Clinical trial NCT05643573
Conditions: Prevention of Stroke or Systemic Embolism Atrial Fibrillation
Sponsor: Bayer
Start date: 2022-12-05; Completion date: 2024-01-31
Enrollment: 14830 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Researchers are looking for a better way to treat people with atrial fibrillation (AF) and prevent stroke or systemic embolism (blood clots travelling through the blood stream to plug another vessel).

Atrial fibrillation is a condition of having irregular and often rapid heartbeat. It can lead to the formation of blood clots in the heart which can travel through the blood stream to plug another vessel, and like this lead to serious and life-threatening conditions, such as a stroke. A stroke occurs because the brain tissue beyond the blockage no longer receives nutrients and oxygen so that brain cells die. As strokes arising from atrial fibrillation can involve extensive areas of the brain, it is important to prevent them.

Blood clots are formed in a process known as coagulation. Medications are already available to prevent the formation of blood clots. When taken by mouth (orally), they are known as oral anticoagulants (OACs) including apixaban. OACs decrease the risk of the above-mentioned serious and life-threatening conditions. The main side effect of OACs is an increase of the risk of bleeding.

The study treatment asundexian is a new type of anticoagulant currently under development to provide further treatment options. Asundexian aims to further improve the standard of care with regard to the risk of bleeding.

The main purpose of this study is to collect more data about how well asundexian works to prevent stroke and systemic embolism and how safe it is compared to apixaban in people with atrial fibrillation and at high risk for stroke.

To see how well the study treatment asundexian works researchers compare:

* how long asundexian works well and
* how long apixaban works well after the start of the treatment. Working well means that the treatments can prevent the following from happening:
* stroke and/or
* systemic embolism. The study will keep collecting data until a certain number of strokes or embolisms happen in the study.

To see how safe asundexian is, the researchers will compare how often major bleedings occur after taking the study treatments asundexian and apixaban, respectively. Major bleedings are bleedings that have a serious or even life-threatening impact on a person's health.

The study participants will be randomly (by chance) assigned to 1 of 2 treatment groups, A and B. Dependent on the treatment group, the participants will either take the study treatment asundexian by mouth once a day or apixaban by mouth twice a day for approximately 9 - 33 months.

Each participant will be in the study for approximately 9 - 34 months. There will be visits to the study site every 3 to 6 months and up to 7 phone calls. Those participants who do not want or are unable to have visits to the study site may join the study remotely in selected locations. The location name contains the abbreviation - DCT in such cases.

During the study, the study team will:

* take blood samples
* do physical examinations
* examine heart health using an electrocardiogram (ECG)
* check vital signs such as blood pressure and heart rate
* do pregnancy tests
* ask the participants questions about their quality of life
* ask the participants questions about how they are feeling and what adverse events they are having.

An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.

Detailed description:

Arms: arm 1: Participants will receive asundexian and apixaban matching placebo. arm 2: Participants will receive apixaban and asundexian matching placebo.
Interventions: intervention 1: Asundexian (BAY2433334) intervention 2: Apixaban intervention 3: Asundexian matching placebo intervention 4: Apixaban matching placebo
Intervention descriptions: intervention 1: Once a day intervention 2: 5 mg or 2.5 mg, twice a day, according to product label. intervention 3: Placebo to asundexian, once a day intervention 4: Placebo to apixaban, twice a day

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A multicenter, international, randomized, active comparator-
controlled, double-blind, double-dummy, parallel group, 2-arm 
Phase 3 study to compare the efficacy and safety of the oral FXIa 
inhibitor asundexian (BAY 2433334) with apixaban for the 
prevention of stroke or systemic embolism in male and female 
participants aged 18 years and older with atrial fibrillation at risk 
for stroke 
NCT Number: 
NCT05643573 
Document Date: 
06-Jan-2023 
 


C O N FI D E N TI A L
L ocal Pr ot oc ol A me n d me nt ( Re p u blic of K orea )
N o. B A Y 2 4 3 3 3 3 4 (as u n de xia n) / 1 9 7 6 7
0 6 J A N 2 0 2 3
K O R - 1
Pa ge:  1 of 1 3 7
Title P a ge
Pr ot oc ol Title: 
A m ultice nter, i nter nati o nal, ra n d o mize d, acti ve c o m parat or -c o ntr olle d, d o u ble -bli n d, d o u ble -
d u m m y , parallel-gr o u p , 2-ar m, P hase 3 st u d y t o c o m pare t he efficac y a n d safet y of t he oral 
F XIa i n hi bit or as u n de xia n ( B A Y 2 4 3 3 3 3 4) wit h a pi xa ba n f or t he pre ve nti o n of str o ke or 
s yste mic e m b olis m i n male a n d fe male partici pa nts a ge d 1 8 years a n d ol der wit h atrial 
fi brillati o n at ris k f or str o ke
Pr ot oc ol N u m ber:
1 9 7 6 7
Pr ot oc ol Versi o n:
K O R - 1
A m e n d me nt N u m ber:
K O R - 1
C o m p o u n d N u m ber:
As u n de xia n ( B A Y 2 4 3 3 3 3 4)
S h ort Title:
P hase 3 st u d y to i n vesti gate t he efficac y an d safet y of t he oral fact or XIa ( F XIa) i n hi bit or 
as u n de xia n ( B A Y 2 4 3 3 3 3 4) c o m pare d wit h a pi xa ba n i n partici pa nts wit h atrial fi brillati o n at 
ris k f or str o ke
St u d y P h ase: P hase 3
Acr o n y m:
O C E A NI C -A F ( P hase 3 pr o gra m of t he O ral faC t or E le ve n A iN hi bit or 
as u n de x Ia n as n o vel a ntit hr o m b oti C - A trial F i brillati o n st u d y)
S p o ns or N a m e: Ba ye r A G
Le g al Re gistere d A d dress:
N o n -U S: Ba y er A G, 5 1 3 6 8 Le ver k use n, Ger ma n y 
U S territ or y : Ba yer Healt h Care P har mace uticals I nc., 1 0 0 Ba yer B o ule var d, P. O. B o x 9 1 5, 
W hi p pa n y  NJ 0 7 9 8 1-0 9 1 5, U S A
Re g ul at or y A ge nc y I de ntifier N u m ber(s):
Re gistr y I D
I ND: 1 4 1 8 0 5
E u dra C T: 2 0 2 2- 0 0 0 7 5 8- 2 8
Pr ot oc ol D ate: 
0 6 J A N 2 0 2 3
Na me:
 M D, M H B A
R ole:
T his is a n electr o nicall y  ge nerate d d oc u me nt t hat d oes n ot bear a n y s p o ns or si g nat ures. T he 
si g nat ure of t he s p o ns or’s me dicall y  res p o nsi ble pers o n is file d i n t he T M F a n d a vaila ble o n 
re q uest.
Me dic al M o nit or n a me a n d c o nt act i nf or m ati o n c a n be f o u n d i n t he Tri al M aster File.
P P D
P P D


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Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.


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Document History Table
DOCUMENT HISTORY
Document
Version 
Date
Comments (if applicable)
KOR-1
KOR-1
06 JAN 2023
Updated to fully reflect the 
changes specific to the 
Republic of Korea (KOR-1)
KOR-1
KOR-1
19 DEC 2022
Prepared to include changes 
specific to the Republic of 
Korea. It was submitted but 
updated prior to approval
Clinical Study Protocol
1.0
01 SEP 2022
-


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Protocol Amendment Summary of Changes Table
KOR-1 (06 JAN 2023)
This amendment is prepared to include country specific changes of the original protocol dated
01 SEP 2022, to meet local requirements valid for the Republic of Korea only. A description 
of the country-specific changes and a brief rationale is outlined in the Appendix 
Country/region-Specific Requirements.
Overall Rationale for the Amendment:
Section # 
and Name
Description of Change
Brief Rationale
Appendix 10.12
Country/region-specific 
Requirements
Republic of Korea-specific 
modification listed in 
Section 10.12.3.1
To follow the request from Ministry of 
Food and Drug Safety (MFDS)


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Table of Contents
Title Page................................................................................................................................... 1
Document History Table.......................................................................................................... 3
Protocol Amendment Summary of Changes Table............................................................... 4
Table of Contents ..................................................................................................................... 5
Table of Tables ......................................................................................................................... 8
Table of Figures........................................................................................................................ 9
List of Abbreviations and Definitions of Terms.................................................................. 10
1.
Protocol Summary .......................................................................................................... 17
1.1
Synopsis......................................................................................................................... 17
1.2
Schema........................................................................................................................... 22
1.3
Schedule of Activities (SoA) ......................................................................................... 23
2.
Introduction..................................................................................................................... 25
2.1
Study Rationale.............................................................................................................. 26
2.2
Background.................................................................................................................... 26
2.2.1
Disease Background ................................................................................................... 26
2.2.2
Treatment Guidelines ................................................................................................. 27
2.2.3
FXIa Inhibition: Mode of Action................................................................................ 27
2.2.4
Asundexian (BAY 2433334)...................................................................................... 28
2.3
Benefit/Risk Assessment ............................................................................................... 29
2.3.1
Risk Assessment......................................................................................................... 29
2.3.2
Benefit Assessment .................................................................................................... 32
2.3.3
Overall Benefit/Risk Conclusion................................................................................ 34
3.
Objectives, Endpoints, and Estimands.......................................................................... 35
4.
Study Design .................................................................................................................... 41
4.1
Overall Design ............................................................................................................... 41
4.1.1
Decentralized Clinical Trial Model............................................................................ 43
4.2
Scientific Rationale for Study Design ........................................................................... 44
4.2.1
Patient Input into Design............................................................................................ 44
4.3
Justification for Dose..................................................................................................... 45
4.4
End of Study Definition................................................................................................. 45
5.
Study Population............................................................................................................. 45
5.1
Inclusion Criteria ........................................................................................................... 45
5.2
Exclusion Criteria .......................................................................................................... 47
5.3
Lifestyle Considerations ................................................................................................ 48
5.4
Screen Failures............................................................................................................... 49
5.5
Criteria for Temporarily Delaying Enrollment or Randomization................................ 49
6.
Study Intervention(s) and Concomitant Therapy........................................................ 49
6.1
Study Intervention(s) Administered............................................................................... 49
6.1.1
Switching to Study Intervention and Back to Open Label Anticoagulant ................. 51
6.1.2
Medical Devices ......................................................................................................... 52
6.2
Preparation, Handling, Storage, and Accountability ..................................................... 52
6.3
Assignment to Study Intervention ................................................................................. 53


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6.4
Blinding ......................................................................................................................... 53
6.4.1
Unblinding.................................................................................................................. 54
6.5
Study Intervention Compliance ..................................................................................... 55
6.6
Dose Modification ......................................................................................................... 55
6.7
Continued Access to Study Intervention after the End of the Study ............................. 55
6.8
Treatment of Overdose .................................................................................................. 56
6.9
Prior and Concomitant Therapy..................................................................................... 56
6.9.1
Guidance for Management of Participants who Have Bleeding During the Study.... 58
6.9.2
Guidance for Management of Participants who Have Surgery or 
Percutaneous/Endoscopic Procedures ........................................................................ 59
6.9.3
Guidance for Management of Participants who Experience Ischemic Stroke 
During the Study......................................................................................................... 60
6.9.4
Guidance for Management of Participants who Experience an Acute Coronary 
Syndrome During the Study ....................................................................................... 61
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 61
7.1
Discontinuation of Study Intervention........................................................................... 61
7.1.1
Permanent Discontinuation of Study Intervention ..................................................... 61
7.1.2
Temporary Discontinuation of Study Intervention..................................................... 63
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 64
7.3
Lost to Follow-Up.......................................................................................................... 64
8.
Study Assessments and Procedures............................................................................... 65
8.1
Administrative and Baseline Procedures ....................................................................... 66
8.2
Efficacy Assessments .................................................................................................... 66
8.2.1
Primary Efficacy Endpoint......................................................................................... 66
8.2.1.1
Stroke ...................................................................................................................... 66
8.2.1.2
Systemic Embolism................................................................................................. 67
8.2.2
Secondary Efficacy Endpoints.................................................................................... 67
8.2.2.1
Cardiovascular Death .............................................................................................. 67
8.2.2.2
Myocardial Infarction.............................................................................................. 67
8.2.3
Exploratory Efficacy Assessments............................................................................. 68
8.2.3.1
EuroQol Group 5-dimension questionnaire (EQ-5D) ............................................. 68
8.3
Safety Assessments........................................................................................................ 68
8.3.1
Primary Safety Endpoint ............................................................................................ 68
8.3.1.1
ISTH Major Bleeding.............................................................................................. 69
8.3.2
Secondary Safety Endpoints....................................................................................... 69
8.3.2.1
Clinically Relevant Non-Major Bleeding ............................................................... 69
8.3.2.2
Minor Bleeding ....................................................................................................... 70
8.3.3
Exploratory Safety Endpoints..................................................................................... 70
8.3.3.1
BARC Bleeding....................................................................................................... 70
8.3.4
Physical Examinations................................................................................................ 71
8.3.5
Vital Signs .................................................................................................................. 71
8.3.6
Electrocardiograms..................................................................................................... 72
8.3.7
Clinical Safety Laboratory Tests ................................................................................ 72
8.3.8
Pregnancy Testing ...................................................................................................... 73
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting.. 73
8.4.1
Time Period and Frequency for Collecting AE and SAE Information....................... 74
8.4.2
Method of Detecting AEs and SAEs.......................................................................... 74


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8.4.3
Follow-up of AEs and SAEs ...................................................................................... 75
8.4.4
Regulatory Reporting Requirements for SAEs .......................................................... 75
8.4.5
Pregnancy ................................................................................................................... 75
8.4.6
Disease-related Events................................................................................................ 76
8.5
Pharmacokinetics........................................................................................................... 77
8.6
Pharmacodynamics ........................................................................................................ 78
8.7
Genetics ......................................................................................................................... 79
8.8
Biomarkers..................................................................................................................... 79
8.9
Immunogenicity Assessments........................................................................................ 79
8.10
Medical Resource Utilization and Health Economics ................................................... 79
8.10.1
Healthcare Resource Utilization (HCRU).................................................................. 79
9.
Statistical Considerations ............................................................................................... 80
9.1
Statistical Hypotheses.................................................................................................... 80
9.1.1
Multiplicity Adjustment ............................................................................................. 81
9.2
Analysis Sets.................................................................................................................. 82
9.3
Statistical Analyses........................................................................................................ 82
9.3.1
General Considerations............................................................................................... 82
9.3.2
Primary Endpoint(s)/Estimand(s) Analysis................................................................ 85
9.3.2.1
Primary Efficacy Estimands.................................................................................... 85
9.3.2.2
Primary Safety Estimand......................................................................................... 86
9.3.2.3
Primary Net Clinical Benefit Estimand................................................................... 87
9.3.3
Secondary Endpoint(s)  Analysis................................................................................ 88
9.3.4
Exploratory Endpoint Analysis .................................................................................. 88
9.3.5
Other Safety Analysis................................................................................................. 88
9.3.6
Other Analysis............................................................................................................ 89
9.4
Interim Analysis............................................................................................................. 90
9.5
Sample Size Determination ........................................................................................... 91
10. Supporting Documentation and Operational Considerations .................................... 94
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 94
10.1.1
Regulatory and Ethical Considerations ...................................................................... 94
10.1.2
Financial Disclosure ................................................................................................... 94
10.1.3
Informed Consent Process.......................................................................................... 95
10.1.4
Recruiting Strategy..................................................................................................... 95
10.1.5
Data Protection ........................................................................................................... 96
10.1.6
Committees Structure ................................................................................................. 96
10.1.6.1
Program Leadership Committee (PLC)................................................................... 96
10.1.6.2
Executive Committee (EC) ..................................................................................... 96
10.1.6.3
Steering Committee (SC) ........................................................................................ 96
10.1.6.4
Independent Data Monitoring Committee (IDMC) ................................................ 97
10.1.6.5
Clinical Events Committee (CEC) .......................................................................... 97
10.1.7
Dissemination of Clinical Study Data ........................................................................ 97
10.1.8
Data Quality Assurance.............................................................................................. 98
10.1.9
Source Documents...................................................................................................... 99
10.1.10 Study and Site Start and Closure................................................................................ 99
10.1.11 Publication Policy..................................................................................................... 100
10.2
Appendix 2: Clinical Laboratory Tests........................................................................ 101
10.2.1
Liver Safety: Follow-up Assessments and Suggested Actions ................................ 102


