficacy assessments up to Day 60 
visit.  


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9.3. 
Populations for Analyses 
A study participant is enrolled in the study the moment he or she has signed the ICF. 
The analysis populations will consist of participants as defined below: 
• The modified intent-to-treat (mITT) population will consist of all randomized participants 
who received study intervention and had at least 1 post-dose ECG by Day 30 post-surgery. 
Analyses will be based on randomized intervention. 
• The safety population will consist of all participants who received study intervention. 
Analyses will be based on actual intervention received. 
9.4. 
Statistical Analyses 
One database lock is planned for this study and will occur when all participants have completed 
the study or exited earlier. Prior to the database lock, an interim analysis of all efficacy data will 
be performed when all randomized participants have completed the Day 60 visit, or exited the 
study earlier.  
The SAP will be developed and finalized before the interim analysis and will describe the 
participant populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 
primary, secondary and additional endpoints.  
9.4.1. 
Efficacy Analyses 
All efficacy analyses will be based on the mITT Population.  
Each participant will be continuously monitored through Day 30, and during the first 7 days 
following Day 60, Day 90, Day 180, Day 270 and Day 360 visits, for all occurrences of AF 
episodes as well as the length of time spent in each of the corresponding AF episodes using ECG 
patches placed on the upper region of the participant’s chest. 
The ECG measurements collected for AF episodes post-surgery will be used to provide 
9 different definitions for POAF for use in statistical analyses, namely:  
1. At least 1 continuous AF episode ≥ 30 seconds  
2. At least 1 continuous AF episode ≥ 2 minutes  
3. At least 1 continuous AF episode ≥ 5 minutes  
4. At least 1 continuous AF episode ≥ 30 minutes  
5. At least 1 continuous AF episode ≥ 1 hour  
6. At least 1 continuous AF episode ≥ 4 hours  


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7. At least 1 continuous AF episode ≥ 6 hours  
8. At least 1 continuous AF episode ≥ 12 hours  
9. At least 1 continuous AF episode ≥ 24 hours  
Based on information collected from continuous monitoring for all occurrences of through 
Day 30, the percent of time spent in AF will be calculated as the total time spent in AF divided 
by the time spent in the study at the Day 30 visit. 
In addition, similar definition of POAF as well as the derivation of the percent of time in AF will 
be obtained based on continuous monitoring of all occurrences of AF during the first 7 days 
following Day 60, Day 90, Day 180, Day 270 and Day 360 visits. 
9.4.1.1. 
Primary Efficacy Variables 
For primary efficacy consideration, POAF will be defined as any continuous episode of AF 
lasting 30 seconds or more during the first 30 days post-surgery. The primary efficacy variable is 
the percentage of participants with at least 1 continuous AF episode ≥ 30 seconds during the first 
30 days post-surgery. AF will be defined as the detection of either AF or atrial flutter.  
9.4.1.2. 
Primary Efficacy Analyses 
The proportion of participants with at least 1 continuous AF episode ≥ 30 seconds during the first 
30 days post-surgery will be presented for each treatment group. Between-group comparisons 
will be performed using the CMH test for general association, stratified by type of surgery 
(presence or absence of valve surgery) and age group (< 65 or ≥ 65 years). Two-sided confidence 
intervals (95%) will be provided for the differences between treatments. The confidence intervals 
will be constructed using the normal approximation to the binomial distribution. 
The primary efficacy variable will also be analyzed using a logistic regression model adjusting 
for baseline risk factors of POAF (type of surgery, and age group). 
9.4.1.3. 
Secondary Efficacy Variables 
The secondary efficacy variables are: 
• Percentage of time spent in AF (AF burden) during the first 30 days post-surgery 
• Percentage of participants with at least 1 event of symptomatic AF during the first 
30 days post-surgery 
• Time to first occurrence of AF during the first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 2 minutes during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 5 minutes during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 30 minutes during the 
first 30 days post-surgery 


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• Percentage of participants with at least 1 continuous AF episode ≥ 1 hour during the first 
30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 4 hours during the first 
30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 6 hours during the first 
30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 12 hours during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 24 hours during the 
first 30 days post-surgery 
9.4.1.4. 
Additional Efficacy Variables 
The additional efficacy variables are: 
• Percentage of participants with clinically important tachycardia in AF (defined as heart 
rate ≥ 100 bpm for at least 2 minutes  
• Percentage of participants needing pharmacologic intervention (ie, anticoagulation, 
antiarrhythmic drugs) during the first 30 days post-surgery due to AF 
• Percentage of participants needing pharmacologic intervention (ie, anticoagulation, 
antiarrhythmic drugs) from Day 31 to Day 360 post-surgery due to AF 
• Percentage of participants needing procedural intervention (ie, cardioversion, ablation, 
additional surgery) during the first 30 days post-surgery due to AF 
• Percentage of participants needing procedural intervention (ie, cardioversion, ablation, 
additional surgery) from Day 31 to Day 360 post-surgery due to AF 
• Time to first prescription of pharmacologic intervention due to POAF during the first 
30 days post-surgery and length of time that prescription is taken.  
• Time of POAF resolution from first dose of prescription of pharmacologic intervention 
• Time to first procedural intervention due to POAF during the first 30 days post-surgery.  
• Time of POAF resolution from first procedural intervention due to AF 
• Length of stay in ICU and reason 
• Length of stay in hospital and reason 
• Number of all-cause re-hospitalizations within 30 days post-discharge 
• Number of non-arrhythmia cardiovascular re-hospitalizations within 30 days 
post-discharge 
• Number of arrhythmia re-hospitalizations within 30 days post-discharge 
• Binary measure (Y/N) of all-cause hospitalizations within 30 days post-discharge 


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• Binary measure (Y/N) of non-arrhythmia cardiovascular hospitalizations within 30 days 
post-discharge 
• Binary measure (Y/N) of arrhythmia hospitalizations within 30 days post-discharge 
• Number of days spent in the hospital: within 30 days post-discharge and within 60 days 
post-surgery 
• Percentage of participants with any occurrence of AF as defined in the primary and 
secondary endpoints during the first 7 days following Day 60, Day 90, Day 180, Day 270 
and Day 360 visits 
• Percentage of participants with at least 1 event of symptomatic AF during the first 7 days 
following Day 60, Day 90, Day 180, Day 270 and Day 360 visits 
• Percentage of time spent in AF (AF burden) during the first 7 days following Day 60, 
Day 90, Day 180, Day 270 and Day 360 visits 
9.4.1.5. 
Secondary and Additional Efficacy Analyses 
For each efficacy variable with binary categorical response outcome, the response proportions 
will be analyzed using the same methods used to analyze the primary efficacy variable. 
Kaplan-Meier curves for time to event data will be produced by treatment group and compared 
using the log-rank test. Time to event data will also be compared between treatment groups using 
Cox proportional hazards models. 
ICU and hospital length of stay will be compared between groups using t-tests as well as linear 
regression models with adjustment for POAF baseline risk factors. The data in both groups will 
first be examined for normality. Should the data have a normal distribution, it will be analyzed 
using an unadjusted t-test. In the event of significant skewedness, the Wilcoxon rank-sum test 
will be used. 
9.4.2. 
Safety Analyses 
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs, physical examination, clinical laboratory tests, 
vital signs, ECG, pulmonary function, and immunogenicity parameters. For each of physical 
examination, clinical laboratory, vital sign, and ECG parameters, the last nonmissing safety 
assessment before the initial dose of treatment will be used as the baseline for all analyses of that 
safety parameter.  
9.4.2.1. 
Adverse Events 
AEs will be coded by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA).  
An AE will be considered a treatment-emergent adverse event (TEAE) if it was present after the 
first dose of study intervention or was present before the date of the first dose of study 
intervention and increased in severity or became serious after the first dose of study intervention.  


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The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by descending percentage in any group, by system organ class, and preferred 
term, and further categorized by severity and causal relationship to the study intervention. If 
more than 1 AE is coded to the same participant, the participant will be counted only once for 
that preferred term using the greatest severity and strictest causality for the summarization by 
severity and causal relationship.  
The total number of TEAEs by severity and causal relationship to the study intervention will be 
summarized by study intervention group.  
The number and percentage of participants who have treatment-emergent SAEs will be 
summarized by preferred term and treatment group. 
The number and percentage of participants in the Safety Population who have AEs leading to 
premature discontinuation of the study intervention will be summarized by preferred term and 
study intervention.  
To assess PDSOT, MedDRA preferred terms that may be associated with botulinum toxin effects 
have been identified over the course of the development programs of botulinum toxin type A by 
the sponsor and will be used for this study. All AEs associated with PDSOT will be tabulated by 
system organ class and treatment group; in addition, all PDSOT AEs will be listed by participant. 
9.4.2.2. 
Clinical Laboratory Assessments 
Descriptive statistics for clinical laboratory values (in SI units) at baseline (screening), and 
changes from baseline at each assessment, will be presented by study intervention for each 
clinical laboratory assessment. 
The criteria for potentially clinically significant (PCS) laboratory values will be detailed in the 
SAP. The number and percentage of participants who have PCS postbaseline clinical laboratory 
values will be tabulated by study intervention at each assessment. The percentages will be 
calculated relative to the number of participants who have available non-PCS baseline values and 
at least 1 postbaseline assessment. The numerator will be the total number of participants with at 
least 1 PCS postbaseline value. A supportive tabular display of participants with PCS 
postbaseline values will be provided, including the participant number, baseline and all 
postbaseline (including non-PCS) values. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided. 
9.4.2.3. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, respiration rate, 
temperature, body weight and abdominal circumference, and body mass index) and changes from 
baseline values at each visit and at the end of study will be presented by treatment group.  
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria. PCS criteria will be specified in the SAP. The number and 
percentage of participants with PCS postbaseline values will be tabulated by treatment group. 
The percentages will be calculated relative to the number of participants with available non-PCS 


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baseline values and at least 1 postbaseline assessment. The numerator will be the total number of 
participants with available non-PCS baseline values and at least 1 PCS postbaseline value. 
A supportive tabular display of participants with PCS postbaseline values will be provided, 
including the participant number, baseline and all postbaseline (including non-PCS) values. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline vital sign values will be provided. 
9.4.2.4. 
Electrocardiograms 
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS interval, 
QT interval, and QTc) and changes from baseline values at each assessment timepoint to the end 
of study will be presented by treatment group.  
Electrocardiographic parameter values are considered PCS if they meet or exceed the 
higher-limit PCS criteria. PCS criteria will be specified in the SAP. The number and percentage 
of participants with PCS postbaseline ECG values will be tabulated by treatment group. The 
percentages will be calculated relative to the number of participants with available non-PCS 
baseline values and at least 1 postbaseline assessment. The numerator is the total number of 
participants with available non-PCS baseline values and at least 1 PCS postbaseline value. 
A supportive tabular display of participants with PCS postbaseline values will be provided, 
including the participant number, baseline, all postbaseline (including non-PCS) values, and 
change from baseline. 
A tabular display showing participants with postbaseline clinically significant ECG 
abnormalities according to the investigator’s overall interpretation will be provided. 
9.4.3. 
Other Analyses 
Fat pads and injection procedure, quality of life outcomes and biomarker analyses, will be 
described in the SAP.  
9.5. 
Interim Analyses 
An interim analysis of all efficacy data will be performed when all randomized participants have 
completed the Day 60 visit or exited the study earlier. The purpose of this analysis is to identify 
early trends in the data for administrative planning of following studies. There is no plan to stop 
the study or drop a treatment arm based on the results from the interim analysis. 
The final analysis will occur when all participants have completed the long-term safety 
follow-up or have exited the study earlier. The details of all analyses will be provided in the SAP 
which will be finalized before the interim analysis.  


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
o Applicable ICH/ISO Good Clinical Practice (GCP) guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The investigator or designee will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the overall conduct of the study at the site or at any home visits 
and adherence to requirements of applicable local regulations, for example 21 CFR, ICH 
guidelines, the IRB/IEC, and European regulation 536/2014 for clinical studies (if 
applicable) 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators and 
sub-investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study site.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant.  
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A signature will be required to document a participant’s agreement to allow any 
remaining specimens to be used for exploratory research.  
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
An independent DSMB will review select safety data at scheduled times during the conduct of 
the study. Ad hoc meetings of the DSMB may be scheduled to evaluate potential safety signals, 
as needed. Policies, procedures, and composition of the DSMB are described separately in the 
DSMB charter for this study. 
10.1.6. 
Posting Clinical Study Data 
Study information and tabular study results will be posted to the US National Institutes of Health 
website www.clinicaltrials.gov. 