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10.3
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................ 105
10.3.1
Definition of AE....................................................................................................... 105
10.3.2
Definition of SAE..................................................................................................... 106
10.3.3
Recording and Follow-Up of AE and/or SAE.......................................................... 107
10.3.4
Reporting of SAEs.................................................................................................... 108
10.4
Appendix 4: Contraceptive and Barrier Guidance....................................................... 110
10.4.1
Definitions ................................................................................................................ 110
10.4.2
Contraception Guidance ........................................................................................... 112
10.5
Appendix 5: Calculating the Child-Pugh Score........................................................... 113
10.6
Appendix 6: Calculating Glomerular Filtration Rate................................................... 114
10.7
Appendix 7: Calculating CHA2DS2-VASc Score........................................................ 115
10.8
Appendix 8: Modified Rankin Scale ........................................................................... 116
10.9
Appendix 9: Outcome Events: Data Collection........................................................... 117
10.10 Appendix 10: DCT Model for DCT Sites Only........................................................... 118
10.10.1 Recruitment, Onboarding, Training in DCT Model................................................. 118
10.10.2 Schedule of Activities for DCT Model (DCT SoA)................................................. 120
10.11 Appendix 11: Tokenization ......................................................................................... 122
10.12 Appendix 12: Country/region-specific Requirements ................................................. 123
10.12.1 China......................................................................................................................... 123
10.12.1.1 CHN: Country/region-specific Changes Valid for China only............................. 123
10.12.2 Japan......................................................................................................................... 127
10.12.2.1 JPN: Country/region-specific Changes Valid for Japan only ............................... 127
10.12.3 Republic of Korea..................................................................................................... 128
10.12.3.1 KOR-1: Country/region-specific Changes Valid for the Republic of Korea only 128
11. References ...................................................................................................................... 134
Table of Tables
Table 1–1: Summary of study objectives and endpoints.......................................................... 18
Table 1–2: PK, PD and Biomarker sampling........................................................................... 25
Table 2–1: Risk assessment...................................................................................................... 30
Table 3–1: Study objectives and endpoints.............................................................................. 35
Table 6–1: Study Interventions Administered ......................................................................... 51
Table 6–2: Study Arms ............................................................................................................ 51
Table 8–1: Reporting of events ................................................................................................ 77
Table 9–1: Analysis sets........................................................................................................... 82
Table 10–1: Protocol-required Safety Laboratory Tests........................................................ 101
Table 10–2: Liver Laboratory Monitoring............................................................................. 104
Table 10–3: Grading of severity of liver disease ................................................................... 113
Table 10–4: Child-Pugh score................................................................................................ 113
Table 10–5: CHA2DS2-VASc score....................................................................................... 115
Table 10–6: Modified Rankin Scale (mRS) and Corresponding Sections of a Structured 
Interview.............................................................................................................. 116


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Table of Figures
Figure 1–1: Study design overview.......................................................................................... 22
Figure 2–1: FXI(a) in the coagulation cascade ........................................................................ 27
Figure 9–1: Graphical testing strategy ..................................................................................... 82


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List of Abbreviations and Definitions of Terms
A1AT
Alpha-1 antitrypsin
AE
Adverse Event
ACC
American College of Cardiology
ADL
Activities of daily living
AF
Atrial fibrillation
AG
Joint stock company, Aktiengesellschaft
AHA
American Heart Association
ALT
Alanine aminotransferase
AMI
Acute myocardial infarction 
ANA
Antinuclear antibodies
AP
Alkaline phosphatase
aPCC
Activated prothrombin complex concentrate
aPTT
Activated partial thromboplastin time
ASA
Acetylsalicylic acid
ASMA
Anti-smooth muscle antibodies
AST
Aspartate aminotransferase
AXIA
Activated Factor XIa activity
BARC
Bleeding Academic Research Consortium
BCRP
Breast Cancer Resistance Protein
BID
Twice a day, Bis in die
BMS
Bristol-Myers Squibb
BP
Blood pressure
BUN
Blood urea nitrogen
BYOD
bring your own device
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CEC
Clinical Events Committee
CEOT
Common End of Treatment
CES1
Carboxylesterase 1
CFR
Code of Federal Regulations
CHEST
American College of Chest Physicians
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CHMP
Committee for Medicinal Products for Human Use
CK
Creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COA
Clinical Outcome Assessment
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus Disease 2019
CPMP
Committee for Proprietary Medicinal Products
CRF
Case report form
CRP
C-reactive protein
CSR
Clinical study report
csHR
Cause-specific hazard ratio


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CV
Cardiovascular
CYP2C8
Cytochrome P450, family 2, subfamily C, polypeptide 8
CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
D
Day
DCT
Decentralized clinical trial
DNA
Desoxyribonucleic acid
DRE
Disease-related Event
DtP
Direct-to-participant
e.g.
For example, exempli gratia
EC
Executive Committee
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
eICF
Electronic Informed consent form
EMA
European Medicines Agency
ePRO
Electronic Patient Reported Outcomes
EQ-5D
European Quality of Life group 5-Dimension questionnaire
ESC
European Society of Cardiology
ET
Early termination
EU
European Union
EudraCT
European Clinical Trials Database
F
Factor
FAS
Full Analysis Set
FDA
Food and Drug Administration
FeCl
Ferric chloride
FEIBA
Factor eight inhibitor bypass activity
FFP
Fresh frozen plasma
4F-PCC
4-factor Prothrombin complex concentrate
FSH
Follicle stimulating hormone
γGT
Gamma glutamyl transpeptidase
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HA
Health Authority
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCM
Hypertrophic cardiomyopathy
HCRU
Healthcare resource utilization
HDPE
High-density polyethylene
HDV
Hepatitis D virus
HFpEF
Heart failure with preserved ejection fraction
HFrEF
Heart failure with reduced ejection fraction
HN
Home nurse
HR
Hazard ratio


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HRS
Heart Rhythm Society
HRT
Hormonal replacement therapy
i.e.
That is, id est
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISTH
International Society on Thrombosis and Hemostasis
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous(ly)
LAA
Left atrial appendage
LAM
Lactational amenorrhea method
LDH
Lactate dehydrogenase
LV
Left ventricular
LVEF
Left ventricular ejection fraction
MD
Medical doctor
MedDRA
Medical Dictionary for Regulatory Activities
MFDS
Ministry of Food and Drug Safety 
MI
Myocardial infarction
mRS
Modified Rankin Scale
N
Total number of participants
NA
Not applicable
NJ
New Jersey
NOAC
Non-Vitamin K oral anticoagulant
NSAID
Nonsteroidal anti-inflammatory drug
OAC
Oral anticoagulant
OD
Once a day
P2Y12
Gi-coupled platelet receptor for adenosine diphosphate
PAD
Peripheral artery disease
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic(s)
P-gp
Permeability glycoprotein
PK
Pharmacokinetic(s)
PLC
Program Leadership Committee
PPIs
Proton pump inhibitor
PROs
Patient Reported Outcomes
PT
Prothrombin time
PtP
Pharmacy-to-participant
QC
Quality control


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RBC
Red blood cell (count)
RCT
Randomized controlled trial
RHR
Resting heart rate
RNA
Ribonucleic acid
RND
Randomization
ROTEM
Rotational thromboelastometry
SAC
Statistical analysis center
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SAS
Statistical analysis software
SC
Steering Committee
SCR
Screening
SD
Single dose
SDLL
Source Data Location List
SFU
Safety follow-up
SI
Study intervention
SoA 
Schedule of activities
StP
Site-to-participant
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment Emergent Adverse Event
TIA
Transient ischemic attack
TKA
Total knee arthroplasty
TM
Trademark
TMF
Trial Master File
U
Unit
ULN
Upper limit of normal
US / USA
United States / United States of America
vs.
As compared to, versus
VKA
Vitamin K antagonist
VTE
Venous thromboembolism
W
Week
WBC
White blood cell (count)
WOCBP
Woman of Childbearing Potential
WONCBP
Woman of Nonchildbearing Potential


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Definitions
BAY 2433334 
Sponsor’s drug number for asundexian. Throughout this 
document, the sponsor’s investigational intervention will 
be referred to as asundexian for better readability.
Bring Your Own Device (BYOD) Participation in the DCT element of the study requires the 
use of a camera-equipped, web-enabled device which can 
be provisioned by the site, or participants can use their 
own – known as ”BYOD” – as long as it meets certain 
minimum hardware requirements.
DCT Platform
Software that acts as the central point for some or all of 
the digital study components of a DCT. 
This can be in the form of a web portal (for use on 
desktop or laptop computers / via web browser on a 
smartphone or tablet) and / or an app to be used on a 
smartphone or tablet and depending on the requirements of 
the study, may be utilized by site teams, remote providers 
(e.g. home nurses) and the participants themselves. The 
platform may act as a ”hub” to more seamlessly connect 
other apps or systems used by the study to improve the 
user experience by reducing the number of interfaces. The 
DCT platform can host patient engagement or learning 
content, reminders or provide a route for participants to 
contact or share information with the site team directly. It 
can also act as a point for remote source data capture (e.g. 
for home nursing). The DCT platform may be able to be 
integrated with other systems such as IRT to allow more 
efficient transfer of data between them.
Direct-to-participant (DtP)
Delivery of the study intervention to the participant’s 
home. There are 3 possible options for DtP shipments, 
depot-to-participant, pharmacy-to-participant (PtP) and 
site-to-participant (StP) and these are chosen based on the 
needs of the trial and country-specific regulations.
eConsent / eICF
The use of electronic systems and processes that may 
employ multiple electronic media, including text, 
graphics, audio, video, podcasts, passive and interactive 
websites, biological recognition devices, and card readers, 
to convey information related to the study and to obtain 
and document informed consent.
This may also include electronic signature of the consent 
form. All or parts of the overall process may be conducted 


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remotely, dependent on study set up and local regulations 
(in some countries all or part of the consenting / signature 
process must be done in person and / or wet ink signatures 
are mandatory).
eCOA / ePRO
eCOA is an electronic method of collecting data about a 
patient’s experience with his / her disease and treatment. 
Patient Reported Outcomes (PROs) are diaries and 
questionnaires that assess the patient’s view.
COAs can be administered by the site during a clinic visit 
or at home using mobile devices to capture the data related 
to the assessment.
Engagement Content
Any content that plays an important role in the 
engagement of the participant in the study. It could be in 
the form of reminders to complete activities, surveys 
regarding certain services, providing educational material, 
a patient community platform, reminders, and 
gamification of the components like ePRO.
Home Nurse (HN)
Home nursing enables nurses / phlebotomists to perform 
study-related procedures such as blood draws, collection 
of vital signs, ECG or drug administration in the 
participant’s home or other suitable location convenient to 
the patient. Nurses are able to process biological samples 
using bench-top devices and can pass processed specimens 
to a courier or will deliver them themselves to a local 
courier depot or site.
In this protocol, ”home nurse” is also referred to as ”home 
health”. 
Participation Kit
This kit provides the participants in the DCT model with 
the technology and instruction guide for remote 
participation. The kit includes an instructional guide, ECG 
device, and a provisioned smartphone, unless the 
participants opt to use their own device.
Patient Service Center
A laboratory or network of laboratories separate from (and 
often independent of) site facilities with a more convenient 
location and ease of access for patients e.g. location within 
a pharmacy. The patient service center can be used to 
facilitate the collection of biological samples such as 
blood and other measurements such as weight, and vital 
signs during a clinical study. 


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Remote Metasite
A site that enrols patients and maintains oversight 
remotely. The site can be an existing brick and mortar site 
that offers remote services.
Teleresearch
Technology that allows long-distance contact between a 
participant and the clinician, using a video call. It can also 
be used in combination with other modules to deliver 
training or monitoring, e.g. if the investigator needs to ask 
certain questions to a participant. In a broader sense this 
also includes phone calls in case a video interaction is not 
accomplishable due to technical reasons.
Visit
Scheduled interaction, i.e. site visit, teleresearch, or phone 
call
Wearables and devices
Digital technologies designed for the monitoring of a 
participant remotely. This could be a connected device, 
e.g. an ECG device.
The monitoring of participants via digital technologies can 
also be referred to as “remote monitoring” or “remote 
patient monitoring”. This is not to be confused with the 
remote monitoring a clinical research associate does as 
part of study oversight.


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1.
Protocol Summary
1.1
Synopsis
Protocol Title:
A multicenter, international, randomized, active comparator-controlled, double-blind, double-
dummy, parallel-group, 2-arm, Phase 3 study to compare the efficacy and safety of the oral 
FXIa inhibitor asundexian (BAY 2433334) with apixaban for the prevention of stroke or 
systemic embolism in male and female participants aged 18 years and older with atrial 
fibrillation at risk for stroke.
Short Title:
Phase 3 study to investigate the efficacy and safety of the oral factor XIa (FXIa) inhibitor 
asundexian (BAY 2433334) compared with apixaban in participants with atrial fibrillation at 
risk for stroke. 
Envisaged indications:
Prevention of stroke and systemic embolism in patients with atrial fibrillation (cardioembolic 
stroke prevention). 
Rationale:
Current guidelines recommend long-term oral anticoagulant therapy such as non-Vitamin K 
oral anticoagulants (NOACs) or Vitamin K antagonists (VKAs) for patients with atrial 
fibrillation (AF) at risk for stroke. Despite the better benefit-risk profile for NOACs when 
compared with VKAs, patients receiving NOACs continue to have an important residual risk 
for experiencing stroke, systemic embolism and cardiovascular (CV) death. In addition, there 
is still an important risk for bleeding. The inhibition of FXIa with asundexian is expected to 
have superior yet at least similar efficacy while leading to less bleeding and an overall net 
clinical benefit when compared with the NOAC apixaban.


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Objectives, Endpoints and Estimands:
Table 1–1: Summary of study objectives and endpoints
Objectives
Endpoints
Primary
Efficacy
To demonstrate that asundexian is superior (at 
least non-inferior) when compared with 
apixaban for prevention of stroke and systemic 
embolism in participants with atrial fibrillation at 
risk for stroke

Composite of stroke or systemic embolism*
Safety
To demonstrate that asundexian is superior to 
apixaban as assessed by ISTH major bleeding 
in participants with atrial fibrillation at risk for 
stroke

ISTH major bleeding*
Net clinical benefit
To demonstrate that asundexian is superior to 
apixaban with respect to benefit and risk

Composite of stroke, systemic embolism, or 
ISTH major bleeding*
Secondary
Efficacy
To compare the effects of asundexian and 
apixaban with respect to composite and 
individual efficacy endpoints

Composite of ischemic stroke or systemic 
embolism*

All-cause mortality*

Ischemic stroke*

CV death*

Composite of CV death, stroke, or 
myocardial infarction*
Safety
To compare asundexian and apixaban with 
respect to composite and individual bleeding 
endpoints

Composite of ISTH major or clinically 
relevant non-major bleeding*

Clinically relevant non-major bleeding*

Hemorrhagic stroke*

Intracranial hemorrhage*

Fatal bleeding*

Minor bleeding*
Net clinical benefit
To compare the benefit and risk of asundexian 
and apixaban with respect to a composite of 
efficacy and safety endpoints 

Composite of stroke, systemic embolism, 
ISTH major bleeding, or all-cause mortality*

Composite of disabling stroke (mRS ≥ 3), 
critical bleedingǂ, or all-cause mortality*
Abbreviations: CV = cardiovascular, ISTH = International Society on Thrombosis and Hemostasis, mRS = 
modified Rankin Scale 
* Time to first occurrence
ǂ Critical bleeding is defined as symptomatic bleeding in either of the following critical locations (intracranial, 
intraspinal, pericardial, intra-articular, or retroperitoneal) or as intraocular bleeding with compromised vision or 
intramuscular bleeding with compartment syndrome
The primary efficacy estimand is the cause-specific hazard ratio of the composite of stroke or 
systemic embolism comparing the assignment to asundexian with the assignment to apixaban 


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in adult patients with atrial fibrillation at risk for stroke while alive and including effects of 
treatment discontinuation or treatment with dual antiplatelet therapy.
The primary safety estimand is the cause-specific hazard ratio of ISTH major bleeding when 
treatment with asundexian is compared to treatment with apixaban in adult patients with atrial 
fibrillation at risk for stroke who have taken at least one dose of asundexian or apixaban while 
alive and while exposed to asundexian or apixaban.
The primary net clinical benefit estimand is the cause-specific hazard ratio of stroke, 
systemic embolism, or ISTH major bleeding (excluding hemorrhagic stroke) when treatment 
with asundexian is compared to treatment with apixaban in adult patients with atrial 
fibrillation at risk for stroke who have taken at least one dose of asundexian or apixaban while 
alive and while exposed to asundexian or apixaban.
Overall Design Synopsis:
OCEANIC-AF (study 19767) is a multicenter, international, randomized, active comparator-
controlled, double-blind, double-dummy, parallel-group, phase 3 study. The overall study 
design is depicted in Figure 1–1. 
Approximately 18000 participants ≥ 18 years of age with atrial fibrillation at risk for stroke, 
will be randomized to 1 of the 2 arms (approximately 9000 participants per arm), as follows:

1 investigational study intervention arm asundexian 50 mg once a day (OD) and 

1 active comparator arm apixaban 5 mg twice a day (BID) or 2.5 mg BID, according 
to label (for details see Section 6.1).
A fully remote decentralized clinical trial (DCT) model may be implemented in selected 
countries.
Randomization will be first stratified by participation in the conventional study model vs. in 
the DCT model. This will be succeeded by stratification for current use vs. no current use of 
single agent antiplatelet therapy planned to continue for at least 6 months after randomization. 
Following stratification, participants will be randomly assigned to 1 of the 2 treatment arms in 
a 1:1 ratio. 
This is an event-driven study, and the sponsor will request termination of the intervention 
period once about 340 participants have experienced a primary efficacy endpoint event. At the 
same time approximately the same number of participants are expected to experience a 
primary safety outcome. The planned individual study duration is expected to be 10-34 
months; however the timelines may vary (i.e. longer or shorter than planned). The study will 
consist of the following study periods:

Screening period (from visit 1 until visit 2): 2 weeks (participants will be screened 
and have to be randomized within 2 weeks after screening). If all information is 
available, a participant can be randomized on the day of screening (visits 1 and 2 are 
combined). For participants in the DCT model, after obtaining informed consent, an 
additional time interval of up to 2 weeks will be required (refer to Section 10.10).

Intervention period (from visit 2 until the common end of treatment [CEOT] 
visit): approximately 9-33 months. The intervention period will end when the required 
number of primary efficacy endpoint events has accrued. For an individual participant 


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the CEOT visit marks the end of the intervention period. For participants permanently 
discontinuing study intervention, see also early termination period.

Common End of treatment period (from CEOT visit until CEOT safety follow-up 
[SFU] visit): 2-week period that will end upon completion of the CEOT SFU visit for 
participants who did continue intake of study intervention as expected. 
Only in case participants permanently discontinue study intervention earlier than planned:

Early termination (ET) period (from ET until CEOT visit): If the study 
intervention is permanently discontinued earlier than expected, the participant will 
enter the ET period and an ET visit has to be performed as soon as possible. All living 
participants who permanently discontinued study intervention prior to the CEOT visit 
are still part of the study and should participate in their visits as scheduled (preferably 
via telephone) as part of their ET period. In those participants also the above 
mentioned CEOT visit will need to be performed, that marks the end of the ET period.
For participants who prematurely discontinue study intervention ≥ 2 weeks prior to the 
CEOT visit, an ET safety SFU visit will also be conducted 2 weeks after permanent 
discontinuation of study intervention. In such a case the CEOT visit will represent the 
last study visit. 
For participants who permanently discontinue study intervention < 2 weeks prior to 
the CEOT visit, the ET SFU visit will be replaced by the CEOT SFU visit, that is to be 
conducted after the CEOT visit and is the last study visit for those participants.
Short Summary:
The purpose of this study is to investigate the efficacy of the oral FXIa inhibitor asundexian in 
prevention of stroke and systemic embolism and its safety (bleeding risk) compared with 
apixaban in adult participants with atrial fibrillation at risk for stroke. The inhibition of FXIa 
with asundexian is expected to have superior yet at least similar efficacy while leading to less 
bleeding when compared with the NOAC apixaban.
Study details include:
The study duration for an individual participant is expected to be up to approximately 34 
months. This is an estimate, and all participants will be followed until the end of the study.

The recruitment period of the study is expected to be approximately 24 months.

The individual treatment duration is expected to be minimum approximately 9 months 
and maximum approximately 33 months.

There will be a screening visit followed by a randomization visit within 2 weeks. The 
visit frequency after randomization will be a first visit after 1 month, the next visit 
after 3 months and then every 3 months until the common end of treatment (CEOT) 
visit. A safety follow-up visit will take place 2 weeks after the CEOT visit. 
Number of Participants:
Approximately 20000 participants will be screened to achieve 18000 randomized participants 
for an estimated total of 9000 randomized participants per intervention group. This is an 
event-driven study. The required target number of study participants who have experienced a 
primary efficacy event is estimated to be approximately 340. The target number of study 


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participants with a primary safety event while exposed to study intervention is 
approximately the same as for primary efficacy. More details are available in Section 9.5.
Study Arms and Duration:
Asundexian is the sponsor’s study intervention under investigation. Apixaban is the 
intervention used as comparator. The following intervention groups are included in the study:

Asundexian 50 mg OD

Apixaban 5 mg or 2.5 mg BID, according to product label.
The total duration of study participation, along with the sequence and the duration of study 
periods, is provided under “Overall Design Synopsis”, and in Section 4.1.
Independent Data Monitoring Committee:
An Independent Data Monitoring Committee (IDMC) will be involved in the review of the 
safety data as well as efficacy data to determine the risk / benefit ratio across the  Phase 3 
studies with asundexian (Section 10.1.6.4). Detailed information on the roles and 
responsibilities of the IDMC will be described in the IDMC Charter. 


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1.2
Schema
Figure 1–1: Study design overview
Abbreviations: BID = bis in die (twice a day), CEOT = common end of treatment, M = month, N = total number of participants, 
OD = once a day, RND = randomization, SFU = safety follow-up, W = weeks
*  if applicable visits will continue after Month 30 in the same way as before until CEOT visit
ǂ the usual dose of apixaban is 5 mg BID, reduced to 2.5 mg BID for participants with 2 or more of the following criteria: 
age 80 years or older, body weight ≤ 60 kg, or serum creatinine level ≥ 1.5 mg/dL
Notes: Participants receiving asundexian will also receive the apixaban matching placebo. 
Participants receiving apixaban will also receive the asundexian matching placebo.
After discontinuation of study intervention, further anticoagulation therapy (e.g. NOAC) is at discretion of the investigator.
Participants of the decentralized clinical trial model will have the screening visit split into a “part a” to initiate operational 
logistics and a “part b” to perform screening procedures. 


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1.3
Schedule of Activities (SoA)
Study periods
Duration
Screening
≤ 2 weeks
before RND
Intervention period
~9 ~33 months*, from RND until Common End of Treatment
(CEOT) visit / Early Termination (ET)
Early Termination period**
ET until CEOT visit
CEOT period
CEOT visit until 2 weeks after
Visit number / acronym
1
2ǂ
3
4
5
6
7
8
9
10
11
12*
13*
ET visit ET SFU visit
≥ 3 13*
CEOT visit
CEOT SFU visit†
Visit type
site
site

site
site

site

site

site

site
site
(site)
(site)
site ()

Visit / Month [M]
Day [D] / ± allowed windows
Week [W] ± allowed windows
SCR
 D -14 1
RND / M 0
D 1
M 1
 30±4
M 3
W 13±1
M 6
26±1
M 9
39±1
M 12
52±1
M 15
65±1
M 18
78±1
M 21
91±1
M 24
104±1
M 27
117±1
M 30
130±1
ET
ET
ET + 2 W
(ET+ 2 W) + 1 W
≥ M 1 M 30
≥ D 30±4 
W 130±1
CEOT
CEOT ± ~3 W
CEOT visit + 2 W 
(CEOT visit + 2 W) + 1 W
Administrative procedures
Informed consent
X
Inclusion / exclusion criteria
X
   X
Demographics / biometrics
X
Medical history
X
   X
Prior / concomitant medication
=====================================continuously=================================== 
AP / AC only X (AP / AC only)
X
Clinical procedures / assessments
ECG
X
  (X)
Vital signs (BP and RHR)
X
  (X)
Adverse events
only procedure
related events
  ==============================continuously===============================
X†
X
Outcome events
    ================================================continuously=====================================================
HCRU
    ================================================continuously=====================================================
EQ-5D
   X
X
X
X
X
X
X
X†
IRT
Randomization /
Visit registration
X
X
X
X
X
X
X
X
X
X
Laboratory assessments
Safety blood sampling
X
  (X)
X
X
X
X
X
X†
Pregnancy test (if WOCBP)
X
   X
X
X†
PD / Biomarkers (a); PK (b)
   a
a, b
a, b
Study intervention (SI) shipment
SI dispensation
       X
X
X
X
X
X
X
SI collection / accountability
X
X
X
X
X
X
X
X†
Note: SoA for the DCT model can be found in Section 10.10.2.


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Annotated Schedule of Activities (Annotated SoA)
Administrative procedures
Informed consent
informed consent must be obtained before initiation of any study-specific procedures
Inclusion / exclusion criteria
in case SCR and RND are performed on the same calendar day, these criteria need to be assessed only once
Demographics / biometrics
biometrics refers to measurement of height and weight and will only be performed and recorded at screening
Medical history
in case SCR and RND are performed on the same calendar day, this needs to be assessed only once
Prior / concomitant medication
in case SCR and RND are performed on the same calendar day, this needs to be assessed only once; in case a participant pretreated with a NOAC (or another antico-
agulant) has already taken the anticoagulant on the planned day of randomization, intake of study intervention should be postponed by one day (Section 6.1.1); if SI is
permanently discontinued ≥ 2W before CEOT visit, only AP / AC need to be reported at scheduled visits, including CEOT visit; otherwise all meds need to be reported
Clinical procedures / assessments
ECG
to display ≥ 6 leads; can also be used if done as part of routine management and no older than 30 days at RND; no need to be repeated once available (Section 8.3.6)
Vital signs (BP and RHR)
can also be used if done as part of routine management and no older than 14 days at RND; no need to be repeated once available (Section 8.3.5)
Adverse events
(S)AEs will be collected from start of SI intake until SFU visit; only study procedure related events will be reported from signing of ICF onward (Section 8.4.1) 
Outcome events
outcome events including all bleeding, death, MI, stroke and systemic embolism, as well as events indicative of a potential outcome (Section 8.4.6) need to be reported
continuously from RND until death or last study visit (= CEOT SFU; only if SI is permanently discontinued ≥2 W prior to CEOT visit reporting occurs until CEOT visit)
HCRU
HCRU (within hospitals) in conjunction with SAEs and outcome events needs to be documented, e.g. time points or periods affected (Section 8.10.1)
EQ-5D
participants should complete the questionnaire during the visits at the timepoints reported in the SoA
IRT
Randomization /
Visit registration
SCR and RND can take place on the same calendar day if all information is available (Visits 1 and 2 are combined); study intervention intake will start as soon as 
possible after randomization (day 1), preferably on the day of randomization, and is expected to continue until the day prior to the CEOT visit
Laboratory assessments
Safety blood sampling
creatinine and eGFR values must be available at RND; if not available from SCR central lab, respective values should be determined in local lab prior to RND; values 
obtained as part of routine management can also be used if no older than 14 days at RND (Section 8); in any case, the full set of safety laboratory tests (Table 10–1) 
needs to be obtained once during the SCR period, at the latest at RND, and at indicated visits thereafter
Pregnancy test (if WOCBP)
a WOCBP must have a negative serum or urine pregnancy test at SCR; a repeat test at RND (before SI intake) is required, unless ≤ 4 days lie between SCR and RND
PD / Biomarkers (a); PK (b)
refer to Table 1–2 regarding further details; pharmacogenetics will be collected in a subset of participants 
Study intervention (SI) shipment
SI dispensation
the term “SI” includes the comparator drug as defined in Section 6.1; at each contact the participants should be instructed regarding SI compliance 
SI collection / accountability
at the CEOT visit the final SI collection occurs: no SI intake should take place on the day of this visit anymore; the last intake of SI occurs on the previous day 
Abbreviations: AP / AC = antiplatelets / anticoagulants, BP = blood pressure, CEOT = Common End of Treatment, D = day, ECG = electrocardiogram, EQ-5D = European Quality of Life group 5-
Dimension questionnaire, ET = early termination, HCRU = healthcare resource utilization, RHR = resting heart rate, ICF = informed consent form, IRT = interactive response technology, M = month,
PD, PK = pharmacodynamic(s), -kinetic(s), RND = randomization, SCR = screening, SFU = safety follow-up, SI = study intervention, W = week(s), WOCBP = woman of childbearing potential
ǂ procedures and assessments at visit 2 should preferably be conducted prior to RND; SI dispensation / intake will usually be concluding the visit 
* if applicable (if the number of efficacy outcome events does not accrue until Month 33 as expected) the visit schedule will continue after Month 30 with the respective labelling, e.g. Visit 14, 15.
The duration of the intervention period (~9 to ~33 months) depends on when a participant joins during the course of the study. Displayed timepoints might therefore not be applicable to all participants.
** An early termination visit is only applicable to participants who prematurely discontinue intake of SI permanently; those should undergo an ET visit as soon as possible after discontinuation of SI. An 
ET SFU visit will occur 2 weeks (+ 7 days window) after the day of the discontinuation of SI (Section 7.1), unless permanent discontinuation occurred < 2 W prior to CEOT visit, in which case a CEOT 
SFU will be performed instead. After permanent discontinuation of SI participants should take part in the remaining visits (via phone) as scheduled, until including the CEOT visit (or CEOT SFU).
† if SI permanently discontinued: item not applicable; only if discontinued < 2 W before CEOT visit, CEOT SFU will replace ET SFU; if SI is permanently discontinued a phone call CEOT visit is expected


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An overview of the PK, PD, and biomarker sampling is shown in Table 1–2:
Table 1–2: PK, PD and Biomarker sampling
Day 1
(Visit 2)
Month 3
(Visit 4)
Month 12
(Visit 7)
Sample timing*
Pre-dose
Pre-dose
Pre-dose
PK**
-
X
X
PD**
X
X
X
Biomarker plasma
X
X
X
Biomarker serum
X
X
X
Biomarker blood for 
pharmacogenetics
X
-
-
Abbreviations: PD = Pharmacodynamic(s), PK= Pharmacokinetic(s)
* at all visits: in order to collect pre-dose samples for PK,PD and biomarker plasma / serum, participants should 
take their study intervention at the site only after blood sampling. The investigator must record the time when 
the study intervention is taken at the site. A phone call to remind the participants is recommended. Biomarker 
blood for pharmacogenetics can be collected at any time in relation to study intervention intake. 
** if study intervention is temporarily discontinued, PK / PD blood samples should only be obtained if the study 
intervention has been restarted and sustained for at least 4 days, see Section 7.1.2
PK samples will be collected in all participants of the conventional study model; PD and biomarkers will be 
collected in subsets of participants if approved by local IECs / IRBs and competent authorities (refer to Sections 
8.5, 8.6 and 8.8). Biomarker blood for pharmacogenetics is generally planned to be collected at the 
randomization visit (Day 1), however, it can also be collected at a later visit in case it has not yet been taken 
(refer to Section 8.7).
The exact time of PK, PD and biomarker sampling needs to be recorded, as well as the time of the most 
recent / associated study intervention intake (i.e. on the PK / PD sampling day, as well as on the day before that).
2.
Introduction
Asundexian is a direct, potent inhibitor of activated coagulation factor XI (FXIa) developed 
for 2 indications:
1. Prevention of stroke and systemic embolism in patients with atrial fibrillation 
(cardioembolic stroke prevention). 
2. Prevention of ischemic stroke in patients after an acute non-cardioembolic ischemic 
stroke or high-risk transient ischemic attack (TIA) in combination with antiplatelet 
therapy (non-cardioembolic ischemic stroke prevention). 
OCEANIC-AF (study 19767) will evaluate the efficacy and safety of asundexian versus 
apixaban, a FXa inhibitor (NOAC), in participants with AF. The study will be an event-driven 
Phase 3 study with expected treatment duration of 9-33 months (refer to Section 9.5 for more 
details). 
The current clinical development of asundexian (FXIa inhibitor) includes 1 additional Phase 3 
study in participants with non-cardioembolic ischemic stroke or high-risk TIA (OCEANIC-
STROKE, study 20604). This study is planned to also be event-driven and will be testing 
asundexian against placebo on top of antiplatelet therapy.
Each individual study will have its own study objectives to further characterize safety and 
efficacy of asundexian in the respective indications.