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Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of Allergan. 
Clinical study reports, safety updates and annual reports will be provided to regulatory 
authorities as required. 
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on eCRFs unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator in compliance with all applicable laws and regulations. No 
records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written 
notification to the sponsor.  
10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• Source data are defined as: original documents, data, and records (eg, hospital records, 
clinical and office charts, diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiche, photographic negatives, microfilm or magnetic 
media, X-rays, participant files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical study). These records include, but are 


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not limited to, original signed and dated consent forms, relevant observations including 
records of AEs, and records of all exposure to study intervention. 
10.1.9. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
10.1.10. 
Publication Policy 
• Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multi-center study except as agreed with Allergan. 
Allergan is solely responsible for determining what and when to publish. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multi-center studies only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.11. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Protocol deviations will be reported to 
the IRB/IEC according to the IRB/IEC’s reporting requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 10–1 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response evaluation. 
If a local sample is required, it is important that the sample for central analysis is obtained at 
the same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
Table 10–1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC indices: 
MCV 
MCH 
MCHC 
% Reticulocytes 
WBC count with differential 
(absolute): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Hematocrit 
Coagulation (prothrombin 
time (PT), activated partial 
thromboplastin time (aPTT), 
and thrombin time (TT)) 
Clinical 
Chemistry 
BUN 
Creatinine 
Glucose 
(nonfasting) 
Hemoglobin A1c 
Potassium 
Sodium 
Calcium 
eGFR 
Chloride 
Albumin 
AST 
ALT 
Alkaline 
phosphatase 
 
Total direct and indirect 
bilirubin  
Total protein 
Lipid profile 
(cholesterol, 
triglycerides, HDL 
cholesterol, LDL 
cholesterol [calculated]) 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
• Microscopic examination (if blood or protein is abnormal)a 
Other Screening 
Tests 
• 
Urine human chorionic gonadotropin (hCG) pregnancy test) as needed for women of 
childbearing potentiala  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; eGFR = estimated glomerular 
filtration rate; HDL = high density lipoprotein; LDL = low density lipoprotein; MCV = mean corpuscular volume; MCH = mean 
corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, RBC = red blood cell, WBC = white blood cell  
a Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 






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b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 






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10.4. 
Appendix 4: Abbreviations 
AE 
 
adverse event 
AESI  
adverse event of special interest 
AF 
 
atrial fibrillation 
AFEQT 
Atrial Fibrillation Effect on Quality-of-life Questionnaire 
AFSS  
University of Toronto Atrial Fibrillation Severity Scale 
ALT 
 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
 
aspartate aminotransferase 
ATS 
 
American Thoracic Society 
BP 
 
blood pressure 
CABG  
coronary artery bypass graft 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
 
code of federal regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH  
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
DASI  
Duke Activity Status Index 
DSMB  
data safety monitoring board 
ECG  
electrocardiogram 
eCRF  
electronic case report form 
  
 
ELISA  
enzyme-linked immunosorbent assay 
EQ-5D-5L 
A measure of health-related quality of life developed by the EuroQol Group 
EuroScore II European System for Cardiac Operative Risk Evaluation II 
FDA  
US Food and Drug Administration 
FEV 
 
forced expiratory volume 
FEV1  
forced expiratory volume in 1 second 
FEV3  
forced expiratory volume in 3 seconds 
FEV6  
forced expiratory volume in 6 seconds 
FSH 
 
follicle-stimulating hormone 


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FVC  
forced vital capacity 
GCP  
good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRQoL 
Health Related Quality of Life  
IB 
 
investigator’s brochure 
ICF 
 
informed consent form 
ICH 
 
International Conference on Harmonisation 
ICU 
 
intensive care unit 
IDR 
 
independent drug reconstitutor 
IEC 
 
independent ethics committee 
IND 
 
Investigational New Drug 
INR 
 
international normalized ratio 
IRB 
 
institutional review board 
IWRS  
Interactive Web Response System 
LAA   
left atrial appendage 
LVEF  
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT  
modified intent-to-treat 
NCI 
 
National Cancer Institute 
NOAC 
non-vitamin K antagonist oral anticoagulant (also referred to as novel oral 
anticoagulant)  
NOEL 
no observed effect level 
PCS 
 
potentially clinically significant 
PD 
 
pharmacodynamic(s) 
PDSOT 
possible distant spread of toxin 
PFT 
 
pulmonary function test 
POAF  
post-operative atrial fibrillation 
PRO  
patient reported outcome 
QTc 
 
QT interval corrected for heart rate 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SF-12v2 
Short-Form-12 Health Survey, Version 2 


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Protocol 1925-201-008 Amendment 1 
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SoA 
 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE  
treatment-emergent adverse event 
WBC  
white blood cell 
WOCBP 
woman of childbearing potential 
 


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Protocol 1925-201-008 Amendment 1 
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10.5. 
Appendix 5: Standard Discontinuation Criteria 
 
CDISC Submission Value 
CDISC Definition 
Adverse event 
Any untoward medical occurrence in a patient or 
clinical investigation subject administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be 
any unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal 
(investigational) product, whether or not related 
to the medicinal (investigational) product. For 
further information, see the ICH Guideline for 
Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting (modified 
from ICH E2A) Synonyms: side effect, adverse 
experience. See also serious adverse event, 
serious adverse experience. (CDISC glossary) 
Death 
The absence of life or state of being dead (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to 
follow-up 
Other 
Different than the one(s) previously specified or 
mentioned (NCI) 
Physician decision 
A position, opinion or judgment reached after 
consideration by a physician with reference to 
subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI) 
Protocol deviation 
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI) 
Site terminated by sponsor 
An indication that a clinical study was stopped at 
a particular site by its sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by 
its sponsor (NCI) 
Withdrawal by subject 
An indication that a study participant has 
removed itself from the study (NCI) 
 


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10.6. 
Appendix 6: Study Tabular Summary 
 
Parameter Group 
Parameter 
Value 
Trial information 
Trial 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 
 
Clinical Study Sponsor 
Allergan 
 
Trial Phase Classification 
Phase 2 
 
Trial Indication 
Post-operative atrial fibrillation 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Efficacy 
Safety 
 
Trial Length 
367 days 
 
Planned Region of Investigational Sites 
North America and Europe 
 
Planned Number of Participants 
330 participants 
 
FDA-Regulated Device Study 
No 
 
FDA-Regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Participant 
information 
Diagnosis Group 
Patients undergoing open-chest cardiac 
surgery 
 
Healthy Participant Indicator 
No 
 
Planned Minimum Age of Participants 
55 years 
 
Planned Maximum Age of Participants 
90 years 
 
Sex of Participants 
Both 
 
Stable Disease Minimum Duration 
Not applicable 


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Parameter Group 
Parameter 
Value 
Treatments 
Investigational Therapy or Treatment 
AGN-151607 
 
Intervention Type 
Drug 
 
Pharmacological Class of Invest. Therapy 
Botulinum toxin type A 
 
Dose per Administration 
125 U or 250 U 
 
Dose Units 
25 U or 50 U per fat pad 
 
Dosing Frequency 
One-time injection 
 
Route of Administration 
Injection 
 
Current Therapy or Treatment 
Standard-of-care 
 
Added on to Existing Treatments 
Yes 
 
Control Type 
Placebo 
 
Comparative Treatment Name 
Not applicable 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
3 
 
Trial is Randomized 
Yes 
 
Randomization Quotient 
1:1:1 
 
Trial Blinding Schema 
Double blind 
 
Stratification Factor 
Age (< 65, ≥ 65 years) 
Type of surgery (presence/absence of 
valve surgery) 
 
Adaptive Design 
No 
 
Study Stop Rules 
No 
 
 


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10.7. 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Male Participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the protocol-defined timeframe in Section 5.1:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent until after Day 60 of the 
study 
• Agree to use a male condom with spermicide when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant 
In addition, male participants with pregnant or breastfeeding partners must also agree to remain 
abstinent from penile-vaginal intercourse until after Day 60 of the study or to use condom with 
spermicide. Male participants must refrain from donating sperm until after Day 60 of the study.  
Female Participants 


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85 
Female participants of childbearing potential are eligible to participate if they agree to use a 
method of contraception (highly effective or acceptable birth control methods) consistently and 
correctly. Highly effective contraceptive methods are described in Table 10–2. 
Table 10–2 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independenta  
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Etonogestrel implant (ie, Nexplanon®) 
Bilateral tubal occlusion 
Intrauterine copper contraceptive (ie, ParaGard®) 
Vasectomized Partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP.  
Sexual Abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies.  
 
Acceptable birth control methods that result in a failure of more than 1% per year include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• Male or female condom with spermicide  
• Cap, diaphragm, or sponge with spermicide 
• Nonhormonal intrauterine device 
• A combination of male condom with either cap, diaphragm, or sponge with spermicide 
(double barrier methods) are also considered acceptable 
Pregnancy Testing: 
• 
WOCBP should only be included after a negative highly sensitive urine pregnancy test at 
screening and also a negative urine test on Day 1. 
• 
Additional pregnancy testing is not required during the study intervention period. 


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Protocol 1925-201-008 Amendment 1 
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• 
Local urine testing will be standard unless serum testing is required by local regulation or 
IRB/IEC. 
Collection of Pregnancy Information: 
Male Participants with Partners Who Become Pregnant  
• 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant after the start of study intervention and until Day 60. 
This applies only to male participants who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female Participants Who Become Pregnant  
• 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant after the start of study intervention and until Day 60. Information will be recorded 
on the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, follow-up will not 
be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. A spontaneous or elective abortion is always considered 
to be an SAE and will be reported as such. Any poststudy pregnancy-related SAE 
considered reasonably related to the study intervention by the investigator will be reported to 
the sponsor as described in Section 8.3.4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• 
Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 


























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Protocol 1925-201-008 Amendment 1 
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11. 
References 
Arsenault KA, Yusuf AM, Crystal E, Healey JS, Morillo CA, Nair GM, Whitlock RP. 
Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery. 
Cochrane Database Syst Rev. 2013;1:CD003611. 
Gillinov AM, Bagiella E, Moskowitz AJ, Raiten JM, Groh MA, Bowdish ME, et al. Rate control 
versus rhythm control for atrial fibrillation after cardiac surgery. N Engl J Med. 
2016;374:1911-1921. 
Hintze J, 2008; PASS 2008, NCSS, LLC. Kaysville, Utah, USA. www.ncss.com 
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 
2014-AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report 
of the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76. 
Katritsis DG, Giazitzoglou E, Zografos T, Pokushalov E, Po SS, Camm AJ. Rapid pulmonary 
vein isolation combined with autonomic ganglia modification: a randomized study. Heart 
Rhythm. 2011;8:672-678. 
Katritsis DG, Pokushalov E, Romanov A, Giazitzoglou E, Siontis GC, Po SS, et al. Autonomic 
denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized 
clinical trial. J Am Coll Cardiol. 2013;62:2318-2325. 
Kertai MD, Li YW, Li YJ, Shah SH, Kraus WE, Fontes ML, et al. G protein-coupled receptor 
kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary 
artery bypass grafting in patients receiving β-blockers. Circ Cardiovasc Genet. 2014;7:625-633. 
LaPar DJ, Speir AM, Crosby IK, Fonner E Jr, Brown M, Rich JB, et al. Postoperative atrial 
fibrillation significantly increases mortality, hospital readmission, and hospital costs. Ann 
Thorac Surg. 2014;98:527-533. 
Lo LW, Chang HY, Scherlag BJ, Lin YJ, Chou YH, Lin WL, et al. Temporary suppression of 
cardiac ganglionated plexi leads to long-term suppression of atrial fibrillation: evidence of early 
autonomic intervention to break the vicious cycle of "AF begets AF". J Am Heart Assoc. 
2016;5:e003309. 
Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, et al. A multicenter risk index 
for atrial fibrillation after cardiac surgery. JAMA. 2004;291:1720-1729. 
Mostafa A, El-Haddad MA, Shenoy M, Tuliani T. Atrial fibrillation post cardiac bypass surgery. 
Avicenna J Med. 2012;2:65-70. 
Oh S, Choi EK, Choi YS. Short-term autonomic denervation of the atria using botulinum toxin. 
Korean Circ J. 2010;40:387-390. 
Oh S, Choi EK, Zhang Y, Mazgalev TN. Botulinum toxin injection in epicardial autonomic 
ganglia temporarily suppresses vagally mediated atrial fibrillation. Circ Arrhythm 
Electrophysiol. 2011;4:560-565. 


CONFIDENTIAL  
Protocol 1925-201-008 Amendment 1 
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101 
Pokushalov E, Romanov A, Katritsis DG, Artyomenko S, Shirokova N, Karaskov A, et al. 
Ganglionated plexus ablation vs linear ablation in patients undergoing pulmonary vein isolation 
for persistent/long-standing persistent atrial fibrillation: a randomized comparison. Heart 
Rhythm. 2013;10:1280-1286. 
Pokushalov E, Kozlov B, Romanov A, Strelnikov A, Bayramova S, Sergeevichev D, et al. 
Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads 
in patients undergoing cardiac surgery: one-year follow-up of a randomized pilot study. Circ 
Arrhythm Electrophysiol. 2015;8:1334-1341. 
Romanov A, Pokushalov E, Ponomarev D, Bayramova S, Shabanov V, Losik D. Long-term 
suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients 
undergoing cardiac surgery: Three-year follow-up of a randomized study. Heart Rhythm. 2019 
Feb;16(2):172-177. 
Tsuboi M, Furukawa Y, Kurogouchi F, Nakajima K, Hirose M, Chiba S. Botulinum 
neurotoxin A blocks cholinergic ganglionic neurotransmission in the dog heart. Jpn J Pharmacol. 
2002;89:249-254. 
Waldron NH, Cooter M, Haney JC, Schroder JN, Gaca JG, Lin SS. Temporary autonomic 
modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery. Heart 
Rhythm. 2019 Feb;16(2):178-184. 