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Thus, the 2 Phase 3 studies in AF and non-cardioembolic stroke are expected to support that 
asundexian may offer a uniform therapeutic option for ischemic stroke patients independent 
of the underlying ischemic stroke’s etiology (cardioembolic or non-cardioembolic).
2.1
Study Rationale
This Phase 3 study will explore asundexian 50 mg once daily to determine a lower risk for 
bleeding as well as an improved efficacy in terms of reduction of thromboembolic events 
when compared with apixaban (NOAC) in patients with AF at risk for stroke.
Current treatment guidelines recommend the use of long-term oral anticoagulant therapy such 
as VKAs, or NOACs in patients with AF at risk for stroke (refer to Section 2.2.2).
Despite a better benefit-risk profile for NOACs when compared with VKAs, patients 
receiving NOACs continue to have an important residual risk for stroke, systemic embolism 
and CV death. In addition, even though NOACs lead to less intracranial hemorrhage 
compared with VKAs, there is still an important risk for bleeding, including major bleeding.
Asundexian, as an oral FXIa inhibitor, is expected to show a benefit in reducing the risk for 
stroke or systemic embolism in patients with AF in Phase 3. This has been demonstrated by 
predictive animal models with asundexian indicating a potential for additional benefit in terms 
of thrombus prevention beyond of what has been shown with a therapeutic dose of NOACs. 
In addition, this is supported by the analysis of genetic data from FXI-deficient individuals. 
At the same time asundexian is expected to have a low risk for bleeding. This is based on the 
available preclinical data, data from patients with inherited FXI deficiency and clinical data 
from 4 Phase 2 proof of concept studies in participants undergoing total knee replacement 
(see Section 2.3), as well as data from the completed dose finding Phase 2 study comparing 
the safety of asundexian to apixaban in patients with atrial fibrillation (PACIFIC-AF(Piccini 
et al. 2022) reported in the Investigator’s Brochure (IB). 
Asundexian is therefore an attractive candidate to be evaluated as a potential replacement for 
NOAC therapy in patients with AF.
2.2
Background
2.2.1
Disease Background
AF is the most common sustained cardiac arrhythmia and is associated with increased rates of 
death, stroke and other thromboembolic events. It has been estimated that about 33.5 million 
patients worldwide are affected by AF (Chugh et al. 2014). AF is a particularly common 
disorder in the elderly, with a prevalence of less than 1% in the population under 60 years of 
age, and with estimates of up to 17% among those over 80 years of age (Wilke et al. 2013). 
As a consequence of the aging population, the prevalence of AF is predicted to rise (Dai et al. 
2021).
Patients who have AF are known to have a markedly increased risk for stroke due to a 
predisposition to the development of atrial thrombi (Wolf et al. 1991). Full anticoagulation 
with Vitamin K antagonists was the recommended therapy until the introduction of NOACs. 


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2.2.2
Treatment Guidelines 
Current guidelines AHA / ACC / HRS 2014 (January et al. 2014), CHEST 2018 (Lip et al. 
2018), as well as the focused update AHA / ACC / HRS 2019 (January et al. 2019), ESC 2020 
(Hindricks et al. 2021) and EHRA 2021 (Steffel et al. 2021) recommend the use of long-term 
oral anticoagulant therapy such as VKAs or NOACs like Factor Xa- (rivaroxaban, apixaban, 
edoxaban) or Factor IIa- (dabigatran) inhibitors for patients with AF at risk for stroke.
2.2.3
FXIa Inhibition: Mode of Action 
Asundexian is an oral direct, potent inhibitor of activated coagulation factor XI (FXIa). 
The plasma serine protease zymogen factor XI (FXI) is activated after initiation of the contact 
activation pathway via factor XIIa (FXIIa) and during the amplification phase as part of a 
positive feedback loop through activation by thrombin (Figure 2–1). FXIa is thought to 
contribute strongly to clot progression, which may potentially lead to vessel occlusion and 
pathological manifestations of thrombosis but has minor impact on hemostasis due to its 
limited role in the initiation phase of the extrinsic (tissue factor) pathway (Heitmeier et al. 
2022). 
FXIa inhibition by asundexian may offer the opportunity to prevent thrombosis without 
interference with hemostasis and to thereby set a paradigm shift compared to Vitamin K 
antagonists (VKAs) and Non-Vitamin K oral anticoagulants (NOACs). 
Figure 2–1: FXI(a) in the coagulation cascade
The Tissue Factor pathway is activated after vascular damage, forming a small amount of thrombin to build a clot at the site of 
injury and thereby stop any bleeding. The Contact pathway is activated by negatively charged surfaces from e.g. activated cells, 
leading to FXI activation and clot formation within the vessel. Thrombin itself activates FXI via the Amplification loop to generate 
a secondary burst of thrombin, allowing an initial clot to grow and obstruct the vessel lumen. While both pathways of thrombus 
formation are inhibited by apixaban, inhibiting FXI(a) maintains the ability to form a clot at the site of vessel wall injury.
Drafted by Heitmeier S and van Giezen JJJ, 2021.


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2.2.4
Asundexian (BAY 2433334)
Preclinical / Toxicology Data
Preclinical data using FXI-deficient mice or studies using pharmacological inhibition of FXIa 
in different animal models, for example a FeCl2-induced thrombosis model, have shown a 
benefit in reduced thrombus formation. The data indicate that higher efficacy might be 
possible to achieve when compared with the therapeutic doses of NOACs. 
The benefit in these animal models was not associated with an increase in bleeding time as is 
seen for NOACs in these models. Importantly, no further increase in bleeding time was seen 
even when asundexian was given on top of dual antiplatelet agents.
Data regarding toxicology studies as well as more preclinical data can be found in the 
Investigator’s Brochure but are also partly described in the benefit / risk section (see 
Section 2.3). 
Clinical Data
As of June 2022, the sponsor conducted 20 Phase 1 studies in more than 550 subjects which 
investigated the safety, tolerability, PK and pharmacodynamic (PD) properties of asundexian. 
Two additional clinical Phase 1 studies are currently ongoing. Doses of asundexian that were 
tested in these studies ranged from 5 mg to 150 mg as single doses, and multiple doses up to 
100 mg once daily.
These studies support further development of asundexian including the planned Phase 3 
studies.
The dose finding Phase 2 PACIFIC studies for 3 selected indications, i.e. AF, acute non-
cardioembolic ischemic stroke, and acute myocardial infarction (AMI), in a total of 4164 
randomized patients have been completed. They allowed for collection of information on the 
safety and efficacy of asundexian in different indications using different comparators 
(placebo / NOAC), and on top of different standard of care (i.e. single or dual antiplatelet 
therapy). 
The objective of the Phase 2 study in patients with AF was to evaluate whether the incidence 
of bleeding with asundexian is lower when compared with a NOAC (apixaban), whereas for 
acute non-cardioembolic ischemic stroke and AMI the aim was to evaluate whether the 
bleeding profile is similar to placebo and there is a benefit in prevention of cerebro- and 
cardiovascular thromboembolic events when testing asundexian against placebo and on top of 
standard of care (single or dual antiplatelet therapy).
In addition to the individual study objectives, each of the Phase 2 studies supported each other 
for the evaluation of safety (bleeding) and efficacy in patients who were at risk for arterial 
thromboembolic events. Since the same dose levels were studied in all 3 studies (with the 
exception of the lowest dose, that was not tested in PACIFIC-AF), this allowed for pooling 
the data across all studies.
To secure an integrated evaluation of the emerging safety and benefit of asundexian in the 3 
Phase 2 studies, one IDMC was set up for the program. In addition, a Clinical Events 
Committee was in place for the adjudication of primary and secondary efficacy and bleeding 
endpoints.
Hence, at the end of the Phase 2 a large and robust data package from 4164 patients with 
exposure up to 12 months was available, which provided a solid ground for dose selection and 
furthermore supports the development of asundexian in Phase 3 clinical studies.


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An overview of the completed and ongoing studies can be found in the Investigator’s 
Brochure.
2.3
Benefit/Risk Assessment
The FXIa inhibitor asundexian is an oral anticoagulant that is planned to be developed for 
patients with AF as well as non-cardioembolic ischemic stroke or high-risk TIA. Phase 2 
studies have been initiated in 2020 in the 2 mentioned indications as well as in AMI and have 
recently ended (AF in October 2021, AMI and non-cardioembolic stroke in February 2022). 
The Phase 2 PACIFIC-AF study was the first study investigating asundexian in patients with 
AF. Once daily doses of 20 mg and 50 mg were tested in the study. Based on analysis of the 
overall data from the Phase 2 studies, a decision was made to select the 50 mg dosage for the 
Phase 3. More details on the justification for this can be found under Section 4.3.
Asundexian as a FXIa inhibitor is expected to have a lower risk for clinically significant 
bleeding when compared with other oral anticoagulants (VKAs and NOACs), while 
potentially leading to an efficacy benefit and thereby conveying an overall net clinical benefit.
The expected clinical profile of asundexian is based on preclinical data as well as 
epidemiological and clinical data from FXI-deficient individuals, other FXI-targeting 
compounds and the Phase 2 results from the PACIFIC program. The separation of bleeding 
and efficacy might be explained by the fact that inhibition of FXIa affects the intrinsic and 
propagation pathways, but keeps the extrinsic pathway unaffected, which is activated in case 
of vessel injury. More detailed information about the known and expected benefits and risks 
and reasonably expected AEs of asundexian can be found in the IB.
2.3.1
Risk Assessment
Potential risks related to the study investigational intervention, together with a brief 
description of strategies to mitigate these risks are displayed in Table 2–1.


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Table 2–1: Risk assessment
Potential Risk of Clinical 
Significance
Summary of Data / Rationale for 
Risk 
Mitigation Strategy
Study Intervention asundexian
A risk for bleeding cannot be 
excluded in participants with AF 
included in the Phase 3 study and 
randomized to asundexian or to 
the comparator apixaban. 
Bleeding is the main safety concern 
related to antithrombotic therapies. 
For an inhibitor of FXIa a lower 
bleeding risk is expected than with 
the comparator drug.
Exclusion criteria are phrased to 
exclude patients with a higher risk 
for bleeding (e.g. recent major 
surgery / active bleeding at 
randomization). Bleeding will be 
closely monitored in the study and 
will be adjudicated by an 
independent Clinical Events 
Committee. Furthermore, an IDMC 
will be installed monitoring 
unblinded study data on an ongoing 
basis.
Liver-related adverse effects.
The findings regarding liver-related 
adverse events were reassuring 
during the PACIFIC Phase 2 
studies. Liver-related adverse 
effects will continue to be monitored 
to further characterize the clinical 
profile of asundexian. 
Patients with known significant liver 
disease or known hepatic 
insufficiency classified as Child-
Pugh B or C will be excluded from 
Phase 3, liver parameters are part 
of the safety laboratory panel and 
follow-up will be required for certain 
liver events. Furthermore, an IDMC 
will be installed monitoring 
unblinded study data on an ongoing 
basis.
Study Procedures
Clinical procedures or 
assessments mandated by the 
protocol (see SoA) are routine 
measures from everyday practice. 
They do not carry a risk of clinical 
significance to the safety of the 
participants.
Procedures or assessments do not
pose more than minimal additional 
risk or burden compared with 
normal clinical practice.
No mitigation strategy is required.
Participation in this study presents 
minimal risk for SARS-CoV-2 
infection during study participation.
As long as the COVID-19 pandemic 
situation is ongoing, there is a risk 
of SARS-CoV-2 infections for study 
participants as for the general 
population. However, this risk 
during study participation is not 
increased compared to the general 
population.
In order to minimize their infection 
risk during study participation, the 
investigators / sites will follow all 
recommendations issued by local 
authorities and guidelines aiming to 
reduce the risk of disease 
spreading. Details on the measures 
are specified by the site and agreed 
with the sponsor.
Measures which prioritize 
participant safety and data validity 
are implemented. In case these 2 
objectives conflict, participant safety 
always prevails. 
During the pandemic situation, 
further measures according to 
recommendations and 
requirements from local health 
authorities may become necessary. 
These will be followed within the 
context of this study as far as 
applicable.
Abbreviations: COVID-19 = Coronavirus Disease 2019, SARS-CoV-2 =  Severe Acute Respiratory Syndrome 
Coronavirus 2


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The following information related to safety as well as potential risks for participants is 
available:
1. Bleeding is the main safety concern with antithrombotic therapies. Inhibition of FXIa is 
expected to have a lower risk for bleeding compared with currently available NOAC and 
VKA therapies. Data supporting this are listed below: 
FXI and risk for bleeding:

Patients with inherited FXI deficiency are typically identified when presenting with a 
prolonged activated partial thromboplastin time (aPTT) in routine clinical testing. 
There is no direct association between FXI activity levels and bleeding risk, though 
historically and predominantly in the Ashkenazi Jewish population, FXI deficiency 
has been categorized as having a mild bleeding phenotype that generally only 
manifests following injury or trauma in tissues with high fibrinolytic activity (Visser 
et al. 2020).
Nonclinical Evidence:

FXI-deficient knockout mice do not show a bleeding phenotype. In addition, in rabbits 
treated with FXIa inhibitors no increase in bleeding time (gum and ear) or blood loss 
(liver injury model) was reported. Importantly, no further increase in bleeding time 
was seen when asundexian was given on top of dual antiplatelet agents. In addition, in 
the toxicology studies no relevant bleeding was reported for up to 31-fold the expected 
human exposure of the planned 50 mg multiple dose in patients.
Clinical Evidence:

In the completed and ongoing Phase 1 studies conducted with asundexian, no relevant 
bleeding events were reported.