SAP_001.pdf: 
Allergan PLC
Page 1 
AGN-151607
1925-201-008 Final Statistical Analysis Plan          
 
31 May 2022
1.0
Title Page 
1925-201-008 
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
STATISTICAL ANALYSIS PLAN  
Final: 31 May 2022 
Confidentiality Statement
This document is the property of Allergan LLC and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan LLC. 
NCT03779841


Allergan PLC 
 
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2.0 
Table of Contents 
1.0 
Title Page ............................................................................................................... 1 
2.0 
Table of Contents .................................................................................................... 2 
List of Tables ................................................................................................................... 3 
3.0 
List of Abbreviations ............................................................................................... 5 
4.0 
Introduction ............................................................................................................ 7 
5.0 
Objectives ............................................................................................................ 11 
5.1 
Primary Efficacy Objectives ........................................................................ 11 
5.2 
Secondary Efficacy Objectives .................................................................... 11 
5.3 
Safety Objectives ....................................................................................... 11 
5.4 
Additional Objectives ................................................................................. 11 
5.5 
Exploratory Objectives ............................................................................... 11 
6.0 
Patient Populations ................................................................................................ 11 
6.1 
Modified Intent-To-Treat Population ............................................................ 11 
6.2 
Safety Population ....................................................................................... 11 
6.3 
Supplementary ePatch Analysis Sets ............................................................ 12 
6.4 
Beta Blocking Agent Withdrawn ePatch Analysis Set .................................... 12 
7.0 
Participant Disposition ........................................................................................... 12 
8.0 
Demographics and Other Baseline Characteristics .................................................... 13 
9.0 
Extent of Exposure ................................................................................................ 14 
10.0 
Efficacy Analyses ................................................................................................. 14 
10.1 
Primary Efficacy Variable ........................................................................... 16 
10.2 
Secondary Efficacy Variables ...................................................................... 17 
10.3 
Additional Efficacy Variables ...................................................................... 19 
10.4 
Exploratory Efficacy Variables .................................................................... 23 
10.4.1 Assessment of Fat Pads and Injection Procedure ................................. 23 
10.4.2 Quality of Life Outcomes ................................................................. 24 
10.4.3 Assessment of Biomarkers ................................................................ 33 
11.0 
Safety Analyses .................................................................................................... 33 
11.1 
Adverse Events .......................................................................................... 34 
11.2 
Clinical Laboratory Parameters .................................................................... 37 


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11.3 
Vital Signs ................................................................................................. 40 
11.4 
Electrocardiogram ...................................................................................... 40 
11.5 
Other Safety Parameters .............................................................................. 41 
11.5.1 Immunogenicity Assessments ........................................................... 41 
11.5.2 Pulmonary Function Test (PFT) ........................................................ 41 
11.5.3 Time to Extubation .......................................................................... 42 
11.5.4 Physical Examination ....................................................................... 42 
12.0 
Interim Analysis ................................................................................................... 42 
13.0 
Determination of Sample Size ................................................................................ 43 
14.0 
Statistical Software................................................................................................ 43 
15.0 
Data Handling Conventions ................................................................................... 43 
15.1 
Visit Time Windows ................................................................................... 43 
15.2 
Repeated or Unscheduled Assessments of Safety Parameters .......................... 44 
15.3 
Missing Severity Assessment for Adverse Events .......................................... 45 
15.4 
Missing Causal Relationship to Study Drug for Adverse Events ...................... 45 
15.5 
Missing Date Information for Adverse Events ............................................... 45 
15.6 
Missing Date Information for Prior or Concomitant Medications ..................... 46 
15.6.1 Incomplete Start Date ....................................................................... 46 
15.6.2 Incomplete Stop Date ....................................................................... 47 
15.7 
Character Values of Clinical Laboratory Parameters ...................................... 48 
15.8 
Datetimes for ePatch Analyses ..................................................................... 48 
16.0 
Changes to Analyses Specified in Protocol .............................................................. 49 
17.0 
Version History .................................................................................................... 49 
18.0 
References............................................................................................................ 51 
 
List of Tables 
Table 4–1 
Schedule of Evaluations: Study 1925-201-008..................................................8 
Table 10–1 
The University of Toronto Atrial Fibrillation Severity Scale Scoring 
Algorithm .........................................................................................................25 
Table 10–2 
The University of Toronto Atrial Fibrillation Severity Scale Scoring 
Clarifications ....................................................................................................26 
Table 10–3 
Duke Activity Status Index (DASI) Score .......................................................29 
Table 11–1 
Cardiovascular Adverse Events of Interest ......................................................35 


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Table 11–2 
Criteria for Potentially Clinically Significant Laboratory Results ..................39 
Table 11–3 
Criteria for Potentially Clinically Significant Vital Signs ...............................40 
Table 11–4 
Criteria for Potentially Clinically Significant Electrocardiograms ..................41 
Table 15–1 
Analysis Visit Windows ..................................................................................44 
Table 15–2 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters ........................................................................................................48 
Table 17–1 
Final Analysis Plan Version History Summary ...............................................49 
 


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3.0 
List of Abbreviations 
AE 
 
adverse event 
AESI  
adverse event of special interest 
AF 
 
atrial fibrillation 
ALT 
 
alanine aminotransferase 
AST 
 
aspartate aminotransferase 
BP 
 
blood pressure 
CABG  
coronary artery bypass graft 
CI 
 
confidence interval 
DSMB  
data safety monitoring board 
ECG  
electrocardiogram 
eCRF  
electronic case report form 
EQ-5D-5L 
A measure of health-related quality of life developed by the EuroQol Group 
FEV 
 
forced expiratory volume 
FEV1  
forced expiratory volume in 1 second 
FEV3  
forced expiratory volume in 3 seconds 
FEV6  
forced expiratory volume in 6 seconds 
FVC  
forced vital capacity 
GCP  
good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
 
investigator’s brochure 
ICF 
 
informed consent form 
ICH 
 
International Conference on Harmonisation 
ICU 
 
intensive care unit 
IDR 
 
independent drug reconstitutor 
ITT 
 
intent-to-treat 
LS 
 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT  
modified intent-to-treat 
NB 
 
negative binomial 
PCS 
 
potentially clinically significant 
PDSOT 
possible distant spread of toxin 
POAF  
post-operative atrial fibrillation 
PRO  
patient reported outcome 
QTc 
 
QT interval corrected for heart rate 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SBP 
 
systolic blood pressure 
SF-12v2 
Short-Form-12 Health Survey, Version 2 
TEAE  
treatment-emergent adverse event 


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WBC  
white blood cell 
ZINB  
zero-inflated negative binomial 


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4.0 
Introduction 
This statistical analysis plan (SAP) provides a detailed elaboration of the statistical analyses of 
the efficacy and safety data as specified in the final protocol of Study 1925-201-008 (amendment 
1 version dated 25 September 2020). Specifications of tables, figures, and data listings are 
contained in a separate document. 
This is a phase 2, multi-center, randomized, double-blind, placebo-controlled, dose-ranging 
study in patients 55-90 years of age who are scheduled to undergo open-chest cardiac surgery.  
The length of this study will be 367 days, not including the screening visit, which may occur up 
to 28 days before the first study day (randomization). Signed informed consent from the 
participant will be obtained before any study-related procedures are begun. Patients meeting the 
inclusion/exclusion criteria will be randomized (1:1:1 ratio) to one of three treatment arms at the 
end of the screening period. Primary and secondary efficacy assessments will be assessed for 30 
days post-surgery. Additional efficacy and exploratory assessments will be assessed through Day 
367 post-surgery. All participants will be followed through Day 367 for safety assessments. 
Every attempt will be made for participants who prematurely discontinue from the study, 
regardless of cause, to be seen for a final evaluation. 
The study schema is presented below. 
 
D = study day; TC = telephone call; U = units; V = Visit 
a 
Hospital discharge could take more than 6 days. 
 
The schedule of evaluations is presented in the Table 4–1 below.  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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Table 4–1 
Schedule of Evaluations: Study 1925-201-008 
Study Period 
Screeninga 
Days 1 to 60 
Day 61 through Day 360 
Early 
Discc 
Visit Number 
V1 
V2 
V3 
V4b 
V5b 
V6b 
V7b 
TC1 
V8 
V9 
V10 
V11 
V12 
V13 
TC2 
Day Number 
(up to 
28 days) 
D1 
D2 
D3 
D4 
D5 
D6 
D14 
D30 
D60 
D90 
D180 
D270 
D360 
D367d 
Visit Windows 
- 
- 
- 
- 
- 
- 
- 
± 3d 
± 3d 
± 3d 
± 7d 
± 7d 
± 7d 
± 7d 
V13 + 
7d 
(+ 7d) 
- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
Xe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Xf 
 
X 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for 
women of childbearing 
potential)e,g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessmentse,h 
X 
X 
 
 
 
 
X 
 
X 
Xi 
Xi 
 
 
Xi 
 
X 
Sample collection for 
biomarker assessmente 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGj  
X 
X 
X 
X 
X 
X 
X 
 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
 
X 
ECG patch 
 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xm 
Xm 
Xm 
Xm 
Xm 
X 
 
Vital signse,n 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and abdominal 
circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense AF symptom diary 
and train participant on proper 
useo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AF symptom diary reviewo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study interventionp 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of fat pads and 
injection procedure 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE reviewq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PFTr 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medication and 
concurrent procedure reviewe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Period 
Screeninga 
Days 1 to 60 
Day 61 through Day 360 
Early 
Discc 
Visit Number 
V1 
V2 
V3 
V4b 
V5b 
V6b 
V7b 
TC1 
V8 
V9 
V10 
V11 
V12 
V13 
TC2 
Day Number 
(up to 
28 days) 
D1 
D2 
D3 
D4 
D5 
D6 
D14 
D30 
D60 
D90 
D180 
D270 
D360 
D367d 
Visit Windows 
- 
- 
- 
- 
- 
- 
- 
± 3d 
± 3d 
± 3d 
± 7d 
± 7d 
± 7d 
± 7d 
V13 + 
7d 
(+ 7d) 
- 
AFEQT 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
AFSS 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
DASI 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
EuroSCORE IIt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-12v2 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
EQ-5D-5L 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Xs 
Record discharge from ICU 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Record discharge from hospital 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Record any additional 
healthcare resource utilization 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum sampling for 
immunogenicity assessmentu 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
AE = adverse event; AF = atrial fibrillation; AFEQT = Atrial Fibrillation Effect on Quality-of-life Questionnaire; AFSS = University of Toronto Atrial Fibrillation Severity Scale; 
D(d) = day; DASI = Duke Activity Status Index; Disc = discontinuation; ECG = electrocardiogram; EQ-5D-5L = A measure of health-related quality of life developed by the 
EuroQol Group; FU = follow-up; ICU = intensive care unit; PFT = pulmonary function test; SAE = serious adverse event; SF-12v2 = Short Form-12 Health Survey, version 2; 
TC = telephone call; V = visit 
a 
Screening and randomization activities can occur on the same day. If screening and randomization occur on the same day, all assessments for Visit 1 and Visit 2 should 
be completed. Duplicate assessments (eg, laboratory assessments) do not have to be completed twice; please note a 12-lead ECG is required both before and after 
surgery. 
b 
These visits are optional and are only required if the participant is still hospitalized. Participants may remain in the hospital beyond Day 6, based on the recovery from 
surgery. The study visit procedures will have to be performed each day until discharge.  
c 
In case of early discontinuation, attempts will be made to follow-up with the participant. 
d 
Day 367 must be at least 7 days and should be no more than 14 days after Visit 13 (Day 360). 
e 
On Day 1, assessments to be performed prior to surgery.  
f 
Physical examinations should be conducted where feasible. If the participant cannot attend the study visit, then the physical examination can be omitted, after sponsor 
approval. 
g 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.  
h 
Laboratory assessments (hematology, chemistry, coagulation and urinalysis) to be performed at screening, Day 1 and day of discharge. The day of discharge can be from 
Day 3 onwards.  
i 
Laboratory assessments should be conducted where feasible. If the participant cannot attend the study visit and/or an in-home assessment is not feasible, then the 
laboratory assessments can be omitted, after sponsor approval. 


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j 
On Visit 2, Day 1, two 12-lead ECGs will be performed; 1 before surgery and 1 after surgery. PFT should be performed at a reasonable time apart from vital signs and 
ECG to avoid confounding ECG and vital signs data.  
k 
12-lead ECGs should be conducted where feasible. If the participant cannot attend the study visit and/or an in-home assessment is not feasible, then the 12-lead ECG can 
be omitted, after sponsor approval. 
l 
ECG patch must be worn for a full 30 days post-surgery, even if Day 30 visit occurs prior to Day 30 due to window allowance. 
m 
ECG patch must be used during the first 7 days following Day 60, Day 90, Day 180, Day 270 and Day 360 visits.  
n 
Vital signs taken after a participant has been in a resting position for a minimum of 5 minutes; include blood pressure, pulse, respiration rate, and body temperature. On 
Visit 2, Day 1, vital signs will be measured before and after surgery.  
o 
AF symptom diary must be used for first 30 days after surgery (or until early discontinuation if before Day 30) and during the first 7 days following Day 60, Day 90, Day 
180, Day 270 and Day 360 visits. The diary should be returned to the site and be part of the medical records. 
p 
Unblinded site pharmacist or designee will prepare drug; injected by investigator who is blinded to study intervention.  
q 
Method of detecting AEs and SAEs: care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and nonleading verbal questioning of the 
participant is the preferred method to inquire about AE occurrences. 
r 
Pulmonary function to be assessed using a spirometer and will include forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1), 3 seconds 
(FEV3) and 6 seconds (FEV6). Note, if local policies contraindicate or prohibit PFT assessments due to potential for viral spread or microbial precautions, then the PFT 
is not required after explicit approval from the sponsor. 
s 
If participant withdraws after Day 180, these early discontinuation procedures will not be performed. 
t 
Impaired prognosis defined as EuroSCORE II > 7% perioperative mortality at screening is exclusionary. 
u 
Serum collection should be conducted where feasible. If the participant cannot attend the study visit and/or an in-home assessment is not feasible, then the serum 
collection can be omitted, after sponsor approval. 
 


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5.0 
Objectives 
5.1 
Primary Efficacy Objectives 
• To compare the efficacy of AGN-151607 with placebo to prevent post-operative atrial 
fibrillation (POAF) in participants who are undergoing open-chest cardiac surgery. 
5.2 
Secondary Efficacy Objectives 
• To compare the efficacy of AGN-151607 with placebo to reduce atrial fibrillation (AF) 
burden in participants who are undergoing open-chest cardiac surgery. 
• To compare the efficacy of AGN-151607 with placebo to prevent POAF using alternative 
definitions for POAF in participants who are undergoing open-chest cardiac surgery. 
5.3 
Safety Objectives 
• To compare the safety of AGN-151607 with placebo in participants undergoing open-chest 
cardiac surgery. 
5.4 
Additional Objectives 
• To compare the clinical benefit of AGN-151607 with placebo in participants who are 
undergoing open-chest cardiac surgery. 
5.5 
Exploratory Objectives 
• Assessment of fat pads and injection procedure 
• Quality of life outcomes 
• Assessment of biomarkers 
6.0 
Patient Populations 
6.1 
Modified Intent-To-Treat Population 
The Modified Intent-to-Treat (mITT) Population will consist of all randomized participants who 
received study treatment and had at least 1 post-dose ECG (by ePatch) by Day 30 post-surgery. 
Analyses will be based on randomized treatment. 
6.2 
Safety Population 
The safety population will consist of all participants who received study treatment. Analyses will 
be based on actual treatment received. 


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6.3 
Supplementary ePatch Analysis Sets 
To conduct supplementary analyses of the primary efficacy and specified secondary efficacy 
variables, two Supplementary ePatch Analysis (SEA) Sets will be defined.  Literature suggests 
that a majority of POAF occurs within one week post-operation (Aranki et. al., 1996).  The first 
SEA set will analyze participants without substantial missingness for their ePatch data during the 
first week post-surgery. The second SEA set will analyze participants that additionally are 
without substantial missingness for their ePatch data during the first 30 days post-surgery.  A 
threshold of 80% of the expected analyzable time will be used to define “without substantial 
missingness”. The two SEA sets are defined as follows: 
• SEA-7 consists of all randomized participants who received study treatment and have at 
least 134.4 hours (5.6 days) of analyzable time of ePatch data for patch “2.1” (the patch 
expected to be worn for the first 7 days post-surgery). 
• SEA-30 consists of all randomized participants who received study treatment and have at 
least 134.4 hours (5.6 days) of analyzable time of ePatch data for patch “2.1” and have at 
least 576 hours (24 days) of analyzable time during the first 30 days post-surgery.  
Analyses will be based on randomized treatment. 
6.4 
Beta Blocking Agent Withdrawn ePatch Analysis Set 
To conduct supplementary analyses of the primary efficacy and specified secondary efficacy 
variables within the subgroup of patients that had a beta blocking agent withdrawn post-surgery, 
the Beta Blocking Agent Withdrawn ePatch Analysis Set will be defined. The Beta Blocking 
Agent Withdrawn ePatch Analysis Set consists of all randomized participants who received 
study treatment, have at least 1 post-dose ECG (by ePatch) by Day 30 post-surgery, and had a 
beta blocking agent at baseline or after surgery that was withdrawn within 3 days post-surgery 
and no replacement (no new beta blocker prescription) within 7 days post-surgery. Analyses will 
be based on randomized treatment. 
7.0 
Participant Disposition 
The number and percentage of participants in the two study populations (Safety and mITT) will 
be summarized by treatment group; the overall number of patients screened will be presented. 
The number and percentage of participants who complete the study and of participants who 
prematurely discontinue the study will be presented for each treatment group and pooled across 
treatment groups for the mITT population. The reasons for premature discontinuation from the 
study as recorded on the termination pages of the electronic case report forms will be 
summarized (number and percentage) by treatment group for the mITT population. All 


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participants who prematurely discontinue during the study will be listed by discontinuation 
reason for the mITT population. 
8.0 
Demographics and Other Baseline Characteristics 
Demographic parameters (age; age group; race; ethnicity; sex), baseline characteristics (weight; 
height; and body mass index, calculated as weight [kg]/(height [m])2), waist circumference (m), 
and other disease characteristics (type of surgery and number of grafts) will be summarized 
descriptively by treatment group for the safety population. Continuous variables will be 
summarized by number of participants and mean, SD, first quartile (Q1), median, minimum, 
third quartile (Q3), and maximum values. Categorical variables will be summarized by number 
and percentage of participants. 
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of participants with medical history ongoing at 
screening will be summarized by system organ class, preferred term, and treatment group for the 
safety population. Data for medical history that is not ongoing at screening will be summarized 
and presented in a similar manner. An overall total will be provided for the study as well as by 
treatment group. 
Prior medication is defined as any medication taken before the study treatment. Concomitant 
medication is defined as any medication taken on or after the day of study treatment.  
Both prior and concomitant medications will be coded using the Anatomical-Therapeutic-
Chemical classification text from World Health Organization (WHO) Drug Dictionary. The use 
of prior and concomitant medications will be summarized by the number and percentage of 
subjects in each treatment group for the safety population. If a participant took a specific 
medication multiple times or took multiple medications within a specific therapeutic class, that 
participant would be counted only once for the coded drug name or therapeutic class. 
In addition to summarizing all medications as discussed above, a separate tabulation will also be 
provided for the following medications of interest: 
• The following antiarrhythmics: quinidine, procainamide, disopyramide, mexiletine, 
flecainide, propafenone, amiodarone (including amiodarone hydrochloride, amiodarone 
hydrochloride w/ glucose and amiodarone;glucose), dronedarone, dofetilide, sotalol 
(including sotalol hydrochloride), and ibutilide. 
• The following anticoagulants: warfarin (including warfarin sodium), dabigatran, 
apixaban, rivaroxaban, and edoxaban (including edoxaban tosilate). 
Concurrent procedures will be presented in a listing. A tabulation will be provided for concurrent 
procedures performed due to atrial fibrillation or atrial flutter. Concurrent procedures performed 


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due to atrial fibrillation or atrial flutter may include: alcohol septal ablation, cardiac ablation, 
cardioversion, and additional cardiac surgery. See Section 10.3 below for additional discussion 
of concurrent procedures performed due to atrial fibrillation or atrial flutter. 
Additional medications or concurrent procedures meeting the classifications above may be added 
at the discretion of the clinical team prior to the interim database lock for the primary analysis. 
9.0 
Extent of Exposure 
All study participants will be treated only once on their day of surgery. Study treatment exposure 
data will be listed for the safety population. 
Descriptive statistics of the study duration, calculated for each participant as the number of days 
from the date of the study treatment to the date the participant exits the study, will be presented 
by treatment group. In addition, the number and percentage of participants whose study duration 
belong to each of the following intervals will also be presented by treatment group: ≥ 6 days, ≥ 
14 days, ≥ 30 days, ≥ 60 days, ≥ 90 days, ≥ 180 days ≥ 270 days, ≥ 360 days. These summaries 
will be based on the safety population. 
10.0 
Efficacy Analyses 
All efficacy analyses will be based on the mITT Population, unless otherwise specified. Note that 
the use of the phrase “AF” or “AF episode” in the section and subsections below implies an 
occurrence of either atrial fibrillation or atrial flutter. Other analyses will be conducted to assess 
only atrial fibrillation, only atrial flutter, only atrial tachycardia, and a combination of either 
atrial fibrillation, atrial flutter, or atrial tachycardia. 
Each participant will be continuously monitored for the first 30 days post-surgery, and during the 
first 7 days following Day 60, Day 90, Day 180, Day 270, and Day 360 visits, for all occurrences 
of AF episodes as well as the length of time spent in each of the corresponding AF episodes 
using ECG patches (ePatch) placed on the participant’s chest. 
Even though each participant is expected to wear the epatch for the first 30 days post-surgery, 
and during the first 7 days following Day 60, Day 90, Day 180, Day 270 and Day 360 visits, all 
analyzable data (interpretable) collected from the epatch will be included in the analysis 
regardless of any deviations from these timeframes. 
The ECG measurements collected for AF episodes post-surgery will be used to provide 
10 different definitions for POAF for use in statistical analyses, namely:  
1. at least 1 continuous AF episode ≥ 30 seconds  
2. at least 1 continuous AF episode ≥ 2 minutes  


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3. at least 1 continuous AF episode ≥ 5 minutes  
4.  at least 1 continuous AF episode ≥ 6 minutes  
5. at least 1 continuous AF episode ≥ 30 minutes  
6. at least 1 continuous AF episode ≥ 1 hour  
7. at least 1 continuous AF episode ≥ 4 hours  
8. at least 1 continuous AF episode ≥ 6 hours 
9. at least 1 continuous AF episode ≥ 12 hours 
10. at least 1 continuous AF episode ≥ 24 hours  
Based on information collected from continuous monitoring for all occurrences of AF during the 
first 30 days post-surgery, the percent of time spent in AF (hereinafter referred to as AF Burden) 
during the first 30 days post-surgery will be calculated as (the total time spent in AF during the 
first 30 days post-surgery divided by the total time of analyzable data obtained from the ECG 
patch during the first 30 days post- surgery) multiplied by 100.  
In addition, similar definitions of POAF as well as the derivation of the AF Burden will be 
obtained based on continuous monitoring of all occurrences of AF during the first 7 days 
following Day 60, Day 90, Day 180, Day 270, and Day 360 visits. 
All analyses using ECG patch data will be based on observed data; no imputation will be 
performed on missing data from the ECG patch device. Descriptive statistics of the total time of 
analyzable data obtained from the ECG patch during the first 30 days post- surgery will be 
presented by treatment group. Similar statistics will be presented for each of the first 7 days 
following Day 60, Day 90, Day 180, Day 270, and Day 360 visits. 
Unless otherwise stated, the ICU admission date for the index surgery (initial care of indication 
under study) will be used as reference timepoint to establish if an event occurred within a 
specified timeframe “post-surgery”. For example, the occurrence of AF during the first 30 days 
post-surgery will imply the occurrence of AF during the first 30 days following the initial ICU 
admission date. 
In general, continuous and ordinal variables will be summarized by descriptive statistics and will 
include sample size, mean, standard deviation, median, minimum, and maximum. Nominal 
variables will be summarized by frequency and percentage. 
Inferential analyses will include 3 treatment groups: Placebo, 125 U, and 250 U of AGN-151607. 
Each dose level of AGN-151607 (125 U and 250 U) will be separately compared to placebo. All 
treatment comparisons will be made at the α = 0.05 level (2-sided). To control for multiplicity in 
comparing 2 doses of AGN-151607 with placebo, the primary efficacy variable will be tested 
sequentially by first comparing the high dose to placebo. The low dose will be compared to 


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placebo only if the comparison to the high dose is found to be statistically significant. There will 
be no adjustment for multiple comparisons for all other efficacy variables. 
Mis-stratified participants, if any, will be analyzed based on the correct stratification group [type 
of surgery (presence or absence of valve surgery) and age group (< 65 or ≥ 65 years)], not the 
stratification group to which the participants were assigned at the time of randomization. 
Unless otherwise stated, the use of the phrase “percentage of participants” for any efficacy 
variable in the sections below assumes the variable is a binary categorical response outcome. 
10.1 
Primary Efficacy Variable 
For primary efficacy consideration, POAF will be defined as any continuous episode of AF 
lasting 30 seconds or more during the first 30 days post-surgery. The primary efficacy variable is 
the percentage of participants with at least 1 continuous AF episode ≥ 30 seconds during the first 
30 days post-surgery. 
For each of the AGN-151607 doses of 125 U and 250 U, the null hypothesis is that there is no 
difference between that dose group and placebo in the percentage of participants with at least 1 
continuous AF episode ≥ 30 seconds during the first 30 days post-surgery.  The alternative 
hypothesis is that there is a difference between the AGN-151607 dose group under consideration 
and placebo. 
The proportion of participants with at least 1 continuous AF episode ≥ 30 seconds during the first 
30 days post-surgery will be presented for each treatment group. Between-group comparisons 
will be performed using the Cochran-Mantel-Haenszel (CMH) test for general association 
stratified by type of surgery (presence or absence of valve surgery) and age group (< 65 or ≥ 65 
years). P-values, adjusted Mantel-Haenszel (MH) odds ratios and relative risks (and their 
corresponding 95% confidence intervals) will be presented for each comparison of AGN-151607 
versus placebo. Exact (Clopper-Pearson) 95% confidence intervals of the observed proportion 
will be presented for each treatment group. In addition, exact unconditional 95% confidence 
interval (using the score method) for the difference in observed proportion between each AGN-
151607 dose group versus placebo will also be presented. 
For the primary efficacy variable, supplementary analyses will be performed based on the 
Supplementary ePatch Analysis Sets (SEA-7 and SEA-30) and the Beta Blocking Agent 
Withdrawn ePatch Analysis Set.  The supplementary analyses will use the same methods 
described for the primary analysis. 
For the primary efficacy variable, subgroup analyses will be performed using the same methods 
described for the primary analysis based on the correct stratification group (with the other 
stratification factor used for the stratified CMH test): 


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• type of surgery (presence or absence of valve surgery) 
• age group (< 65 or ≥ 65 years)] 
10.2 
Secondary Efficacy Variables 
The secondary efficacy variables are: 
• Percentage of time spent in AF (AF Burden) during the first 30 days post-surgery 
• Percentage of participants with at least 1 event of symptomatic AF (symptoms occurring 
within 2 hours of an AF episode) during the first 30 days post-surgery 
• Time to first occurrence of AF during the first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 2 minutes during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 5 minutes during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 6 minutes during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 30 minutes during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 1 hour during the first 
30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 4 hours during the first 
30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 6 hours during the first 
30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 12 hours during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous AF episode ≥ 24 hours during the 
first 30 days post-surgery 
• Percentage of participants with at least 1 continuous atrial fibrillation (excluding atrial 
flutter) episode ≥ 30 seconds during the first 30 days post-surgery 
• Percentage of participants with at least 1 continuous atrial flutter episode ≥ 30 seconds 
during the first 30 days post-surgery 


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• Percentage of participants with at least 1 continuous atrial tachycardia episode (defined as 
the duration of the longest SVT run) ≥ 30 seconds during the first 30 days post-surgery 
• 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 
Between-group treatment comparisons in the percentage of time spent in AF (AF burden) during 
the first 30 days post-surgery will be performed for each AGN-151607 treatment arm versus 
placebo using the stratified Wilcoxon (Van Elteren) test stratified by age group and type of 
surgery. Calculation of time spent in AF (AF burden) will exclude continuous AF episodes < 30 
seconds in duration. For participants with no AF during the first 30 days post-surgery, the AF 
burden will be set to 0. 
For each efficacy variable with binary categorical response outcome, the response proportions 
will be analyzed using the same methods used to analyze the primary efficacy variable. For 
symptomatic AF, symptoms that occur in the interval that starts two hours prior the onset of the 
AF episode and ends two hours after the conclusion of the AF episode will meet the definition of 
“within 2 hours of an AF episode”.  As noted in the protocol, participants will mark the date and 
time that a symptom is experienced by pressing a button on the ECG patch itself. 
For each treatment group, the Kaplan-Meier (KM) survival analysis methodology will be used to 
estimate the median time (days) to first occurrence of AF during the first 30 days post-surgery 
using each of the 9 definitions of POAF stated in Section 10.0 above. Furthermore, the 25th and 
75th percentiles of the time to the first occurrence of AF during the first 30 days post-surgery 
will also be estimated. The associated 95% CIs calculated using Greenwood’s formula for the 
variance of the KM estimate will also be presented for each treatment group. Pairwise treatment 
comparisons of the KM curves will be performed primarily by using the log rank test stratified 
by type of surgery and age group. Time to event data will also be compared between treatment 
groups using Cox proportional hazards models adjusting for baseline risk factors of POAF (type 
of surgery, and age group), with hazard ratios and their 95% CIs presented for each pairwise 
comparison.  Cox proportional hazards models additionally adjusting for total analyzable time 
during the first 30 days post-surgery will also be analyzed.  The difference in restricted mean 
survival time between treatment groups for time to first occurrence of AF during the first 30 days 
post-surgery (i.e., restricted time τ = 30 days) will be compared using a nonparametric K-sample 
chi-square test stratified by type of surgery and age group. Participants who do not experience an 
AF episode during the first 30 days post-surgery will be censored at the maximum timepoint 
during the first 30 days post-surgery for which they have recorded data. 
For the time to first occurrence of AF during the first 30 days post-surgery, a supplementary 
analysis will be performed based on the Supplementary ePatch Analysis Sets (SEA-7 and SEA-
30).  The supplementary analysis will use the same methods described above.   