The completed Phase 2 studies showed less bleeding when compared to apixaban in 
patients with atrial fibrillation and no clinically relevant increase in bleeding when 
compared to placebo on top of antiplatelet therapy in patients with AMI or non-
cardioembolic stroke.
A risk for bleeding cannot be excluded in participants with AF included in the Phase 3 
study, especially also in patients that receive concomitant therapy with antiplatelet 
therapy. Specific eligibility criteria have been implemented to exclude patients with a 
higher risk for bleeding (e.g. with a known bleeding disorder or on dual antiplatelet 
therapy; refer to Section 5.2). Bleeding will be closely monitored in the study and will 
be adjudicated by an independent and blinded Clinical Events Committee.
2. In toxicology studies, the liver was identified as a target organ in the rat but not in the dog. 
This included dose-dependent spontaneous, mostly transient increases in liver enzymes in 
single animals without clear correlation to histopathological findings in the hepatic tissue. 
Based on this, patients with a > 2.5-fold ALT or AST increase were excluded from the 
PACIFIC Phase 2 studies and liver findings during the studies were defined as AE of 
special interest. Analysis of the AEs of special interest as well as laboratory elevations of 
transaminases from the more than 3000 exposed participants were reassuring, with no 
cases identified meeting Hy’s law criteria (i.e. any elevated ALT or AST > 3 x ULN, AP 
< 2 x ULN, and associated with an increase in bilirubin ≥ 2 x ULN and no alternative 
explanation). Nevertheless, patients with known significant liver disease or known hepatic 
insufficiency classified as Child-Pugh B or C will be excluded in Phase 3, liver parameters 


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are part of the safety laboratory panel and follow-up will be required for certain liver 
events (refer to Section 10.2.1).
3. In all completed Phase 1 and 2 studies asundexian was well tolerated and no additional 
safety signal was identified regarding general safety, laboratory parameters or vital signs 
and ECGs. The dedicated Phase 1 thorough QT study was negative, i.e. asundexian did 
not have an influence on the corrected QT interval at single doses of 50 mg and 150 mg. 
The completed Phase 2 PACIFIC program showed no specific safety concerns regarding 
laboratory parameters or vital signs. Furthermore, no new or unexpected safety topic has 
been identified in the Phase 2 studies. In these studies, the characteristics of SAEs 
(including life-threatening and fatal SAEs) in general are consistent with the 
corresponding clinical populations.
In order to ensure the safety of the patients enrolled in each of the Phase 3 studies, an IDMC 
will monitor the safety with a focus on bleeding and general safety during the study conduct 
for each of the Phase 3 indications. Furthermore, there will be an overarching IDMC 
assessing the data from all 2 studies together.
In conclusion, asundexian is believed to represent a potentially improved new therapeutic 
option for thrombosis prevention in life-threatening thrombotic diseases with superior 
bleeding safety compared to oral anticoagulants and without a significant increase in bleeding 
risk on top of available antiplatelet therapy. This also could permit treatment of patients at 
higher risk for bleeding events than current standards of care allow. Moreover, the dose 
selection was not limited by bleeding in Phase 2, thus choosing the highest dose studied in 
Phase 2, 50 mg once daily, for further investigation in Phase 3. Ultimately, currently available 
preclinical and clinical data from the ongoing and completed studies regarding the key risks 
do not indicate an unfavorable risk profile for asundexian.
2.3.2
Benefit Assessment
At this stage of development there is clinical evidence available suggesting the efficacy 
benefit of asundexian in the non-cardioembolic-stroke indication. The Phase 2 PACIFIC-AF 
study was not planned for assessment of efficacy of asundexian versus apixaban due to the 
limited number of participants with efficacy events within a 3-month intervention period 
(< 0.5% at 3 months), however, the data supporting that this compound is expected to lead to 
prevention of thrombosis events in the intended indications are the following:
FXI and risk for thrombotic events:

In subjects with inherited Factor XI deficiency, a rare coagulation deficiency caused 
by either reduced production of factor XI or by production of a loss-of-function factor 
XI molecule, a lower risk for venous thromboembolic events as well as cardiovascular 
events and especially stroke has been reported. The lower stroke risk was particularly 
evident in patients with atrial fibrillation (Georgi et al. 2019). 

Increased levels of FXI are reported as a risk factor for venous thromboembolism and 
myocardial ischemia or stroke. Whether there is a causal relationship is unclear 
(Schumacher et al. 2010). 
Nonclinical evidence:  

FXI-deficient knockout mice are protected from thrombosis (Wang et al. 2005). In 
addition, in various thrombosis models in rabbits, administration of asundexian 


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resulted in a dose-dependent thrombus weight reduction compared to control animals, 
and this was seen when given alone or on top of dual antiplatelet treatment. While 
clinically relevant doses of NOACs translate into 20-30% thrombus weight reductions 
in such models, asundexian was able to reduce the thrombus formation by up to ~90%
at doses with aPTT prolongations similar to the ones of the 20 and 50 mg doses tested 
in the PACIFIC Phase 2b program (Heitmeier et al. 2022, Piccini et al. 2022).
Clinical evidence: 

Phase 1 Pharmacodynamics:
Studies of asundexian in healthy volunteers are not able to assess efficacy. However, 
after multiple dosing the 50 mg once daily dose in the Phase 1 multiple dose 
escalation study (also the highest dose being tested in Phase 2) lead to nearly complete 
inhibition of FXIa during 12 hours of the day as measured in a fluorogenic assay of 
activated FXIa (AXIA) in plasma. This was combined with a mean prolongation of 
activated partial thromboplastin time (aPTT) of ~105%. In addition, the compound 
was shown to be safe and well tolerated (Kubitza et al. 2005).

Phase 2b Clinical Pharmacodynamics:
In the PACIFIC studies, concentration-dependent, near complete inhibition of FXIa, 
measured with the AXIA assay (Heitmeier et al. 2022), was observed across the 
program. 50 mg OD asundexian led to rapid, sustained and near complete inhibition of 
FXIa, and this observation was consistent across all Phase 2 studies. 
At the same time, the trough mean aPTT prolongation ratio predicted by the current 
popPK-PD model is 1.55 (for PACIFIC-AF) and 1.6 (for PACIFIC-STROKE and 
PACIFIC-AMI) for the 50 mg OD asundexian dose.

Phase 2b Clinical Efficacy:
Data from the PACIFIC-STROKE study indicate a benefit in the prevention of 
ischemic strokes (and TIA) in patients receiving asundexian 50 mg once daily. This 
trend is further supported by post-hoc characterization of relevant subgroups.

Clinical Evidence from Other FXI(a)-Targeting Compounds:
A first proof of concept targeting FXI as anticoagulant had been shown by a FXI 
Antisense Oligonucleotide (Büller et al. 2015), as well as a FXIa antibody (osocimab) 
(Weitz et al. 2020). Reducing FXI levels in patients undergoing total knee arthroplasty 
(TKA) led to an improved prevention of postoperative venous thromboembolism 
(VTE), when compared with enoxaparin. This was confirmed by 2 more recent studies 
with a further antibody compound (abelacimab) (Verhamme et al. 2021), as well as a 
small molecule compound (milvexian) (Weitz et al. 2021), both also tested in TKA 
patients.
Overall, there is no direct clinical evidence yet in patients with atrial fibrillation available 
which confirms the benefit of asundexian for stroke prevention in patients with atrial 
fibrillation. However, based on the clinical, nonclinical, and genetic data presented above, the 
sponsor expects asundexian to bring at least similar if not superior reduction in the risk for 
stroke or systemic embolism when compared to apixaban in patients with atrial fibrillation. 
Significant reduction in stroke in patients with non-cardioembolic stroke or high-risk TIA 
when compared to placebo on top of standard antiplatelet therapy is also expected and 


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supported by available data. Therefore, the data continue to support further development of 
these indications in Phase 3.
2.3.3
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with asundexian are justified by the anticipated 
benefits that may be afforded to participants with atrial fibrillation at risk for stroke. More 
detailed information about the known and expected benefits and risks and commonly reported 
AEs of asundexian may be found in the Investigator’s Brochure.
In light of all measures implemented in this study to prevent infection of study participants 
with SARS-CoV-2 during the entire study conduct, the benefit / risk assessment for the 
conduct of this study is not altered by the COVID-19 pandemic in its current extent. The 
benefit / risk assessment will be continuously monitored during the conduct of this study and 
will be updated in accordance to changes of the COVID-19 pandemic situation and related 
authority regulations and recommendations.


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3.
Objectives, Endpoints, and Estimands
Objectives and endpoints (primary, secondary and exploratory) and estimands of the study 
are reported below.
Table 3–1: Study objectives and endpoints
Objectives
Endpoints
Primary
Efficacy
To demonstrate that asundexian is superior (at 
least non-inferior) when compared with 
apixaban for prevention of stroke and systemic 
embolism in participants with atrial fibrillation at 
risk for stroke

Composite of stroke or systemic embolism*
Safety
To demonstrate that asundexian is superior to 
apixaban as assessed by ISTH major bleeding 
in participants with atrial fibrillation at risk for 
stroke

ISTH major bleeding*
Net clinical benefit
To demonstrate that asundexian is superior to 
apixaban with respect to benefit and risk

Composite of stroke, systemic embolism, or 
ISTH major bleeding*
Secondary
Efficacy
To compare the effects of asundexian and 
apixaban with respect to composite and 
individual efficacy endpoints

Composite of ischemic stroke or systemic 
embolism*

All-cause mortality*

Ischemic stroke* 

CV death*

Composite of CV death, stroke, or 
myocardial infarction*
Safety
To compare asundexian and apixaban with 
respect to composite and individual bleeding 
endpoints

Composite of ISTH major or clinically 
relevant non-major bleeding*

Clinically relevant non-major bleeding*

Hemorrhagic stroke*

Intracranial hemorrhage*

Fatal bleeding*

Minor bleeding*


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Net clinical benefit
To compare the benefit and risk of asundexian 
and apixaban with respect to a composite of 
efficacy and safety endpoints

Composite of stroke, systemic embolism, 
ISTH major bleeding, or all-cause mortality*

Composite of disabling stroke (mRS ≥ 3), 
critical bleedingǂ, or all-cause mortality*
Exploratory
Efficacy
To further investigate the efficacy of the study 
intervention 

Composite of CV death, stroke, or systemic 
embolism*

Systemic embolism*

Hemorrhagic stroke*

Disabling stroke (mRS ≥ 3)*
To investigate the effect of the study 
interventions on quality of life

EQ-5D
Safety
To further investigate the safety of the study 
intervention

Gastrointestinal bleeding*

All bleeding*

BARC type 3 and 5 bleeding*

BARC type 2, 3 and 5 bleeding*

BARC type 1 bleeding* 

Total number of ISTH major bleeding events
Net clinical benefit
To further investigate the benefit and risk of the 
study intervention

Composite of weighted vascular efficacy 
and bleeding safety outcomes as defined by 
formal assessment of patient or physician 
preference

Total number of hospitalizations due to 
efficacy or safety outcome events
Other 
To further investigate the study intervention, 
and drugs with similar, e.g. mode-of-action 
related effects, and to further investigate 
pathomechanisms deemed relevant to 
cardiovascular diseases and associated health 
problems

PK and various biomarkers (e.g. diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers)
Abbreviations: BARC = Bleeding Academic Research Consortium, CV = cardiovascular, EQ-5D = European 
Quality of Life group 5-Dimension questionnaire, ISTH = International Society on Thrombosis and Hemostasis, 
mRS = modified Rankin Scale, PK = Pharmacokinetic(s)
* Time to first occurrence
ǂ Critical bleeding is defined as symptomatic bleeding in either of the following critical locations (intracranial, 
intraspinal, pericardial, intra-articular, or retroperitoneal) or as intraocular bleeding with compromised vision or 
intramuscular bleeding with compartment syndrome
The estimands for the primary efficacy, safety and net clinical benefit objectives are 
described as follows:
For the primary efficacy objective:
to demonstrate that asundexian is superior (at least non-inferior) when compared with 
apixaban for prevention of stroke and systemic embolism in participants with atrial 
fibrillation at risk for stroke


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the primary efficacy estimand for non-inferiority and for superiority assessment is 
described by the following attributes:

Population: Adult individuals with AF at risk for stroke 

Treatment condition:

Experimental: once daily oral administration of 50 mg of asundexian

Control: twice daily oral administration of 5 mg of apixaban (or reduced dose of 
2.5 mg)

Endpoint: time to first occurrence of stroke or systemic embolism

Population-level summary: Cause-specific hazard ratio (i.e. ratio of cause-specific 
hazard rates of the primary endpoint) comparing the two treatment conditions

Intercurrent events and strategies: 

Early discontinuation of assigned treatment: addressed by the treatment policy 
strategy, i.e. the treatment effect including effects of treatment discontinuation is 
of interest and primary endpoint events and observation time will be used 
regardless of treatment discontinuation

Death: addressed by the “while alive” strategy, i.e. primary endpoint events and 
observation time up until death will be used

Treatment with dual antiplatelet therapy: addressed by the treatment policy 
strategy, i.e. the treatment effect includes the effect of dual antiplatelet therapy

Other intercurrent events related to COVID-19: will be handled according to the 
treatment policy strategy, i.e. the treatment effect includes the effect of intercurrent 
events related to COVID-19 (other than the mentioned intercurrent events).
Rationale for the primary efficacy estimand:
The clinical question related to the primary efficacy endpoint has two parts: 
1. The first part of the objective is to show non-inferiority
2. The second part of the objective is to demonstrate superiority
of assigning asundexian versus apixaban for preventing stroke or systemic embolism in adult 
patients with AF at risk for stroke. 
Relative to apixaban it is expected that asundexian will reduce the instantaneous risk for 
experiencing a stroke or systemic embolism in patients with AF over time. To summarize the 
relative effect of the two treatment conditions over time, the ratio of cause-specific hazard 
rates of the primary efficacy outcome is considered an appropriate summary measure. It will 
be supplemented with estimates of the cumulative incidence over time.
In terms of observing a primary efficacy outcome, death of participants after treatment 
assignment is considered a competing risk because it would preclude the primary efficacy 
outcome from occurring. Therefore, it is of interest to characterize the treatment effect prior to 
the death of a study participant, using the “while alive” strategy. In this setting, information 
on the treatment effect on the competing event “death” itself will complement the 
understanding of the treatment effects on outcome events other than death.
Further, it is assumed that an early discontinuation of asundexian or apixaban will alter the 
probability of the occurrence of a primary efficacy outcome event. 