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For each minimum duration specified above for the percentage of participants with at least 1 
continuous AF episode during the first 30 days post-surgery, a supplementary analysis will be 
performed based on the Supplementary ePatch Analysis Sets (SEA-7 and SEA-30). The 
supplementary analysis will use the same methods used to analyze the primary efficacy variable. 
For these endpoints, subgroup analyses will also be performed using the same methods described 
above based on the correct stratification group [type of surgery (presence or absence of valve 
surgery) and age group (< 65 or ≥ 65 years)]. 
10.3 
Additional Efficacy Variables 
Hospital and ICU Length of Stay 
Hospital length of stay for the initial care of indication under study is defined as the time (days) 
from ICU admission date/time to the date/time of discharge from the hospital. ICU length of stay 
is defined as the time (hours) from the ICU admission date/time to the date/time of discharge 
from the ICU.  For participants not admitted to the ICU, ICU length of stay will be set to zero 
and hospital length of stay will be defined as the time (days) from end date/time of study drug 
administration to date/time of discharge from hospital. For subjects missing ICU admission 
date/time, ICU admission date/time will be imputed to the end date/time of study drug 
administration. The date/time of death will be used to derive hospital length of stay for 
participants who died at the hospital (and ICU length of stay, for participants who die in the 
ICU). 
Descriptive statistics (n, mean, SD, Q1, median, Q3, min, max) for hospital and ICU length of 
stay will be presented by: 
• treatment group 
• region (U.S. versus non-U.S.) and treatment group 
• country and treatment group 
• sites and treatment group 
Between-group treatment comparisons in hospital and ICU length of stay will be performed for 
each AGN-151607 treatment arm versus placebo using the following methods: 
• An ANOVA model with treatment group, type of surgery, age group, and region as 
factors 
• An ANOVA model with treatment group and region as factors 
• An ANOVA model with treatment group and country as factors 


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• A stratified Wilcoxon (Van Elteren) test, stratified by type of surgery, age group, and 
region 
• A stratified Wilcoxon (Van Elteren) test, stratified by type of surgery and age group 
Descriptive statistics of hospital length of stay measured from the time of initial hospital 
admission to discharge will be presented by: 
• treatment group 
• region (U.S. versus non-U.S.) and treatment group 
• country and treatment group 
• sites and treatment group 
ANOVA models, as described above, will be used to estimate confidence intervals for difference 
in mean hospital length of stay measured from the time of initial hospital admission between 
each AGN-151607 treatment arm and placebo. 
Descriptive statistics of number of days spent in the hospital within 30 days post-discharge and 
within 60 days post-surgery will be presented by treatment group. Summary statistics will also 
be presented by treatment group for the reasons for hospital and ICU admissions. 
Rehospitalization within 30 Days Post-Discharge and 60 Days Post-Surgery 
The percentage of participants with at least one all-cause rehospitalization within 30 days post-
discharge and percentage of participants with at least one all-cause rehospitalization 60 days 
post-surgery will each be presented by treatment group. Similar summaries will be presented for 
non-arrhythmia cardiovascular rehospitalization and arrhythmia cardiovascular rehospitalization. 
These variables will be analyzed using the same method presented for the primary efficacy 
variable in Section 10.1. Descriptive statistics of the total number of rehospitalizations within 30 
days post-discharge and 60 days post-surgery as well as the length of rehospitalization stay will 
also be presented by treatment group for each of the different causes of rehospitalizations (all-
cause, non-arrhythmia cardiovascular and arrhythmia cardiovascular). 
The time (days) to the first all-cause rehospitalization will be calculated as the date/time of first 
re-hospitalization minus the date/time of hospital discharge after surgery. This will be analyzed 
using the KM method discussed in Section 10.2. Participants with no rehospitalizations will be 
censored at their respective study exit day. Similar analyses will be performed for non-
arrhythmia cardiovascular rehospitalization and arrhythmia rehospitalizations. 


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Healthcare Resource Utilization within 30 Days, 60 Days, and 365 days Post-Discharge 
The proportion of participants with any healthcare resource utilization (outside of any planned 
in-patient hospitalization, procedures and medications) within 30 days, 60 days, and 365 days 
post-discharge will be presented by treatment group. The type of resource utilized (e.g., 
Outpatient hospital, Physician’s office, etc.) as well as the reason for the visit will also be 
tabulated in a similar manner. Descriptive statistics of the number of times each participant 
utilizes a healthcare resource within each of the specified timeframe will also be presented by 
treatment group. Note that any unplanned inpatient hospitalization will also be included in these 
summaries. 
Need for Medical or Procedural Intervention Due to AF 
The following five binary (yes/no) variables will be used to analyze the need for pharmacologic 
and/or procedural intervention due to AF during the first 30 days post-surgery: 
1. at least one pharmacologic intervention (i.e., anticoagulation or antiarrhythmic drugs)?  
2. at least one anticoagulation pharmacologic intervention? 
3. at least one antiarrhythmic pharmacologic intervention? 
4. at least one procedural intervention (see list in Section 8.0)? 
5. at least one pharmacologic or procedural intervention?  
In addition, time to event variables will also be created for each of the corresponding 5 variables 
above. The time to the first event will be used for analysis. All these variables will be analyzed 
using the same methods for similar variables in Sections 10.1 and 10.2. 
The need for pharmacologic and/or procedural intervention due to AF from Day 31 to Day 360 
post-surgery will be analyzed in a similar fashion. Participants with no events who exit the study 
prior to Day 360 will be censored at their respective study exit day minus 30 days, while 
participants with no events who exit the study on or beyond day 360 will be censored at day 330 
(360 – 30 = 330).  Pharmacologic and/or procedural interventions due to AF with onset dates 
prior to day 31 that are ongoing at day 31 will count as events for these endpoints, with a time-
to-event equal to zero. 
Descriptive statistics will be presented by treatment group for each of the following: 
• time to POAF resolution from first dose of prescription of pharmacologic intervention 
• time to POAF resolution from first procedural intervention 
• types of pharmacologic interventions used due to POAF 


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• average duration of pharmacologic interventions due to POAF. In addition, this summary 
will be further categorized by “medication of interest” (antiarrhythmics versus 
anticoagulants) as defined in Section 8.0 above. 
• yes/no: Beta blocking agent (ATC code: C07A) withdrawn within 3 days post-surgery 
and no replacement (no new beta blocker prescription) within 7 days post-surgery 
Other Efficacy Variables 
• Percentage of participants with clinically important tachycardia in AF (defined as heart 
rate ≥ 100 bpm for at least 2 minutes) within 30 days post-surgery 
• Percentage of participants with any occurrence of AF as defined in the primary and 
secondary endpoints during the first 7 days following Day 60, Day 90, Day 180, Day 
270, and Day 360 visits 
• Percentage of participants with at least 1 event of symptomatic AF (symptoms occurring 
within 2 hours of an AF episode) during the first 7 days following Day 60, Day 90, Day 
180, Day 270, and Day 360 visits 
• Percentage of participants with actionable AF within 30 days post-surgery. Actionable 
AF is defined as meeting at least one of the following conditions: hospitalization due to 
AF, or medicinal or procedural intervention due to AF 
• Percentage of participants discharged from hospital (after initial care of indication under 
study) without prescription of any of the medication of interest listed in Section 8.0 
• Percentage of participants free from AF through 12 months post-surgery and not taking 
any antiarrhythmic drugs (as defined in Section 8.0)  
• Percentage of participants free from AF through 12 months post-surgery and not taking 
any anticoagulant drugs (as defined in Section 8.0)   
• Percentage of time spent in AF (AF burden) during the first 7 days following Day 60, 
Day 90, Day 180, Day 270, and Day 360 visits 
The first 6 variables above will be analyzed using the same method used to analyze the primary 
efficacy variable in Section 10.1. Similarly, the AF burden will be analyzed using the same 
method discussed in Section 10.2. In addition, descriptive statistics of the AF Burden, including 
tertiles, will be presented by treatment group. For symptomatic AF, symptoms that occur in the 
interval that starts two hours prior the onset of the AF episode and ends two hours after the 
conclusion of the AF episode will meet the definition of “within 2 hours of an AF episode”. The 
date and time when a symptom is experienced is marked by a participant pressing a button on the 
ePatch itself. 


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• A negative binomial (NB) regression model will be used to model the number of AF 
events (using ≥ 30 seconds definition of AF) within 30 days post-surgery, with treatment, 
type of surgery, and age group as factors and log(total analyzable time) as the offset in 
the model. A zero-inflated negative binomial (ZINB) regression model will also be 
estimated with treatment, type of surgery, and age group as factors in both the main and 
zero-count models and log(total analyzable time) as the offset. If p < 0.05 for the Scaled 
Pearson chi-square goodness of fit statistic for the NB model (suggesting overdispersion 
may be present), then the ZINB model will be considered the primary analysis; 
otherwise, the NB model will be considered the primary analysis. Sensitivity analyses of 
the number of AF events using Poisson regression and zero-inflated Poisson regression 
using similar models will be performed. Least squares (LS) mean differences and 
incidence rate ratios with 95% CIs will be presented for all models. A supplementary 
analysis of the number of AF events will also be performed based on the SEA-30 set 
using the same models. 
• The win ratio unmatched approach (Pocock et. al., 2012) will be used to analyze the 
following composite endpoint:  
1. Death 
2. Stroke  
3. All-cause 30-day rehospitalization 
4. Use of pharmacologic or procedural intervention of interest due to AF 
5. Hospital length of stay  
The components of the endpoints are listed in order of clinical importance. The win ratio, 
with the associated 95% CI and p-value will be presented for the composite endpoint, as 
well as for each of the component endpoints. Two win ratios analyses will be performed. 
The first will analyze binary outcomes for each of the components (with the fifth 
component being “Hospital length of stay > median hospital length of stay for the total 
study population”). The second will analyze time-to-event outcomes for each of the 
components (with the time-to-first-event used for components with multiple events 
experienced, and with the fifth component being time-to-hospital-discharge from initial 
care). A list of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms 
for stroke will be provided by the clinical team. All-cause 30-day rehospitalization 
includes any hospitalization within 30 days of (first) discharge from the hospitalization 
for initial care. 
10.4 
Exploratory Efficacy Variables 
10.4.1 
Assessment of Fat Pads and Injection Procedure 


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Descriptive 
or summary statistics will be presented by treatment groups for each of these assessments as 
appropriate. 
10.4.2 
Quality of Life Outcomes 
Each quality-of-life questionnaire discussed below will be completed by the participants at 
Screening (baseline), Day 30, Day 90, Day 180 or at early discontinuation visit if necessary.  
Descriptive statistics for each of the aggregate measures and their corresponding change from 
baseline scores will be presented by treatment group at each visit. 
The change from baseline in each of the aggregate scores will be analyzed using a mixed model 
for repeated measures (MMRM). The model will include treatment group, visit, age group, type 
of surgery, and treatment group by visit interaction as categorical fixed effects, and baseline 
score as a continuous fixed effect. Restricted maximum likelihood method will be used. The 
within-patient correlation will be modeled using the unstructured covariance matrix. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Contrasts will be constructed to obtain the treatment effects at each postbaseline visit (i.e., Day 
30, Day 90, and Day 180) to compare each AGN-151607 treatment group versus the placebo 
group. Each treatment effect and treatment comparisons will be estimated by the LS Means and 
their differences in LS Means, along with their SE and 95% confidence intervals, and the p-value 
corresponding to the between-treatment group difference. 
10.4.2.1 
University of Toronto Atrial Fibrillation Severity Scale (AFSS) 
A self-reported, disease-specific quality of life instrument used to capture subjective and 
objective ratings of disease burden in patients with AF. The AFSS consists of 19 items. It 
contains a visual analogue scale, 4 items on AF frequency, duration and severity that are used to 
calculate AF burden, 4 items on health care utilization, and 7 items regarding the severity of 
specific symptoms. See Appendix 10.9 of study protocol for more details. 
The tables below show the scoring algorithm for some of the items on the questionnaire as well 
as the derivation of the following aggregate measures: 
• Total AF Burden 
• AF Symptoms Score 


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Table 10–1 
The University of Toronto Atrial Fibrillation Severity Scale Scoring Algorithm 
Question Number (range) 
Scoring 
Q4 (1-10) Global well-being 
Raw score 
Q5 (1-11) AF frequency  
*lower scores denote more frequent AF 
Continuous = 1 
More than twice a day = 2 
Daily or almost daily = 3 
4 - 5 times a week = 4 
2 - 3 times a week = 5 
About once a week = 6 
About twice a month = 7 
About once a month = 8 
About 2-4 times a year = 9 
About once a year = 10 
Less than once a year = 11 
Q6 (1-8) AF duration  
*lower scores denote AF of longer duration 
Continuous = 1 
Several days = 2 
All day = 3 
Several hours = 4 
About 1 hour = 5 
30 - 45 minutes = 6 
< 30 minutes = 7 
A few minutes = 8 
Q7, Q8 (1-10) AF severity 
*higher scores denote more severe AF 
Arithmetic mean of 2 scores 
Q10 (0-7) ER visits 
0 = 0 
1 = 1 
2 = 2 
3 = 3 
4 = 4 
5 to ≤ 10 = 5 
> 10 to ≤ 15 = 6 
> 15 = 7 
Q11 (0-7) Hospitalizations 
0 = 0 
1 = 1 
2 = 2 
3 = 3 
4 = 4 
5 to ≤ 10 = 5 
> 10 to ≤ 15 = 6 
> 15 = 7 






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Subscale scores are computed similarly to the overall score from each subscale used to generate 
its own score. The 18 questions are grouped into 3 functional subscales as described below: 
Subscales 
Questions 
Symptoms 
1, 2, 3, and 4 
Daily Activities 
5, 6, 7, 8, 9, 10, 11, and 12 
Treatment Concern 
13, 14, 15, 16, 17, and 18 
 
The 2 treatment satisfaction questions (Questions 19 and 20) are not part of the overall AFEQT 
score but are computed as its own subscale similarly to the overall score. 
Subscale 
Questions 
Treatment Satisfaction 
19, 20 
 
Overall or subscale scores range from 0 to 100. A score of 0 corresponds to complete disability, 
while a score of 100 corresponds to no disability. 
Separate analyses will be performed for each of the following scores: 
• Overall AFEQT score  
• Symptoms subscale score 
• Daily activities subscale score 
• Treatment concern subscale score 
• Treatment satisfaction subscale score 
10.4.2.3 
Duke Activity Status Index (DASI) 
A 12-item, self-administered questionnaire which provides a standardized assessment of 
functional status that uses the patient’s ability to perform a set of common activities of daily 
living to gauge functional capacity. Scoring of the Activity Status Index is shown on the table 
below. 


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Table 10–3 
Duke Activity Status Index (DASI) Score 
Questions 
Scores (only for response “Yes, with no difficulty”)a 
1 
2.75 
2 
1.75 
3 
2.75 
4 
5.50 
5 
8.00 
6 
2.70 
7 
3.50 
8 
8.00 
9 
4.50 
10 
5.25 
11 
6.00 
12 
7.50 
a 
All other responses gets a score of zero for that question. 
 
The DASI score is obtained by summing all the scores from the 12 items on the questionnaire. 
The higher the score (maximum 58.2), the higher the functional status. 
10.4.2.4 
European Quality of Life - 5-Dimensional - 5-Level (EQ-5D-5L) 
The EQ-5D-5L is made up of two components: health state description and evaluation. The 
description component consists of five dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The mobility dimension queries the participant’s 
walking ability. The self-care dimension queries the participant’s ability to wash or dress by 
himself. The usual activities dimension assesses the participant’s performance in “work, study, 
housework, family or leisure activities”. The pain/discomfort dimension measures how much 
pain or discomfort a participant has. The anxiety/depression dimension assesses how anxious or 
depressed a participant is. The respondents rate their level of severity for each dimension using a 
5-level scale (EQ-5D-5L) by ticking (or placing a cross) in the box against the most appropriate 
statement in each of the 5 dimensions. The second component of the EQ-5D-5L is a visual 
analogue scale (EQ-VAS) by which participants can rate their overall health from 0 (worst 
imaginable health state) to 100 (best imaginable health state).  
With the EQ-5D-5L, rating levels can be coded as numbers 1, 2, 3, 4 or 5 which correspond to 
“have no problems”, “have slight problems”, “have moderate problems”, “have severe 
problems”, and “unable to do/have extreme problems”, respectively. As a result, a participant’s 
health state can be defined by a 5-digit number by combining the numeric levels from the 5 
dimensions, ranging from 11111 (“have no problems” in all 5 dimensions) to 55555 (“unable to 


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do/have extreme problems” in all 5 dimensions). The US-based value set for the EQ-5D-5L will 
be derived using an international standardized protocol (Pickard et. al., 2019). 
The EQ-5D-5L will be completed by the participants at Screening, Day 30, Day 90, Day 180 or 
at early discontinuation visit if necessary. 
10.4.2.5 
Short Form-12 Health Survey (SF-12v2) 
The SF-12v2 health survey is a generic assessment of health-related quality of life from patient’s 
perspective. It consists of 12 items that measures 8 health domain scales: physical functioning 
(PF), role limitations due to physical health problems (RP), bodily pain (BP), general health 
(GH), vitality (energy/fatigue) (VT), social functioning (SF), role limitations due to emotional 
problems (RE), and mental health (physiologic distress and physiologic well-being) (MH). The 8 
scales are aggregated into 2 summary measures: the Physical Component Summary (PCS) and 
the Mental Component Summary (MCS) scores, which range from 0 to 100, with higher scores 
indicating better quality of life. 
Within each scale, if there are less than or equal to 50% of the item scores missing, the missing 
item score(s) will be imputed using the mean score of the non-missing items and used to 
calculate the scale score. If more than 50% of the item scores are missing, no imputation will be 
performed, and the scale score will be set to missing. 
The component summary scores will be derived using the following scoring algorithm.  
Step 1: Item coding 
Code the response to each item as follows such that higher score indicates better health state. 
Response to Item 1 
Response Choices 
Precoded Item Value 
Final Item Value 
Excellent 
1 
5.0 
Very Good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.0 
Poor 
5 
1.0 
 
 
 
Response to Items 2a and 2b 
Respond Choices 
Precoded Item Value 
Final Item Value 
Yes, limited a lot 
1 
1 
Yes, limited a little 
2 
2 
No, not limited at all 
3 
3 
 
 
 


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Response to Items 3a, 3b, 4a, 4b and 7 
Response Choices 
Precoded Item Value 
Final Item Value 
All of the time 
1 
1 
Most of the time 
2 
2 
Some of the time 
3 
3 
A little of the time 
4 
4 
None of the time 
5 
5 
 
 
 
Response to Item 5 
Response Choices 
Precoded Item Value 
Final Item Value 
Not at all 
1 
5 
A little bit 
2 
4 
Moderately 
3 
3 
Quite a bit 
4 
2 
Extremely 
5 
1 
 
 
 
Response to Items 6a, 6b and 6c 
Response Choices 
Precoded Item Value 
Final Item Value 
All of the time 
1 
5 
Most of the time 
2 
4 
Some of the time 
3 
3 
A little of the time 
4 
2 
None of the time 
5 
1 
 
Step 2: Computing raw scale scores 
After item recoding, a raw score is computed for each scale which is the simple algebraic sum of 
the final item values for all items in that scale as shown in the below table. For example, the raw 
score for PF scale is the sum of the final item values of items 2a and 2b. 


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Scale 
Sum Final Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
PF 
Items 2a + 2b 
2, 6 
4 
RP 
Items 3a + 3b 
2, 10 
8 
BP 
Item 5 
1, 5 
4 
GH 
Item 1 
1, 5 
4 
VT 
Item 6b 
1, 5 
4 
SF 
Item 7 
1, 5 
4 
RE 
Items 4a + 4b 
2, 10 
8 
MH 
Items 6a + 6c 
2,10 
8 
 
Step 3: Transforming raw scale scores 
Transforming the raw scale score to a 0-100 scale using the formula below. The table above 
include the lowest possible and possible range of raw score for each scale. 
 
For example, the transformed score for PF scale is (Raw PF score – 2) / 4. 
Step 4: Standardizing transformed scale scores 
Each transformed scale is standardized to a z-score using scale means and standard deviations 
from the 1998 general United States population as shown in the below table. 
Scale 
Mean 
Standard Deviation 
PF 
81.18122 
29.10558 
RP 
80.52856 
27.13526 
BP 
81.74015 
24.53019 
GH 
72.19795 
23.19041 
VT 
55.59090 
24.84380 
SF 
83.73973 
24.75775 
RE 
86.41051 
22.35543 
MH 
70.18217 
20.50597 
 
The formula for z-score transformation is: 
Z-score standardized scale = (Transformed scale score – Mean) / Standard Deviation 
For example, the z-score of PF scale = (Transform PF score – 81.18122) / 29.10558.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Step 5: Aggregating scale scores to compute raw component summary scores 
The standardized scales are aggregated using weights (factor score coefficients) from the 1998 
general United States population to derive raw component summary scores (PCS and MCS). 
Formulae for aggregating z-score standardized scales are: 
Raw PCS = PF ×.42402 + RP × .35119 + BP × .31754 + GH × .24954 + 
 
 
 VT × .02877 + SF × -.00753 + RE × -.19206 + MH × .22069 
Raw MCS = PF ×-.22999+ RP × -.12329 + BP × -.09731 + GH × -.01571 + 
 
 
 VT × .23534 + SF × .26876+ RE × .43407+ MH × .48581 
Step 6: Standardizing composite summary scores 
The raw PCS and MCS scores are standardized as follows such that the final PCS and MCS 
scores have values with mean 50 and standard deviation 10. 
PCS = 50 + Raw PCS ×10 
MCS = 50 + Raw MCS ×10 
10.4.3 
Assessment of Biomarkers 
Blood samples will be collected from all participants in this study prior to dosing on day 1 and at 
days 2, 3, and 4. These samples will be used to test for biomarkers involved in the inflammatory 
process and in the autonomic nervous system, including the inflammatory panel (IFNγ, IL1β, 
IL2, IL4, IL6, IL8, IL10, IL13, and TNFα), Catecholamines (Epinephrine, norepinephrine and 
dopamine) and hsCRP. 
Descriptive statistics and graphs will be presented by treatment group for each biomarker of the 
following: 
• Biomarker concentration at baseline and each timepoint post treatment 
• Change from baseline (CFB) in biomarker concentration. 
Exploratory analysis of biomarker concentration and their CFB following treatment will be 
conducted in correlation with the observed clinical response to study treatment. 
11.0 
Safety Analyses 
The safety analysis will be performed using the safety population. The safety parameters will 
include adverse events (AEs), physical examinations, clinical laboratory test results, vital sign 


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measurements, electrocardiograph (ECG) results, and pulmonary function testing. For each of 
the physical examinations, clinical laboratory test results, vital sign measurements, and ECG 
parameters, the last non-missing safety assessment before the study treatment will be used as the 
baseline for all analyses of that safety parameter. Continuous variables will be summarized by 
number of participants and mean, SD, first quartile (Q1), median, minimum, third quartile (Q3), 
and maximum values. Categorical variables will be summarized by number and percentage of 
participants. 
11.1 
Adverse Events 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date/time of the study 
injection. Per case report form instructions, a new AE record will be created with a new AE 
onset date/time for any AE that worsens. Therefore, TEAEs can simply be identified as those 
AEs with recorded onset date/time on or after the date/time of the study injection. 
The number and percentage of participants reporting TEAEs in each study treatment group will 
be tabulated by descending percentage of the total across treatment groups, by system organ 
class and preferred term, and further categorized by severity and relationship to the study 
treatment. If more than 1 TEAE is coded to the same preferred term for the same participant, the 
participant will be counted only once for that preferred term. For tables presented by severity, the 
greatest severity observed will be used. 
The number and percentage of participants who have treatment-emergent serious adverse events 
(TESAE) will be summarized by system organ class, preferred term and treatment group. A 
similar summary will be presented for subjects with TEAEs leading to discontinuation from the 
study. In addition, separate subject listings will be generated for deaths, serious adverse events 
(SAEs), and TEAEs leading to study discontinuation. 
Cardiovascular events of interest in this study are: heart failure or congestive heart failure, stroke 
or transient ischemic attack, myocardial infarction, renal failure, respiratory failure, ventricular 
arrhythmias, and supraventricular arrhythmias. The number and percentage of participants who 
have treatment-emergent cardiovascular event of interest will be presented by treatment group. 
The list of preferred terms within each of the cardiovascular events of interest is provided below: 