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The primary clinical question is about the difference between assigning asundexian versus 
apixaban including effects of treatment discontinuation and implicitly, also including 
subsequent open label treatment with an anticoagulant. Assuming a beneficial effect of 
asundexian, using the treatment policy strategy is considered to produce a conservative 
estimate of the average effect that might be seen in clinical practice.
The need of dual antiplatelet therapy after randomization and intercurrent events related to the 
COVID-19 pandemic are addressed with the “treatment policy strategy”, meaning that the 
effects of these intercurrent events are included into the estimation of the treatment effect. 
Thus, the estimation of the treatment difference reflects the clinical practice of confounding 
factors that cannot be controlled for.
The same estimand was defined for both the non-inferiority and the superiority evaluation and 
is in line with CPMP “Points to consider on switching between superiority and non-
inferiority” (Committee for Proprietary Medicinal Products 2001). The trial will be carried out 
in accordance with the strict requirements (in terms of protocol deviations) of a non-
inferiority trial and measurements of protocol deviations as well a premature discontinuation 
will be monitored during the conduct of the study.
To support decision making a supplemental analysis will be performed for an estimand more 
specifically targeting the non-inferiority objective to provide additional insights into the 
understanding of the treatment effect.
For the primary safety objective: 
to demonstrate that asundexian is superior to apixaban in participants with atrial fibrillation 
as assessed by ISTH major bleeding 
the primary estimand for safety assessment is described by the following attributes:

Population: Adult individuals with AF at risk for stroke exposed to at least one dose 
of treatment

Treatment condition: 

Investigational: once daily oral administration of 50 mg of asundexian 

Control: twice daily oral administration of 5 mg of apixaban (or reduced dose of 
2.5 mg)

Endpoint: time to first occurrence of ISTH major bleeding

Population-level summary: Cause-specific hazard ratio (i.e. ratio of cause-specific 
hazard rates of the primary safety endpoint) comparing the two treatment conditions

Intercurrent events and strategies: 

Early discontinuation of assigned treatment: addressed by the “while on treatment” 
strategy, i.e. primary safety events and observation time prior to the occurrence of 
the intercurrent event (here: up to the date of last intake of assigned treatment plus 
2 calendar days) will be used 

Death: addressed by the “while alive” strategy, i.e. primary safety events and 
observation time up until death will be used 

Treatment with dual antiplatelet therapy: addressed by the treatment policy 
strategy, i.e. the treatment effect includes the effect of dual antiplatelet therapy


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
Other intercurrent events related to COVID-19: will be handled according to the 
treatment policy strategy, i.e. the treatment effect includes the effect of intercurrent 
events related to COVID-19 (other than the mentioned intercurrent events).
Rationale for the primary safety estimand:
The clinical question related to the primary safety endpoint is about a reduced risk for ISTH 
major bleeding when treating adult patients with AF at risk for stroke with asundexian as 
compared to apixaban.
The ratio of cause-specific hazard rates of the primary safety outcome is expected to 
summarize the relative effect of the two treatment conditions over time. As the hazard rate for 
asundexian is assumed to be constant over time and the same holds true for apixaban after 
some time of treatment, the ratio is assumed to be constant. Deviations from that assumption 
are negligible.
Similar to what has been described for the efficacy estimand, in terms of observing a primary 
safety outcome, death (unrelated to bleeding) of patients after treatment initiation is 
considered a competing risk because it would preclude the primary safety outcome from 
occurring. Therefore, it is of interest to characterize the treatment effect prior to the death of a 
study participant, using the “while alive” strategy. In this setting, information on the treatment 
effect on the competing event “death” itself will complement the understanding of the 
treatment effects on outcome events other than death.
An early discontinuation of asundexian or apixaban (or the underlying reasons leading to 
treatment discontinuation) could alter the probability of the occurrence of a primary safety 
outcome event. It is of interest to quantify the risk associated with the intake of asundexian, 
i.e. while patients are exposed to the treatments. A participant is to be assumed exposed to 
study intervention up to 2 days after the last intake of study intervention. Therefore, the 
proposed estimand for the safety question addresses early treatment discontinuation using a 
“while exposed to randomized treatment” strategy (in the past: “on treatment effect”). This 
decision implies that early treatment discontinuation is considered a (”soft”) competing risk. 
Information on the treatment effect on the competing event “early treatment discontinuation” 
itself will complement the understanding of the treatment effects on outcome events. 
Similar to the efficacy estimand the intercurrent events “treatment with dual antiplatelet 
therapy after randomization” and “intercurrent events related to the COVID-19 pandemic” 
will be addressed with the “treatment policy strategy” with the same rationale as for the 
efficacy estimand.
Patients who were assigned to a treatment arm (i.e. randomized) but never took a single dose 
of randomized treatment will be addressed via the population attribute of the estimand, i.e. the 
population is defined as those patients taking randomized treatment at least once.
For the primary net clinical benefit objective:
to demonstrate that asundexian is superior when compared to apixaban with respect to 
benefit and risk 
the estimand for net clinical benefit assessment is described by the following attributes:

Population: Adult individuals with AF at risk for stroke exposed to at least one dose 
of treatment

Treatment condition: 


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
Investigational: once daily oral administration of 50 mg of asundexian

Control: twice daily oral administration of 5 mg of apixaban (or reduced dose of 
2.5 mg)

Endpoint: time to first occurrence of stroke, systemic embolism, or ISTH major 
bleeding (excluding hemorrhagic stroke)

Population-level summary: Cause-specific hazard ratio (i.e. ratio of cause-specific 
hazard rates of the net clinical benefit endpoint) comparing the two treatment 
conditions

Intercurrent events and strategies: 

Early discontinuation of assigned treatment: addressed by the “while on treatment” 
strategy, i.e. events of the net clinical benefit endpoint and observation time prior 
to the occurrence of the intercurrent event (here: up to the date of last intake of 
assigned treatment plus 2 calendar days) will be used 

Death: addressed by the “while alive” strategy, i.e. net clinical benefit events and 
observation time up until death will be used 

Treatment with dual antiplatelet therapy after randomization: addressed by the 
treatment policy strategy, i.e. the treatment effect includes the effect of dual 
antiplatelet therapy

Other intercurrent events related to COVID-19: will be handled according to the 
treatment policy strategy, i.e. the treatment effect includes the effect of intercurrent 
events related to COVID-19 (other than the mentioned intercurrent events)
Rationale for primary net clinical benefit assessment estimand:
The clinical question related to the net clinical benefit endpoint is about a positive net clinical 
benefit effect of treatment with asundexian as compared with apixaban in adult patients with 
AF at risk for stroke. 
With respect to intercurrent events, it will follow the strategies as described for the primary 
safety outcome as the objective of the investigation of this endpoint is to describe a broader 
safety profile including the benefit of prevention of stroke and systemic embolism and the risk 
of more bleeding.
Further secondary estimand(s)
Estimands for other secondary efficacy, safety and net clinical benefit endpoints are defined 
following the same approach as done for their primary estimands.
Please refer to Section 9 for a description how data is handled in the statistical analysis to 
estimate the defined estimands.


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4.
Study Design
4.1
Overall Design
Study 19767 is a multicenter, randomized, active comparator-controlled, double-blind, 
double-dummy, parallel-group, 2-arm, Phase 3 study. The overall study design is depicted in 
Figure 1–1. 
Approximately 18000 participants ≥ 18 years of age, will be randomized to 1 of the 2 arms 
(approximately 9000 participants per arm), as follows:

1 investigational study intervention arm (asundexian) or

1 active comparator arm (apixaban),
in addition to their potential background therapy (see Section 6.9).
Patients will be eligible for the study based on their CHA2DS2-VASc risk score, among other 
criteria. With a score of ≥ 3 if male or ≥ 4 if female, patients can get enrolled straight into the 
study. Patients with a CHA2DS2-VASc score of 2 if male or 3 if female can participate in the 
study by meeting at least one of the following enrichment criteria in addition:

age ≥ 70

previous stroke, transient ischemic attack, or systemic embolism

renal dysfunction with eGFR < 50 ml/min within 14 days prior to randomization

prior episode of non-traumatic major bleeding

current single agent antiplatelet therapy planned to continue for at least 6 months after 
randomization

≤ 6 consecutive weeks of treatment with oral anticoagulant prior to randomization
In order to offer study participation to patients who might be unwilling or unable to 
participate in a conventional, on-site study model, a fully remote decentralized clinical trial 
(DCT) model may be implemented in select countries where feasible and local 
laws / regulations allow (refer to Section 10.10, if applicable). For sites participating in the 
DCT model, remote visit activities are completed in place of on-site visits.
Randomization will be first stratified by participation in the conventional study model vs. in 
the DCT model. This will be succeeded by stratification for current use vs. no current use of 
single agent antiplatelet therapy planned to continue for at least 6 months after randomization. 
Following stratification, participants will be assigned randomly via IRT to 1 of the 2 arms, in 
a 1:1 ratio. 
This is an event-driven study, and the sponsor will request termination of the intervention 
period once about 340 participants have experienced a primary efficacy endpoint event. At the 
same time approximately the same number of participants are expected to experience a 
primary safety outcome. The planned individual study duration is expected to be 10-34 
months; however the timelines may vary (i.e. longer or shorter than planned) depending on 
enrollment rate and incidence rate in the study. The study will consist of the following study 
periods:

Screening period (from visit 1 until visit 2): 2 weeks (participants will be screened 
and have to be randomized within 2 weeks after screening). There will be a screening 


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visit followed by a randomization visit within 2 weeks. If all information is available, 
a participant can be randomized on the day of screening (visits 1 and 2 are combined).
For participants in the DCT model, after obtaining informed consent, an additional 
time interval of up to 2 weeks will be required, during which operational logistics will 
be initiated (refer to Section 10.10 for more details).

Intervention period (from visit 2 until the CEOT visit): approximately 9-33 
months. 
The visit frequency after randomization will be a first visit after one month, the next 
visit after 3 months and then every 3 months. Site visits (remote visits for DCT 
model) will take place after 3 months, 6 months and then every 6 months until the 
CEOT visit. Phone visits will take place after 1 month, 9 months and then every 6 
months in between site visits (remote visits). Safety follow-up visits will take place as 
phone calls, unless the investigator and the participant agree that those should be 
preferably done at the site. 
The last day of intake of study intervention will be on the day before the CEOT visit. 
For an individual participant the CEOT visit marks the end of the intervention period 
(for participants permanently discontinuing study intervention, refer to “early 
termination period”). For planning the CEOT visits, the sponsor will notify the sites in 
advance of the CEOT date, which is an actual calendar date at which time it is 
projected that the required number of primary endpoint events will have accrued (see 
Section 9.5 for details). The sites will be informed of the allowed window for the 
CEOT visits (CEOT date ± 3 weeks approximately). 
If the number of events does not accrue as quickly as expected, visits in the 
intervention period might need to be continued longer than anticipated (expected 
individual time in intervention period: 9-33 months). This will be done in the same 
way as before until the CEOT visit, i.e. site visits and phone visits will be performed 
in alternating order every 3 months.

Common End of treatment period (from CEOT visit until CEOT SFU visit): 2 
week period that will end upon completion of the CEOT SFU visit for participants 
who did continue intake of study intervention as expected. 
A participant only temporarily interrupting study intervention intake and taking the last dose 
within less than 2 weeks before the CEOT visit will complete the study upon completion of 
the CEOT SFU visit. A participant temporarily interrupting study intervention with a final 
dose taken 2 or more weeks before the CEOT will complete the study upon completion of the 
CEOT, and in such a case no additional SFU telephone call will be required thereafter.
Only in case participants permanently discontinue study intervention earlier than planned:

Early termination (ET) period (from ET until CEOT visit): If the study 
intervention is permanently discontinued earlier than expected (earlier than on the day 
before the CEOT visit), the participant will enter the ET period and an ET visit has to 
performed as soon as possible. In addition a SFU visit will also need to be conducted 2 
(+1) weeks after permanent discontinuation.
All living participants who permanently discontinued study intervention prior to the 
CEOT visit are still part of the study and should participate in their visits as scheduled 
as part of their ET period. Those visits are foreseen to take place via telephone calls, 
unless participant or investigator prefer on-site visits. In those participants also the 


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above mentioned CEOT visit will need to be performed, that marks the end of the ET 
period.
For participants who permanently discontinue study intervention 2 or more weeks 
prior to the CEOT visit, an ET SFU visit will also be conducted 2 weeks after 
permanent discontinuation of study intervention. If the ET visit is delayed and is 
conducted 2 or more weeks after permanent discontinuation of study intervention, an 
additional ET SFU visit will not be performed. In any of these participants the CEOT 
is supposed to be the last study visit.
For participants who permanently discontinue study intervention less than 2 weeks 
prior to the CEOT visit, the ET SFU visit will be replaced by the CEOT SFU visit, 
that is to be conducted after the CEOT visit and is the last study visit in those 
participants. Further details on premature discontinuation of the study intervention are 
reported in Section 7.1.
Details of study procedures and their timing are summarized in the SoA (Section 1.3).
4.1.1
Decentralized Clinical Trial Model
This fully remote DCT model intends to follow the conventional on-site activity schedule as 
much as possible. The DCT model will substitute remote visits where on-site visits are 
conducted in the conventional model, and it will incorporate more patient-centric and 
convenient methods for obtaining blood samples, vital signs and for dispensation of study 
investigation. Participants following the DCT model will utilize technology (mobile 
application and / or web-based platform) to access study-specific applications, including 
eConsent, ePRO, sensor data (ECG), and a teleresearch visit tool. Participants will be 
provided with a “participation kit” which, as a standard, will include instructional guide, ECG 
device and a provisioned smartphone, unless the participants opt to use their own device 
(BYOD). Participants may be supported by home health or family member / caregiver with 
the participation kit, if needed.
In the DCT model, remote visits requiring laboratory samples will be divided into 2 parts. For 
the first part, home nurses will visit the participant at home to complete the designated study 
procedures (see Section 10.10.2), or the option to visit a patient service center may be 
possible for collection of lab samples or execution of other procedures in some locations. For 
the second part of the visit, the investigator, or designee, will conduct the specified study 
procedures with the participant via teleresearch video call. Remote visits without laboratory 
sampling will be conducted via teleresearch only. Subsequent to the visit, the relevant IRT 
transaction will be made, and supply of study intervention requested. Study intervention will 
be shipped DtP in appropriate shipping containers (see Section 6 for more information). Due 
to the timelines associated with shipping new study intervention to the participant’s home for 
remote visits, it is possible that study intervention resupply does not happen within the 
scheduled visit window. This should be avoided, yet it is not considered a protocol deviation.
Technology will also provide the investigator and authorized site representatives access to a 
web-based portal via unique credentials to review and perform study activities.


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4.2
Scientific Rationale for Study Design
This pivotal Phase 3 study will evaluate the efficacy and safety of asundexian compared with 
apixaban for the prevention of stroke or systemic embolism in participants with atrial 
fibrillation. The study aims at showing that the oral FXIa inhibitor asundexian (50 mg once 
daily dosage) when compared with apixaban (a NOAC, FXa inhibitor, 5 mg / 2.5 mg  doses 
twice daily according to label) leads to a similar or lower cause-specific hazard ratio of the 
composite of stroke or systemic embolism as well as a lower cause-specific hazard ratio of 
ISTH major bleeding. 
Study 19767 is a randomized, active comparator-controlled, double-blind, double-dummy, 
parallel-group, 2-arm, Phase 3 study in 18000 participants (9000 participants per arm) with 
atrial fibrillation. The study will apply the principles of randomization and double-blinding in 
order to prevent bias in the inclusion of participants or reporting of safety or efficacy events.
There is no requirement for a dose escalation or reduction approach for asundexian, because 
based on the available preclinical and clinical data for asundexian there are no safety concerns 
related to the selected dose of 50 mg once daily tested in the study (see section 6.1). 
The study will include participants who have been treated with an oral anticoagulant for no 
more than 6 consecutive weeks at randomization (labelled “OAC naïve”), e.g. participants 
newly diagnosed with AF. Furthermore, participants on an OAC for more than 6 consecutive 
weeks at randomization can participate (labelled “OAC experienced”). Participants on VKA 
are excluded from the study, unless they have stopped treatment with a Vitamin K antagonist 
at least 10 days prior to randomization and their INR is < 2, as the switch from VKA to study 
intervention may otherwise lead to bleeding events related to overlapping PD effects in the 
period and not to the assigned study intervention itself.
A limited number of sites and participants will execute study activities remotely, following 
the DCT model (see Section 10.10). DCTs are an operational strategy leveraging technology 
to enable clinical study activities in settings more local to the participants. This approach 
centers the clinical study around the participant, allowing individuals more choice in how they 
participate. There is a growing body of evidence supporting the use of broadband internet 
access, home computing and smartphones as well as digital health technologies enabling 
remote interactions and robust monitoring, support, and management of trial participants. 
DCTs are intended to reduce the burden on clinical study participants and make a study more 
visible and accessible to patients independently of referring physicians.
4.2.1
Patient Input into Design
Feedback was collected from the AF patient population through patient surveys with the 
intent to:

Seek input on the content and visual design of study-related awareness and 
educational materials

Gather patient perspective on weighting of different study endpoints

Gather patient view on the relevance of the DCT approaches

Identify potential hurdles to recruitment, adherence with the study procedures, and 
participant retention 

Gather patient perspective on the selection of technologies.


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4.3
Justification for Dose
The study will test 50 mg of asundexian once daily.
The selection of the dose in this study was based on the safety and tolerability data from 
toxicology studies, the results of the human Phase 1 studies conducted in healthy volunteers, 
as well as the results of the Phase 2 PACIFIC program conducted in participants with AF, 
non-cardioembolic stroke and AMI.
The dose of 50 mg was widely tested among the 3 different indications of the Phase 2 
PACIFIC program and demonstrated favorable bleeding safety against apixaban (in the 
PACIFIC-AF study), as well as no relevant increase in bleeding in participants treated with 
asundexian compared to placebo (PACIFIC-STROKE and PACIFIC-AMI). Across the Phase 
2 studies, the evaluation of the AEs, laboratory parameters, vital signs and ECG did not show 
any unfavorable safety signals for asundexian. The dose selection was not limited by bleeding 
in Phase 2, thus choosing the highest dose studied in Phase 2, 50 mg once daily, for further 
investigation in Phase 3. The PACIFIC-AF Phase 2 study was neither powered nor designed 
to test for differences in rates of efficacy events, and in consequence those were only 
described in an exploratory fashion. In PACIFIC-STROKE a favorable trend in benefit for 
symptomatic ischemic stroke in participants taking asundexian was seen. Based on the 
available data, asundexian 50 mg leads to a near complete inhibition of FXIa, showing a 
favorable benefit-risk profile. Taken all together, the current results support further 
development of asundexian in Phase 3. More detailed information may be found in the 
Investigator’s Brochure.
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 
globally. The date of the last visit of the last participant in the study globally will also be 
regarded as primary completion date according to the FDA Amendment Act.
5.
Study Population
The study will enroll adult participants with AF at moderate to high risk for future 
thromboembolic events and who therefore qualify for oral anticoagulant therapy.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
In order to have a balanced study population across the eligibility criteria, and to avoid 
overrepresentation of any single entry criterion, recruitment of participants will be monitored 
on an ongoing basis. If an imbalance is observed (e.g. overrepresentation of CHA2DS2-VASc 
score of 2 if male, or 3 if female), enrolment based on the affected criterion may be restricted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. 18 years of age or older (at legal age of consent according to local legislation) 
at the time of signing the informed consent.


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Type of Participant and Disease Characteristics
2. Atrial fibrillation documented by ECG evidence* with an indication for indefinite 
treatment with an oral anticoagulant
3. CHA2DS2-VASc score ≥ 3 if male or ≥ 4 if female,
OR
CHA2DS2-VASc score of 2 if male or 3 if female and
at least one of the following enrichment criteria:

age ≥ 70

previous stroke, transient ischemic attack, or systemic embolism

renal dysfunction with eGFR < 50 ml/min within 14 days prior to randomization

prior episode of non-traumatic major bleeding

current single agent antiplatelet therapy planned to continue for at least 6 months 
after randomization

≤ 6 consecutive weeks of treatment with oral anticoagulant prior to randomization.
Sex and Contraceptive / Barrier Requirements
4. Male or female
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Male participants: there are no measures required for the study
Female participants: a female participant is eligible to participate if she is not 
pregnant or breastfeeding, and one of the following conditions applies:

is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 4
OR

is a woman of childbearing potential (WOCBP) and using a contraceptive method 
that is highly effective, with a failure rate of < 1%, as described in Appendix 4 
during the study intervention period and for at least 4 days after the last dose of 
study intervention. The investigator should evaluate the potential for contraceptive 
method failure (e.g. noncompliance, recently initiated) in relationship to the first 
dose of study intervention.
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 4 days before the first dose of study 
intervention, see Section 8.3.8. If a urine test cannot be confirmed as negative (e.g. 
an ambiguous result), a serum pregnancy test is required. In such cases, the 
participant must be excluded from participation if the serum pregnancy result is 
positive. See country-specific requirements for the Republic of Korea (KOR-1) in 
Section 10.12.3.1.

Additional requirements for pregnancy testing during and after study intervention 
are located in Section 8.3.8. The investigator is responsible for review of medical 
                                                
* AF should be documented within the last 12 months prior to randomization, either on a 6 (or more)-lead ECG 
or otherwise as an episode of AF of at least 30 seconds in case of continuous ECG recording, rhythm strip, 
pacemaker or implantable cardiac defibrillator interrogation


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history, menstrual history, and recent sexual activity to decrease the risk for 
inclusion of a woman with an early undetected pregnancy.
Informed Consent
5. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Mechanical heart valve prosthesis (not including transcatheter aortic valve 
replacement)
2. Moderate-to-severe mitral stenosis at the time of inclusion into the study
3. Atrial fibrillation only due to reversible cause (e.g. thyrotoxicosis, endocarditis, 
pneumonia, pulmonary embolism)
4. Participants after successful ablation therapy without documented recurrent AF or 
participants after left atrial appendage (LAA) occlusion / exclusion or plan for ablation 
or LAA occlusion / exclusion within the next 6 months starting from randomization
5. Recent ischemic stroke (within 7 days prior to randomization)
6. Active non-trivial bleeding; known chronic bleeding disorder (e.g. von Willebrand 
disease or other coagulopathies); history of non-traumatic intracranial hemorrhage 
(does not include cerebral microbleeds or asymptomatic hemorrhagic transformation 
of an ischemic stroke)
7. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) 
or known hepatic insufficiency classified as Child-Pugh B or C at randomization. See 
country-specific requirements for the Republic of Korea (KOR-1) in Section 10.12.3.1.
8. Estimated glomerular filtration rate (eGFR) < 25 mL/min/1.73 m2 within 14 days prior 
to randomization, calculated by Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula (see Section 10.6), or on dialysis or expected to be started on 
dialysis within the next 12 months starting from randomization
9. Major surgery during the last 30 days prior to randomization
10. Known allergy, intolerance or hypersensitivity to either of the study interventions 
(active substance or excipients)
11. Any contraindication for the use of an anticoagulant or listed in the local labelling for 
apixaban. See country-specific requirements for the Republic of Korea (KOR-1) in 
Section 10.12.3.1.
Prior / Concomitant Therapy
12. Requirement for chronic anticoagulation for a different indication than AF, e.g. 
mechanical heart valve or left ventricular cardiac thrombus (atrial thrombus is 
allowed), or dual antiplatelet therapy (single agent therapy is allowed)


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13. Treatment with Vitamin K antagonist (VKA) in the 10 days prior to randomization 
(International Normalized Ratio [INR] ≥ 2 prior to randomization if VKA was used)
14. Concomitant use of or anticipated need for:

daily or near daily (> 5 days per week) therapy with nonsteroidal anti-
inflammatory drugs (NSAIDs) for more than 4 weeks during the study period

herbal or traditional medicine, and / or supplements with known anticoagulant 
and / or antiplatelet effect

combined P-glycoprotein (P-gp) and strong cytochrome P450 isoenzyme 3A4 
(CYP3A4) inhibitors e.g. human immunodeficiency virus protease inhibitors, 
systemically used azole antimycotic agents, clarithromycin, nefazodone

combined P-gp and strong / moderate CYP3A4 inducers, e.g. phenytoin, 
carbamazepine, phenobarbital, rifampicin or St. John’s wort
Respective substances (apart from NSAIDs) must be stopped – in case of combined 
inhibitors / inducers of CYP3A4 and P-gp for at least 14 days (or at least five half-
lives of the active substance, whichever is longer) – before randomization and first 
intake of study intervention.
Prior / Concurrent Clinical Study Experience
15. Previous (within 30 days or 5 half-lives of the investigational drug, whichever is 
longer) or concomitant participation in another clinical study with investigational 
medicinal product(s) or device(s). Registries and observational studies are allowed.
Other Exclusions
16. Known current alcohol and / or illicit drug abuse that may interfere with the 
participant’s safety and / or compliance at the discretion of the investigator
17. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
or a dependent person (e.g. employee or student of the investigational site or the 
sponsor)
18. Any other history, condition or therapy, or uncontrolled intercurrent illness which 
would make the participant unsuitable for the study (e.g. noncompliance) or otherwise 
vulnerable (e.g. participant in custody by order of an authority or a court) or life 
expectancy < 12 months.
For DCT model only
19. Not willing or able to use the smartphone and / or electronic devices to access the web-
based platform / app required for the DCT-elements.
For country-specific requirements for the Republic of Korea (KOR-1), please see Section 
10.12.3.1.
5.3
Lifestyle Considerations
No restrictions during any of the study periods pertaining to lifestyle (except for the above 
mentioned substance abuse) and / or diet apply.


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5.4
Screen Failures
A screen failure occurs when a participant consents to participate in the clinical study but is 
not subsequently randomly assigned to study intervention. 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, and eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at any time within the recruitment period. This also applies if a participant 
had successfully passed the screening procedures, but could not be randomized to treatment 
on schedule (e.g. due to unavailability of study intervention). The investigator has to ensure 
that the repeated screening procedures do not expose the participant to an unjustifiable health 
risk. In the event of rescreening, participants should be assigned a new participant number. 
Please refer to Section 10.1.3 for the informed consent process for rescreening.
5.5
Criteria for Temporarily Delaying Enrollment or Randomization
Not applicable.
6.
Study Intervention(s) and Concomitant Therapy
Study interventions are all pre-specified investigational and non-investigational medicinal 
products, devices and other interventions (e.g. surgical and behavioral) intended to be 
administered to the study participants during the study conduct.
6.1
Study Intervention(s) Administered
The following study interventions will be administered in the study:

Asundexian: sponsor’s study intervention under investigation

Placebo to asundexian

Apixaban: marketed product used as comparator 

Placebo to apixaban
Asundexian is taken orally once a day, if possible in the morning, preferably around the same 
time each day (for exceptions see Section 8.5). The immediate-release tablets will be provided 
as pink, oval, film-coated tablets containing 50 mg of asundexian (see Table 6–1).
Apixaban, the active comparator used in this study, is a selective, orally active inhibitor of 
the coagulation Factor Xa (FXa) developed by Bristol-Myers Squibb (BMS) and Pfizer as an 
anticoagulant agent. It is supplied as 5 mg and 2.5 mg tablets. Apixaban is taken orally twice 
a day. The usual dose is 5 mg, reduced to 2.5 mg for participants with any 2 of the following 
criteria: age 80 years or older, body weight of 60 kg or less, or serum creatinine level of 1.5 
mg per dL (133 µmol/L) or more. Participants have to receive the dose of apixaban according 
to the label and the respective initial dosage of apixaban for the first intake of study 
intervention will be determined based on the values current at the randomization visit. If a 
participant will manifest at least 2 of the characteristics requiring dose adjustment while on 
study intervention, the apixaban (or placebo) dosage regimen may be adjusted at the 
subsequent study intervention dispensation. In case a participant starts with receiving a dose 


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of 2.5 mg BID, and later on fewer than 2 of the characteristics apply, adjustment to 5 mg BID 
at the following study intervention dispensation time point should be considered. In case a 
participant is affected by a sustained decrease of kidney function (eGFR < 30 ml/min) there is 
the option to reduce the apixaban dose to 2.5 mg BID – independent of meeting at least 2 of 
the above mentioned dose reduction criteria – if this is according to the locally applicable 
apixaban label. In any case, dose modifications will need to be registered within the IRT 
(including documentation of the applicable justifying criteria leading to the dosage change) as 
well as in the CRF. See country-specific requirements for the Republic of Korea (KOR-1) in 
Section 10.12.3.1.
The study interventions (tablets) are not to be broken, halved or crushed, and should be 
swallowed whole with a glass of water. Both asundexian as well as apixaban can be taken 
irrespective of food intake.
Matching placebos for asundexian and both strengths of apixaban are supplied in the same 
way. 
For apixaban / placebo one tablet in the morning and one tablet in the evening are to be taken 
from the apixaban bottle. For asundexian / placebo one tablet only is to be taken from the 
respective bottle, if possible in the morning. At Visits 4 and 7 participants should not take 
study intervention as usual in the morning at home, as a PK / PD sample will be drawn at the 
site before intake of study intervention (refer to Table 1–2). Study intervention at those visits 
should be taken out of the respective bottle that participants receive at their dispensation visit 
(i.e. at Visit 4 and Visit 7).
The planned double-blind intervention period starts at randomization and ends when study 
intervention is permanently discontinued. Study intervention intake will start as soon as 
possible after randomization (day 1), preferably on the day of randomization (unless e.g. 
medical reasons do not allow for this), and is expected to continue through the end of the 
planned treatment. For participants in the DCT model, please see Section 10.10.
Missed study intervention dose
If a dose of asundexian is missed, the participant should take a dose immediately on the same 
day, up until 12 hours after the scheduled intake. After this time point, the dose should be 
skipped, and the next scheduled dose should be taken.
If a dose of apixaban is missed, the dose should be taken as soon as possible on the same day, 
up until 6 hours after the scheduled intake. After this time point, the dose should be skipped, 
and the next scheduled dose should be taken. If possible a twice daily administration should 
be resumed.
The dose of either study intervention should not be doubled to make up for a missed dose.


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Table 6–1: Study Interventions Administered
Intervention 
Arm Label
Asundexian
Apixaban
Intervention 
Name
Asundexian 
Placebo to 
apixaban
Apixaban
Placebo to 
asundexian
Dose
Formulation
tablet
tablet
tablet
tablet
Unit Dose 
Strength(s)
50 mg
NA
5 mg OR
2.5 mg
NA
Dosage Level(s)
50 mg
NA
5 mg OR
2.5 mg
NA
Frequency
Once a day, 
preferably in the 
morning
Twice a day
Twice a day
Once a day, 
preferably in the 
morning
Route of 
Administration
oral
oral
oral
oral
Use
Experimental
Placebo 
(comparator)
Active 
comparator
Placebo 
(experimental) 
Packaging and 
Labeling
HDPE bottles. 
Each bottle will 
be labeled as per 
country 
requirement
HDPE bottles. 
Each bottle will 
be labeled as per 
country 
requirement
HDPE bottles. 
Each bottle will 
be labeled as per 
country 
requirement
HDPE bottles. 
Each bottle will 
be labeled as per 
country 
requirement
Abbreviations: HDPE = high-density polyethylene, NA = not applicable
Table 6–2: Study Arms
Arm Title
Asundexian
Apixaban
Arm Type
Experimental
Active comparator
Arm Description
Participants will receive 
asundexian
Participants will receive apixaban
Associated 
Intervention Labels
Asundexian and placebo to 
apixaban
Apixaban and placebo to 
asundexian
6.1.1
Switching to Study Intervention and Back to Open Label 
Anticoagulant
When being enrolled, or in case of the DCT model before the start of the clinical assessments 
and procedures of the screening phase (Visit 1b), study participants may be treated with a 
NOAC or may not be treated with any oral anticoagulant.
Participants treated with a VKA are only eligible if the VKA was stopped at least 10 days 
prior to randomization. Furthermore, INR must not be ≥ 2 prior to randomization. Use of a 
bridging anticoagulant after stopping a VKA is left to the discretion of the investigator and 
treating physicians in accordance with local and international guidelines.


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After the participant is determined to be eligible for the study during the screening period, he 
or she should be instructed to take the last dose of the open label NOAC (or non-oral 
anticoagulant if applicable) on the day prior to study intervention intake. Hence, a participant 
should not take an open label NOAC (or any other non-oral anticoagulant) on the day of the 
first dose of study intervention. If a participant has already taken an open label NOAC (or 
other non-oral anticoagulant) on the planned day of randomization, randomization can be 
performed but the administration of study intervention should only be started on the next day. 
Transition from blinded study intervention to an open label anticoagulant (NOAC or another 
recommended anticoagulant as deemed appropriate by the investigator) after final 
discontinuation of study intervention must be done without breaking the study blind. The 
suggested procedure is to start with an open label anticoagulant on the next day following the 
last day of intake of the blinded study intervention (i.e. on the day of the CEOT visit, as no 
study intervention intake should take place on the day of this visit anymore). As all properly 
enrolled participants will still be at risk for stroke at the end of the study (or after permanent 
discontinuation of study intervention) they should accordingly be considered for stroke 
prevention following final discontinuation of study intervention.
Guidelines and practical guides regarding switching, for instance to (open label) NOAC 
treatment need to be considered in this situation (Chen et al. 2020, Steffel et al. 2021). The 
same applies in case of switching back and forth between open label anticoagulation and 
study intervention that might occur during the study period in case of non-permanent 
discontinuation of study intervention.
6.1.2
Medical Devices 
Not applicable.
6.2
Preparation, Handling, Storage, and Accountability
All study interventions will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and GMP requirements and the instructions given by the clinical 
supplies department of the sponsor or its affiliates
1. The investigator or designee must confirm study intervention has been received and, if 
a temperature data logger has been included, appropriate temperature conditions have 
been maintained during transit. Any discrepancies are to be 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, where local regulations permit, may supply or administer study 
intervention. 
3. 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.
4. The investigator, institution or the head of the institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, reconciliation, 
and record maintenance (i.e. receipt, reconciliation, and final disposition records). 