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Table 11–1 
Cardiovascular Adverse Events of Interest 
Heart failure or Congestive heart failure 
Cardiac failure 
Cardiac failure acute 
Cardiac failure chronic 
Cardiac failure congestive 
Cardiac failure high output 
Cardiopulmonary failure 
Acute left ventricular failure 
Acute right ventricular failure 
Chronic left ventricular failure 
Chronic right ventricular failure 
Left ventricular failure 
Right ventricular failure 
Ventricular failure 
Cardiogenic shock 
Acute pulmonary oedema 
Pulmonary oedema 
Cor pulmonale 
Cor pulmonale acute 
Cor pulmonale chronic 
Low cardiac output syndrome 
Stroke or Transient ischemic attack 
Cerebrovascular accident 
Cerebral infarction 
Embolic cerebral infarction 
Thrombotic cerebral infarction 
Cerebellar infarction 
Haemorrhagic infarction 
Haemorrhagic cerebral infarction 
Ischaemic cerebral infarction 
Infarction 
Lacunar infarction 
Basal ganglia infarction  
Basal ganglia stroke 
Brain stem infarction  
Brain stem stroke 
Cerebellar stroke 
Embolic stroke 
Haemorrhagic stroke 
Haemorrhagic transformation stroke 
Ischaemic stroke 
Lacunar stroke 
Cerebral septic infarct 
Thalamic infarction 
Post procedural stroke 
Pseudostroke 
Stroke in evolution 
Thrombotic stroke 
Vertebrobasilar stroke 
Basilar artery thrombosis 
Brain stem embolism 
Brain stem thrombosis 
Cavernous sinus thrombosis 
Cerebellar artery thrombosis 
Cerebellar embolism 
Cerebral artery embolism 
Cerebral artery thrombosis 
Cerebral gas embolism 
Cerebral microembolism 
Cerebral thrombosis 
Cerebral venous thrombosis 
Intracranial venous sinus thrombosis 
Precerebral artery thrombosis 
Superior sagittal sinus thrombosis 
Transverse sinus thrombosis 
Vertebral artery thrombosis 
Basal ganglia haemorrhage 
Brain stem haemorrhage 
Brain stem microhaemorrhage 
Central nervous system haemorrhage 
Cerebellar haemorrhage 
Cerebellar microhaemorrhage 
Cerebral arteriovenous malformation   
haemorrhagic 
Cerebral cyst haemorrhage 
Cerebral haemorrhage 
Cerebral microhaemorrhage 
Epidural haemorrhage 
Extra-axial haemorrhage 
Haemorrhage intracranial 
Intracranial tumour haemorrhage 
Intraventricular haemorrhage 
Meningorrhagia 
Pituitary haemorrhage 
Subarachnoid haemorrhage 
Subdural haemorrhage 
Thalamus haemorrhage 
Traumatic intracranial haemorrhage 
Transient ischaemic attack 
Brain stem ischaemia 
Cerebral ischaemia 
Cerebellar ischaemia 
Cerebral small vessel ischaemic 
 
disease 
Reversible ischaemic neurological 
 
deficit 
Delayed ischaemic neurological 
 
deficit 
Myocardial infarction 
Acute myocardial infarction 
ECG signs of myocardial infarction 
Myocardial infarction 
Periprocedural myocardial infarction 
Post procedural myocardial 
 
infarction 
Silent myocardial infarction 
Papillary muscle infarction 
Myocardial necrosis 
Myocardial ischaemia 
Subendocardial ischaemia 
Renal failure 
Renal failure 
Postrenal failure 
Acute kidney injury 


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To assess possible distant spread of toxin (PDSOT), 40 MedDRA preferred terms that may be 
associated with botulinum toxin effects have been identified. All TEAEs associated with PDSOT 
will be tabulated by SOC, preferred term and treatment group; in addition, all PDSOT TEAEs 
will be listed by subject. The 40 terms are listed below. 
Hepatorenal failure 
Postoperative renal failure 
Prerenal failure   
Chronic kidney disease 
Ventricular arrhythmias 
Ventricular arrhythmia 
Ventricular tachyarrhythmia 
Arrhythmia 
Accelerated idioventricular rhythm 
Cardiac fibrillation 
Cardiac flutter 
Extrasystoles 
Parasystole 
Rhythm idioventricular 
Tachyarrhythmia 
Torsade de pointes 
Ventricular extrasystoles 
Ventricular fibrillation 
Ventricular flutter 
Ventricular parasystole 
Ventricular pre-excitation 
Ventricular tachycardia 
Anomalous atrioventricular 
 
excitation 
Ventricular asystole 
Supraventricular arrhythmias 
Arrhythmia supraventricular 
Atrial fibrillation 
Atrial flutter 
Atrial parasystole 
Atrial tachycardia 
Junctional ectopic tachycardia 
Sinus tachycardia 
Supraventricular extrasystoles 
Supraventricular tachyarrhythmia 
Supraventricular tachycardia 
Paroxysmal arrhythmia 
Bradyarrhythmia 
Nodal arrhythmia 
Nodal rhythm 
Sinus arrest 
Sinus arrhythmia 
Sinus bradycardia 
Sinus node dysfunction 


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MedDRA Preferred Terms Evaluated for Possible Distant Spread of Toxin 
 
Cardiac Disorders 
          Bradycardia  
 
Eye Disorders 
          Accommodation disorder  
          Diplopia 
          Opthalmoplegia 
          Eyelid function disorder 
          Eyelid ptosis 
          Pupillary reflex impaired 
          Vision blurred 
 
Gastrointestinal Disorders 
          Constipation 
          Dry mouth  
          Dysphagia 
          Ileus paralytic 
 
Infections and Infestations 
          Botulism 
 
Musculoskeletal and Connective Tissue 
Disorders           
          Muscular weakness 
Nervous System Disorders 
          Bell’s palsy 
          Bulbar palsy  
          Cranial nerve palsies multiple 
          Cranial nerve paralysis 
          Dysarthria 
          Facial paralysis 
          Facial paresis 
          Hyporeflexia 
          Hypotonia     
          Paralysis 
          Paresis cranial nerve 
          Peripheral nerve palsy 
          Peripheral paralysis 
          Speech disorder 
          Vocal cord paralysis 
          Vocal cord paresis 
 
Renal and Urinary Disorders 
          Urinary retention   
 
Respiratory, Thoracic and Mediastinal Disorders 
          Aspiration  
          Diaphragmatic paralysis 
          Dysphonia 
          Dyspnoea 
          Pneumonia aspiration 
          Respiratory arrest 
          Respiratory depression 
          Respiratory failure 
 
Reproductive System and Breast Disorders 
          Pelvic floor muscle weakness 
 
11.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each assessment time point will be presented by visit and treatment group for all 
continuous laboratory parameters. Categorical laboratory parameters will be presented in listings. 
The laboratory parameters are: 
Hematology: 
Basophils absolute cell count, eosinophils absolute cell count, hematocrit, 
hemoglobin, lymphocytes absolute cell count, monocytes absolute cell count, 
neutrophil absolute cell count, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume 
(MCV), platelet count, percentage reticulocytes, red blood cell (RBC) count, 
and white blood cell (WBC) count. 


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Chemistry: 
Albumin, alanine aminotransferase (ALT), alkaline phosphatase, aspartate 
aminotransferase (AST), direct bilirubin, indirect bilirubin, total bilirubin, 
blood urea nitrogen (BUN), calcium, chloride, total cholesterol, creatinine, 
estimated glomerular filtration rate (eGFR), glucose non-fasting, triglycerides, 
HDL, LDL, Hemoglobin A1c, potassium, total protein, and sodium. 
Urinalysis: 
Bilirubin, blood, glucose, ketones, leukocyte esterase, nitrite, pH, protein, 
specific gravity, urobilinogen, and microscopic examination (if blood or 
protein is abnormal) 
Coagulation: 
Prothrombin time (PT), activated partial thromboplastin time (aPTT), and 
thrombin time (TT). 
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 11–2. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by treatment group at each assessment. The percentages will be calculated relative to the number 
of participants with available non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator will be the total number of participants with available non-PCS baseline values 
and at least 1 PCS postbaseline value. A supportive listing of participants with PCS postbaseline 
values will be provided, including the PID number, baseline and all postbaseline (including non-
PCS) values. 
Shift tables from baseline to each post-baseline visit for clinical laboratory parameters will be 
presented by treatment group for the following categories: low, normal, and high, which are 
provided by lab vendor. 


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Table 11–2 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Alanine aminotransferase 
U/L 
— 
≥ 3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥ 3 × ULN 
Aspartate aminotransferase 
U/L 
— 
≥ 3 × ULN 
Bilirubin, total 
μmol/L 
— 
> 1.5 × ULN 
Calcium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Cholesterol 
mmol/L 
— 
> 1.3 × ULN 
Creatinine 
μmol/L 
— 
> 1.3 × ULN 
Glucose, fasting 
mmol/L 
< 0.8 × LLN 
> 1.2 × ULN 
Glucose, nonfasting 
mmol/L 
< 0.8 × LLN 
> 1.4 × ULN 
Potassium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Protein, total  
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Sodium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Triglycerides 
mmol/L 
— 
> 2 × ULN 
Urea nitrogen 
mmol/L 
— 
> 1.2 × ULN 
Uric acid  
μmol/L 
— 
> 1.2 × ULN 
HEMATOLOGY 
Basophils, absolute cell count 
109/L 
— 
> 3 × ULN 
Neutrophils, absolute cell 
count 
109/L 
< 0.8 × LLN 
> 1.5 × ULN 
Hematocrit 
Ratio 
< 0.9 × LLN 
> 1.1 × ULN 
Hemoglobin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Platelet count 
109/L 
≤ 0.5 × LLN 
≥ 1.5 × ULN 
Red blood cell count 
1012/L 
< 0.9 × LLN 
> 1.1 × ULN 
White blood cell count 
109/L 
≤ 0.7 × LLN 
≥ 1.5 × ULN 
URINALYSIS 
pH 
— 
< 0.9 × LLN 
> 1.1 × ULN 
Specific gravity 
— 
— 
> 1.1 × ULN 
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités (International System of 
Units); ULN = upper limit of normal value provided by the laboratory. 
 


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11.3 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, pulse rate, respiration 
rate, temperature, body weight, abdominal circumference, and body mass index) and changes 
from baseline values at each visit will be presented by treatment group. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 11–3. The number and percentage of participants 
with PCS postbaseline values will be tabulated by treatment group. The percentages will be 
calculated relative to the number of participants with available baseline values and at least 1 
postbaseline assessment. The numerator will be the total number of patients with available 
baseline values and at least 1 PCS postbaseline value. A supportive listing of participants with 
PCS postbaseline values will be provided, including the PID number, baseline and all 
postbaseline (including non-PCS) values. 
Table 11–3 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Sitting systolic blood 
pressure, mm Hg 
High 
≥ 160 
Increase of ≥ 20 
Low 
≤ 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
≥ 105 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
≥ 110 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Weight, kg 
High 
— 
Increase of ≥ 7% 
Low 
— 
Decrease of ≥ 7% 
a 
A postbaseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria. 
bpm = beats per minute. 
 
11.4 
Electrocardiogram 
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTc) and changes from baseline values at each assessment time point to the end of 
study will be presented by treatment group. The QTc will be calculated using both the Bazett and 
Fridericia corrections (if the vendor does not provide). 
Electrocardiographic parameter values are considered PCS if they meet or exceed the higher-
limit PCS criteria listed in Table 11–4. The number and percentage of participants with PCS 
postbaseline ECG values will be tabulated by treatment group. The percentages will be 


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calculated relative to the number of participants with available baseline values and at least 1 
postbaseline assessment. The numerator is the total number of participants with available 
baseline values and at least 1 PCS postbaseline value. A supportive listing of participants with 
PCS postbaseline values will be provided, including the PID number, baseline, all postbaseline 
(including non-PCS) values, and change from baseline. 
Table 11–4 
Criteria for Potentially Clinically Significant Electrocardiograms 
Parameter 
Unit 
Higher Limit 
QRS interval 
msec 
≥ 120 
QRS interval 
msec 
>120 and increase from baseline > 25% 
PR interval 
msec 
≥ 230 
PR interval 
msec 
>230 and increase from baseline > 25% 
QTc  
msec 
>480 or increase from baseline > 60 
QTc  
msec 
increase from baseline > 30 
QTc = QT interval corrected for heart rate. 
 
11.5 
Other Safety Parameters 
11.5.1 
Immunogenicity Assessments 
Blood samples will be collected from all participants prior to dosing on day 1 and at the day 30 
and day 90 follow-up visits. A 2-tier assay approach will be used for the detection of binding and 
neutralizing antibodies to AGN-151607 in human serum. 
Immunogenicity findings (positive) will be tabulated with the number and percentage of 
participants at each visit separately for each AGN-151607 treatment group. Percentages will be 
based on the number of treated participants with interpretable antibody assays in each treatment 
group at the specified visit. A cumulative summary based on positive findings at any visit will be 
done for each AGN-151607 treatment group. 
11.5.2 
Pulmonary Function Test (PFT) 
Study participant pulmonary function will be assessed at the screening and day 30 visits using 
forced procedures and compared across all 3 study groups. To demonstrate reproducibility of 
results, participants will be required to perform at least 3 acceptable spirometry maneuvers up to 
a maximum of 8 attempts. The results of all respiratory measures will be reviewed for clinically 
significant findings. 


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The assessments will include the following: 
1. Forced vital capacity (FVC) measured from a maximal forced exhalation 
2. Forced expiratory volume (FEV) in 1 second (FEV1), 3 seconds (FEV3) and 6 seconds 
(FEV6) 
3. FEV1/FVC ratio 
The average and the maximum of the measurements recorded on the eCRF for each of the PFT 
parameters (FVC, FEV1, FEV3, FEV6, and FEV1/FVC ratio) at each visit will each be used in 
the data analysis. Descriptive statistics for each PFT parameter and changes from baseline values 
at each assessment time point will be presented by treatment group. 
11.5.3 
Time to Extubation 
Descriptive statistics for time to extubation will be presented by treatment group. Time to 
extubation is defined as the time (hours) from the date/time of intubation to the date/time of 
extubation. 
11.5.4 
Physical Examination 
Physical examination will be performed at screening, Day 30, Day 360 and at early 
discontinuation visits. All findings at the screening visit will be recorded on the medical history 
eCRF page. Any new or worsening condition observed after study injection will be recorded on 
the adverse event eCRF page. Hence summaries for physical examinations will be captured in 
summaries presented for medical history and adverse events. 
12.0 
Interim Analysis 
An interim analysis of all efficacy data will be performed when all randomized participants have 
completed the Day 60 visit or exited the study earlier. The purpose of this analysis is to identify 
early trends in the data for administrative planning of following studies. There is no plan to stop 
the study or drop a treatment arm based on the results from the interim analysis.  The interim 
analysis will serve as the primary analysis for the study. 
Specifications of tables, figures, and data listings to be generated during the interim analysis are 
provided in a separate document. On completion of the database lock for the interim/primary 
analysis, the study will be unblinded to AbbVie study personnel. However, investigators and 
study sites personnel will remain blinded until completion of the final analysis. The final analysis 
will occur when all participants have completed the long-term safety follow-up or have exited 
the study earlier. 


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An independent data safety monitoring board (DSMB) will hold meetings after 5%, 25%, 50% 
and 75% of the total planned study population has completed Day 14 to evaluate partially 
blinded safety data for possible harmful effects of AGN-151607. More details regarding the 
policies, procedures, and composition of the DSMB, including precautions that will be employed 
to assure that inadvertent unblinding of parties does not occur; are described in the DSMB 
charter for this study. In addition, a separate SAP will be finalized before the first DSMB 
meeting. 
13.0 
Determination of Sample Size 
A sample size of 100 randomized participants per treatment group will provide approximately 
80% power to detect the treatment difference between each of the AGN-151607 doses (assumed 
equally effective) and placebo for the primary efficacy endpoint. The power calculations are 
based on the following assumptions: 
• The expected incidence of early postoperative AF within 30 days post-surgery will be 
47.8% in the placebo group and 27.8% in each of the AGN-151607 groups. This 
assumption is based on the results observed in the Pokushalov study (Pokushalov 2015) 
and the Duke University Medical Center clinical trial (Waldron et. al., 2019). 
• Two-sided Mantel-Haenszel test statistic and a significance level of 0.05 for the test. 
Calculations were performed using commercial software PASS 2008 (Hintze 2008). Assuming 
that approximately 10% in each intervention group will drop out early from the study, a total of 
approximately 330 participants will be randomly assigned to study intervention, in order to have 
approximately 300 participants complete all the efficacy assessments up to Day 60 visit.  
14.0 
Statistical Software 
Statistical analyses will be performed using version 9.2 (or newer) of SAS on a Linux operating 
system. 
15.0 
Data Handling Conventions 
15.1 
Visit Time Windows 
Table 15–1 presents the visits assigned for safety analyses and the corresponding range of 
treatment days (window) during which an actual visit may occur.  Unless otherwise specified, 
efficacy parameters collected by visit (e.g., Quality of Life Outcomes) will use the same 
windows during which an actual visit may occur.  All analyzable ePatch data collected from 
ePatches with a start date within the visit window will be included in the analysis for the derived 
visit for Days 60, 90, 180, 270, and 360. 


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Table 15–1 
Analysis Visit Windows 
Scheduled Visit 
Study Daya 
Time Window (Study Day Range) 
Baseline 
1 
1 
Day 2 
2 
2 
Day 3 
3 
3 
Day 4 
4 
4 
Day 5 
5 
5 
Day 6 
6 
[6, 10] 
Day 14 
14 
[11, 21] 
Day 30 
30 
[22, 45] 
Day 60 
60 
[46, 75] 
Day 90 
90 
[76, 135] 
Day 180 
180 
[136, 225] 
Day 270 
270 
[226, 315] 
Day 360 
360 
> 315 days 
a 
Relative to the date of the study treatment. Day 1 = the date of the study treatment. 
 
If the assessment date (if the assessment date is unavailable, use visit date instead) is on or after 
the date of the study treatment, the study day is calculated by assessment date – date of the study 
treatment + 1. If the assessment date is before the date of the study treatment, the study day is 
calculated by assessment date – date of the study treatment. Therefore, a negative day indicates a 
day before the start of the study treatment. 
If a subject has 2 or more visits within the same window, the last visit with a non-missing value 
will be used for analysis. All postbaseline assessments will be considered for PCS categorization. 
All assessments will be included in respective listings. 
15.2 
Repeated or Unscheduled Assessments of Safety Parameters 
If a patient has repeated assessments before the start of the study treatment, the results from the 
last non-missing assessment made prior to the start of the study treatment will be used as 
baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last non-
missing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics. However, all postbaseline assessments will be used for PCS value 
determinations, and all assessments will be presented in the data listings. 


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15.3 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the study treatment, an intensity of 
mild will be assigned. If severity is missing for an AE that started on or after the date of the 
study treatment, an intensity of severe will be assigned. The imputed values for severity 
assessment will be used for the incidence summary; the values will be shown as missing in the 
data listings. 
15.4 
Missing Causal Relationship to Study Drug for Adverse Events 
If the causal relationship to the study treatment is missing for an AE that started on or after the 
date of the study treatment, a causality of yes will be assigned. The imputed values for causal 
relationship to study treatment will be used for the incidence summary; the values will be shown 
as missing in the data listings. 
15.5 
Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(i.e., partly missing). 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the study treatment, the 
month and day of the study treatment will be assigned to the missing fields 
• If the year of the incomplete start date is before the year of the study treatment, 
December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the study treatment, January 1 
will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the study treatment, the day of the study treatment will be assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the study 
treatment or if both years are the same, but the month of the incomplete start date is 
before the month of the date of the study treatment, the last day of the month will be 
assigned to the missing day 


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• If either the year of the incomplete start date is after the year of the date of the study 
treatment or if both years are the same, but the month of the incomplete start date is after 
the month of the date of the study treatment, the first day of the month will be assigned to 
the missing day 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date: 
• If the stop date is after the date of the study treatment, the date of the study treatment will 
be assigned to the missing start date 
• If the stop date is before the date of the study treatment, the stop date will be assigned to 
the missing start date 
15.6 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (i.e., partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a patient, the start date will be imputed first. 
15.6.1 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date. 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the study treatment, the 
month and day of the study treatment will be assigned to the missing fields 
• If the year of the incomplete start date is before the year of the study treatment, 
December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the study treatment, January 1 
will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure 


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Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the study treatment, the day of the study treatment will be assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the study 
treatment or if both years are the same, but the month of the incomplete start date is 
before the month of the date of the study treatment, the last day of the month will be 
assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the study 
treatment or if both years are the same, but the month of the incomplete start date is after 
the month of the date of the study treatment, the first day of the month will be assigned to 
the missing day 
15.6.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the study exit is missing, the last available 
study visit date will be used as the study exit date. 
Missing month and day 
• If the year of the incomplete stop date is the same as the year of the study exit, the month 
and day of the study exit will be assigned to the missing fields 
• If the year of the incomplete stop date is before the year of the study exit, December 31 
will be assigned to the missing fields 
• If the year of the incomplete stop date is after the year of the study exit, January 1 will be 
assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the study exit, the day of the study exit will be assigned to the missing day 
• If either the year of the incomplete stop date is before the year of the date of the study 
exit or if both years are the same, but the month of the incomplete stop date is before the 
month of the date of the study exit, the last day of the month will be assigned to the 
missing day 


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• If either the year of the incomplete stop date is after the year of the date of the study exit 
or if both years are the same, but the month of the incomplete stop date is after the month 
of the date of the study exit, the first day of the month will be assigned to the missing day 
15.7 
Character Values of Clinical Laboratory Parameters 
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, a 
coded value must be appropriately determined for use in the statistical analyses. The actual 
values, however, as reported in the database will be presented in the data listings. 
Table 15–2 shows examples of how some possible laboratory results should be coded for the 
analysis. 
Table 15–2 
Examples of Coding Special Character Values for Clinical Laboratory Parameters 
Laboratory Test, SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
CHEMISTRY 
ALT, U/L 
< 5 
5 
AST, U/L 
< 5 
5 
Bilirubin, total, μmol/L 
< 2 
2 
URINALYSIS 
Glucose, mmol/L 
= OR > 55, ≥ 55, > 0 
Positive 
≤ 0, negative 
Negative 
pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5 
8.5 
Protein 
= OR > 3.0, ≥ 3.0, > 0 
Positive 
≤ 0 
Negative 
 
15.8 
Datetimes for ePatch Analyses 
For analyses of time to first occurrence of AF, datetimes from the internal clock on the ePatch 
device will be used to determine the onset of event occurrence. During study conduct, it was 
discovered that some ePatches experienced an internal clock reset prior to collecting data, such 
that the internal clock was reset to a much earlier calendar date (e.g., a date in the year 1999 or 
2000).  But, the measurements of sequential time relative to the reset calendar datetime was 
determined to be accurate. 
To correct for this clock reset issue and still utilize all collected data, the recording start time of 
each ePatch was compared to the application time reported by the site on the eCRF.  For each 


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ePatch such that the application time reported on the eCRF – ePatch-reported recording start time 
> 30 days, the following adjustment was made to all times on that ePatch prior to analysis: 
adjusted time = ePatch-reported time + offset 
 
where ‘offset’ was calculated as: eCRF application time – ePatch-reported recording start time. 
In other words, when the ePatch-reported recording start time was more than 30 days earlier than 
the application time reported on the eCRF, all times on the ePatch were adjusted by the 
difference between the application time reported on the eCRF and the ePatch-reported recording 
start time.  No adjustments were made to ePatch-reported times when the application time 
reported on the eCRF – ePatch-recording start time ≤ 30 days. 
 
16.0 
Changes to Analyses Specified in Protocol 
The following changes were made to analyses specified in the protocol: 
• Logistic regression models adjusting for baseline risk factors of POAF (type of surgery, 
and age group) will not be performed for the primary endpoints of the proportion of 
participants with at least one continuous AF Episode during the first 30 days post-
surgery.  
o Rationale: adjusted odds ratios, stratified by type of surgery (presence or absence 
of valve surgery) and age group (< 65 or ≥ 65 years), with associated 95% CIs 
and P-values, are already presented using the CMH test. 
• In lieu of t-tests, ANOVA models will be used to analyze hospital and ICU length of stay.  
Stratified Wilcoxon (Van Elteren) tests will be used for supplementary analyses for these 
variables, regardless of skewedness. 
o Rationale: ANOVA models are commonly used for stratified analyses of 
continuous outcomes.  The stratified Wilcoxon (Van Elteren) test may provide 
value as a supplementary analysis even if the distribution is not skewed. 
• Percentage of participants with at least 1 continuous AF episode ≥ 6 minutes during the 
first 30 days post-surgery was added as a secondary efficacy variable based on input from 
cardiology experts. 
17.0 
Version History 
DOCUMENT HISTORY 
 
Document 
Date 
Original Final Analysis Plan 
26 Apr 2021 
Amendment 1 
19 Nov 2021 
Amendment 2 
31 May 2022 
Table 17–1 
Final Analysis Plan Version History Summary 
Amendment 
Date 
Summary 
 
26 Apr 2021 
Original version 
1 
19 Nov 2021 
• 
Added supplementary analyses using Supplementary ePatch Analysis Sets, 
described in Sections 6.3, Section 10.1 and Section 10.2; 


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Amendment 
Date 
Summary 
• 
Added list of antiarrythmics and concurrent procedures due to atrial 
fibrillation or atrial flutter to Section 8.0; 
• 
Edited so that mis-stratified participants, if any, will be analyzed based on 
the correct stratification group in Section 10.0; 
• 
Added percentage of patients at least 1 continuous AF episode ≥ 6 minutes 
during the first 30 days post-surgery as a secondary efficacy variable in 
Section 10.0 and Section 10.2; 
• 
Clarified definition of “symptomatic AF” in Section 10.2; 
• 
Added Cox proportional hazards models as additional analyses for time-to-
event endpoints in Section 10.2; 
• 
Added imputation rules for missing ICU admission date/times in Section 
10.3; 
• 
Added stratified Wilcoxon (Van Elteren) tests for length of stay endpoints 
in Section 10.3; 
• 
Added hospital length of stay measured from the time of initial hospital 
admission to discharge as an endpoint in Section 10.3; 
• 
Added clarification for Poisson regression model and an additional 
analysis using total analyzed time in the model in Section 10.3; 
• 
Added components to the composite endpoint, specified binary and time-
to-event versions, and clarified definitions of terms for the Win Ratio 
analysis in Section 10.3; 
• 
Added changes to analyses specified in protocol in Section 16.0. 
2 
31 May 2022 
• 
Added supplementary analyses using Beta Blocking Agent Withdrawn 
ePatch Analysis Set, described in Sections 6.4 and Section 10.1; 
• 
Clarified that calculation of time spent in AF (AF burden) will exclude 
continuous AF episodes < 30 seconds in duration in Section 10.2; 
• 
Added restricted mean survival time (RMST) to time-to-event analyses 
described in Section 10.2; 
• 
Added negative binomial, zero-inflated negative binomial and zero-inflated 
Poisson models to analysis of number of AF events in Section 10.3; 
• 
Added ‘Percentage of participants free from AF through 12 months post-
surgery and not taking any anticoagulant drugs’ as Additional Efficacy 
variable in Section 10.3; 
• 
Updated that TEAEs would be sorted based on descending frequency of 
total percentage across treatment groups and not just descending frequency 
in the AGN-151607 250 U arm; 
• 
Added FEV1/FVC ratio and maximum of measurements to analysis of PFT 
parameters in Section 11.5.2 to reflect parameters analyzed in other studies 
of botulinum toxins; 
• 
Removed cardiac pacemaker insertion from list of procedures of interest 
due to atrial fibrillation or atrial flutter in Section 8.0 (at time of SAP 
amendment, no such procedures were marked as due to atrial fibrillation or 
atrial flutter); 
• 
Added description of datetime adjustment for ePatch analyses to correct for 
instances of internal clock resets as Section 15.8. 


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18.0 
References 
Pokushalov E, Kozlov B, Romanov A, Strelnikov A, Bayramova S, Sergeevichev D, et al. 
Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads 
in patients undergoing cardiac surgery: one-year follow-up of a randomized pilot study. Circ 
Arrhythm Electrophysiol. 2015;8:1334-1341. 
Waldron NH, Cooter M, Haney JC, Schroder JN, Gaca JG, Lin SS, Sigurdsson MI, Fudim M, 
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