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Drug returns, reconciliation and destruction return information will be captured in 
IRT. 
5. Further guidance and information for the final disposition of unused study 
interventions are provided in the Investigator Site File.
For sites following the DCT model, where DtP distribution of study intervention occurs as 
part of remote visits, the investigator delegates distribution responsibility to the sponsor. The 
investigator maintains responsibility and control for dispensing via IRT by confirming 
whether or not DtP distribution of study intervention can be triggered. Participants who 
receive study intervention via DtP will return all unused investigational product and empty 
bottles to their study (meta)site.
6.3
Assignment to Study Intervention
All participants will be centrally assigned to randomized study intervention using an 
Interactive Response Technology (IRT). To accomplish random assignments, computer-
generated randomization lists specified by the sponsor’s responsible statistician will be 
prepared by the study sponsor or delegate. The randomization lists are provided to an IRT 
vendor. Before the study is initiated, the log in information and directions for the IRT will be 
provided to each site.
Randomization will be first stratified by participation in the conventional study model vs. 
DCT model. This will be succeeded by stratification for current use vs. no current use of 
single agent antiplatelet therapy planned to continue for at least 6 months after randomization. 
Following stratification, participants will be randomly assigned to 1 of the 2 treatment arms in 
a 1:1 ratio (see Section 1.1).
Study intervention will be dispensed at the study visit 2 (randomization), as summarized in 
the SoA, and again at the next visit after 3 months. Subsequently, the Month 6 visit follows, 
marking the start of 6-monthly on-site visit intervals (on-site visits will be conducted as 
remote visits for participants in the DCT model). From this visit onward, participants will 
receive study intervention at on-site visits which will last them until the next 6-monthly visit. 
The Month 6 visit should be scheduled ≤ 14 weeks after the Month 3 visit (even though in 
theory up to 15 weeks could lie between Visit 4 and Visit 5). Otherwise participants will need 
to get equipped with additional bottles of each of the study interventions to prevent 
insufficient supply until the Month 6 visit. At each contact, hence also at the intermittent 
telephone visits, the participants should be instructed regarding study intervention compliance 
(refer to Section 6.5).
From the Month 3 visit onward, unused study intervention will get returned to the site and 
should not be re-dispensed to the participants.
6.4
Blinding 
Participants will be randomly assigned in a 1:1 ratio to receive study intervention. 
Investigators, participants and study personnel will remain blinded to each participant’s 
assigned study intervention throughout the course of the study. Sponsor personnel responsible 
for bioanalytics will be unblinded and will have access to the randomization list.


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Tablets containing 50 mg of asundexian and matching placebo are identical in appearance and 
packed in bottles labeled with a unique number which will be pre-printed on each bottle. 
Tablets containing apixaban and corresponding placebo are identical in appearance and 
packed in bottles labeled with a unique number which will be pre-printed on each bottle. In 
order to achieve the double-blind, double-dummy design, participants will be provided with 
bottles either with active drugs (asundexian or apixaban), or placebo depending on the 
randomization outcome.
6.4.1
Unblinding
Unnecessary unblinding should be avoided and should only be undertaken by the investigator 
when it is essential for the participant’s safety and treatment decision. The IRT will be 
programmed with blind-breaking instructions. In case of an emergency, the investigator has 
the responsibility for determining if unblinding of a participant’s treatment assignment is 
warranted. If the investigator is unavailable, and a treating physician not associated with the 
study requests emergency unblinding, the emergency unblinding requests are forwarded to the 
study-specific emergency medical advice 24 hours / 7-day service. Participant safety must 
always be the first consideration in making such a determination. If the investigator decides 
that unblinding is warranted, the investigator should attempt to contact the sponsor prior to 
unblinding a participant’s treatment assignment, unless this could delay emergency treatment 
of the participant. If a participant’s treatment assignment is unblinded, the sponsor should be 
notified preferably within 24 hours after breaking the blind. The date and reason that the blind 
was broken must be recorded in the source documentation and case report form, as applicable.
Asundexian is known to prolong the activated partial thromboplastin time (aPTT) in a dose-
dependent manner. aPTT is a commonly used functional coagulation test widely used in 
clinical practice in participants using anticoagulants and is as well commonly used during 
acute hospitalizations, and as pre-procedural screening test. Thus, inadvertent unblinding of 
the participant or investigator might take place in cases where aPTT test results are known.
Therefore, the measurement of aPTT during the study conduct is strongly discouraged and 
should only be done in case of (emergency) situations where aPTT may help to guide 
treatment decision. Determinations of aPTT that might be obtained as part of the study 
protocol will therefore not be reported to investigators during the study in order to maintain 
the blinding.
The same inadvertent unblinding of the participant or investigator might be applicable to 
apixaban in case prothrombin time (PT) or its derived measure of the international normalized 
ratio (INR) are being assessed, as apixaban is known to be associated with a notable increase 
in those parameters. Hence the measurement of PT or INR after randomization is strongly 
discouraged and should only be done in case of (emergency) situations where this may help to 
guide treatment decision, e.g. to assess liver function. Prior to randomization INR 
measurements might be required as part of local laboratory assessments to determine 
randomization eligibility in case a participant has been pretreated with a VKA.
Pharmacokinetic and exposure-response analysis may be performed using population 
approaches. Such evaluations will be described in a separate analysis plan and will be 
reported separately and may be started prior to database lock. If this is applicable, appropriate 
measures will be taken to maintain blinding of the sponsor’s study team, e.g. data will be 
stored separately, and members of the study team will neither have access to the 
randomization list nor to individual data.


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6.5
Study Intervention Compliance
Study intervention will be dispensed according to the schedule provided in the SoA 
(Section 1.3). The date of dispensing the study intervention to the participant will be 
documented. 
Participants will be instructed to take study intervention as scheduled, and to return all unused 
study intervention and empty packages at the on-site visits for accountability purposes. 
Participant compliance with study intervention will be assessed at each visit by direct 
questioning. At the regular on-site visits, compliance will be assessed by counting returned 
tablets. The need for compliance assessment applies also to participants prematurely and 
permanently discontinuing study intervention who will undergo that assessment at the early 
termination visit. For participants taking study intervention until the regular end of the 
intervention period this assessment will occur for the last time at the CEOT visit. Tablets not 
returned will be considered to have been taken unless otherwise specified.
To monitor compliance, the investigator will be required to document drug dispensing and 
return for each participant in the source documents and this record must be reconciled with 
study intervention and compliance records. An adequate record of receipt, distribution and 
return / destruction of all study intervention must be captured on the dispensing log and / or in 
the IRT.
Intervention start and stop dates, including dates for apixaban dose reductions or increases (if 
applicable) will also be recorded. Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF. 
Any discrepancies between actual and expected amount of returned study medication must be 
discussed with the participant at the time of the visit and any deviation as well as explanation 
for deviation(s) from the prescribed dose regimen should be recorded in the CRF.
Overall compliance with study intervention intake should be between 80% and 120% of the 
scheduled dose at the end of treatment with study intervention. 
Participants following the DCT model will be instructed to retain all unused study 
intervention and empty packages for accountability purposes. At home nurse visits, the nurse 
may support the investigator site with the compliance assessment by performing a pill count. 
Participants will be provided shipping materials and instructions to return all unused study 
intervention and packaging to the investigator site for formal accountability as outlined in the 
DCT SoA in Section 10.10.2.
6.6
Dose Modification
This protocol does not allow any alteration from the currently outlined dosing schedule of 
asundexian (Section 6.1).
For dosing modifications of the active comparator, refer to Section 6.1. 
6.7
Continued Access to Study Intervention after the End of the Study
No further study intervention is planned following the End of the Study. For the definition of 
“End of Study” please refer to Section 4.4. 


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Any further therapy at the end of the study is at the discretion of investigator / treating 
physician (see Section 6.1.1).
6.8
Treatment of Overdose
For this study, any dose of asundexian greater than 3 assigned daily dosages (i.e. more than 3 
tablets) within a 24-hour time period will be considered an overdose.
The sponsor does not recommend specific treatment for an overdose of asundexian, as a 
specific antidote for the study intervention is not available. The use of activated charcoal to 
reduce absorption may be considered.
For participants receiving comparator treatment, and in line with the apixaban label, 
administration of activated charcoal may be useful in the management of apixaban overdose 
(i.e. the accidental or intentional ingestion of any dose of apixaban that is considered both 
excessive and medically important) by leading to a more rapid fall in apixaban blood levels. 
For further details the investigator / treating physician should refer to the approved product 
label of apixaban.
Due to the mechanism of action, an overdose of either of the study interventions could 
potentially result in hemorrhage. In case of bleeding linked to overdose the guidance on 
bleeding management as found in section 6.9.1 should be followed. 
In the event of an overdose, the investigator should:
1. Evaluate the participant to determine in consultation with the medical monitor, if 
possible, whether study intervention should be interrupted.
2. Closely monitor the participant for any AE / SAE and laboratory abnormalities as 
medically appropriate and until the study intervention can no longer be detected 
systemically (at least 5 days).
3. Document the quantity of the excess dose as well as the duration of the overdose.
6.9
Prior and Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, and / or herbal supplements) or vaccine that the participant is receiving at the time 
of enrollment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The medical monitor (sponsor’s Study Medical Expert) should be contacted if there are any 
questions regarding prior or concomitant therapy.
Special focus needs to be on antiplatelet and anticoagulant medications, for which any change 
in 30 days before screening and concomitant use from study entry until the last scheduled 
study visit of the participant, needs to be captured on the specified concomitant medication 
page.


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Single agent antiplatelet therapy is permitted for use any time during the study. Dual 
antiplatelet therapy (e.g. ASA together with P2Y12 inhibitors) in combination with the study 
interventions is only allowed in exceptional cases, such as an AMI and / or a PCI, 
symptomatic peripheral artery disease or carotid artery stenting occurring during the study. 
Such combination treatment with antiplatelet drugs may be administered as per discretion of 
the investigator, after thorough assessment of the risk / benefit ratio of such a potential 
combination therapy approach.
Sustained use of anticoagulation during study conduct for a different indication than AF will 
require at least an interruption of study intervention, if not permanent discontinuation (refer to 
Section 7.1). In this situation the anticipated duration of anticoagulation treatment and the 
expected remaining intervention period of the study should be taken into consideration. The 
assessment on whether to temporary or permanently discontinue the study intervention is left 
to the investigator’s discretion.
Venous thromboembolism prophylaxis with low-molecular-weight heparin or unfractionated 
heparin for short periods of time while taking study intervention is discouraged due to the 
potentially increased bleeding risk of combined NOAC and heparin intake (Fujikawa et al. 
2020).
The concomitant use of NSAID therapy during the study is strongly discouraged since this 
has been shown to increase the risk for gastrointestinal (GI) bleeding. However, if a NSAID 
must be temporarily used, it is recommended that the lowest possible dosage for the shortest 
duration possible is selected, not to exceed 4 consecutive weeks. Should analgesics be needed, 
use of paracetamol / acetaminophen is recommended. 
Proton pump inhibitors (PPIs) may be considered to reduce the risk for gastrointestinal 
bleeding and accompanying hospitalizations, especially in those with a history of GI bleeding 
or ulcer and patients requiring concomitant use of (dual) antiplatelet therapy, as recommended 
by guidelines (Steffel et al. 2021).
Potential for drug-drug interactions:
At supratherapeutic doses asundexian is a weak inhibitor of the cytochrome P450 isoenzyme 
2C8 (CYP2C8) and two transporter proteins, i.e. breast cancer resistance protein (BCRP) and 
P-glycoprotein (P-gp). The risk for clinically relevant drug-drug interactions at a dose of 
50 mg asundexian due to inhibition of the respective proteins is regarded as low, but cannot 
be excluded. If sensitive substrates of the mentioned proteins are taken concomitantly, the 
pertinent medication labels should be consulted, especially for:

rosuvastatin 20 mg daily or higher dose or atorvastatin 80 mg daily, for which 
additional monitoring may be warranted

digoxin or paclitaxel, which should be used with caution and for which additional 
monitoring may be warranted

repaglinide or pioglitazone, for which additional blood glucose monitoring might be 
warranted. 
Furthermore, the respective drug labels should be consulted, if asundexian is given 
concomitantly with other medication that may increase the exposure of BCRP, P-gp, and 
CYP2C8 substrates (a list of relevant substances will be provided to the investigators 
separately).


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Prohibited concomitant medications:
Concomitant therapy with any of the following drugs is prohibited from 14 days (or at least 
five half-lives of the active substance, whatever is longer) before randomization and first 
study intervention administration, until at least 48 hours after last study intervention 
administration:

Strong combined inhibitors of CYP3A4 and P-gp, e.g. human immunodeficiency virus 
protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir, or telaprevir), 
systemically used azole antimycotic agents (ketoconazole, itraconazole, or 
posaconazole), clarithromycin, nefazodone

Strong / moderate combined inducers of CYP3A4 and P-gp, e.g. phenytoin, 
carbamazepine, phenobarbital, rifampicin, or St. John’s wort
See also country-specific requirements for the Republic of Korea (KOR-1) in Section 
10.12.3.1.
A separate, more detailed list with prohibited medications will be provided to the investigator.
For participants who have permanently discontinued study intervention after completing their 
applicable early termination safety follow-up visit, only information on concomitant 
antiplatelet and anticoagulant medications needs to be collected at the remaining regular study 
visits until the CEOT visit (those visits are expected to occur as telephone visits during the 
early termination period; see Section 1.3).
6.9.1
Guidance for Management of Participants who Have Bleeding During 
the Study
In general, the management of bleeding is under the discretion of the treating physician and 
should follow local practice.
Participant’s bleeding events should be assessed in relation to the last intake of the study 
intervention, considering that asundexian has a total clearance of about 2.1 L/h and a half-life 
of approximately 21.5 hours, while apixaban has a total clearance of about 3.3 L/h and a half-
life of approximately 12 hours.
If a participant has a clinically relevant bleeding or serious bleeding during the study 
intervention period that requires hospitalization, the following routine measures should be 
considered:

Consider usual supportive treatments for bleeding, including local control of bleeding 
through standard procedures based upon the bleeding location, fluid replacement, 
blood transfusion, and fresh frozen plasma (FFP) transfusion. Consideration may also 
be given to the use of an antifibrinolytic agent (according to the package insert / label), 
such as tranexamic acid or ε-amino caproic acid (Tomaselli et al. 2017). 

Temporarily or permanently discontinue the study intervention. The decision to 
discontinue study intervention, temporarily or permanently, will be at the discretion of 
the treating physician and must be documented.

Temporarily discontinue antiplatelet therapies (i.e. ASA) until the bleeding event is 
sufficiently controlled, based upon the discretion of the treating physician. 


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
Investigate other causes of serious bleeding such as coagulopathies, 
thrombocytopenia, kidney / liver dysfunction, or other concomitant medications. 
If bleeding cannot be controlled by the above measures, consider urgent surgical or non-
surgical procedures to stop the bleeding (e.g. emergency surgery, arterial embolization, 
endoscopic cauterization) and unblinding of the randomized treatment assignment.
For those participants treated with asundexian, administration of the following procoagulants 
should also be considered (according to the package insert / label of the respective 
procoagulant) (Salomon and Gailani 2022), but there are no definite data in support of use of 
these agents:

Recombinant FVIIa (NovoSeven) or Activated prothrombin complex concentrate 
(aPCC) / factor 8 inhibitor bypass activity (FEIBA), based on in vitro data showing 
that these can fully reverse the prolongation of aPTT and ROTEM clotting time 
induced by asundexian.

FXI concentrate (FXI).
For those participants treated with apixaban, the following agents may be administered 
(according to the package insert / label of the respective agent):

The antidote to apixaban, andexanet alfa, which is a recombinant modified human 
Factor Xa protein (labelled in the US as ANDEXXA and in the European Union (EU) 
as Ondexxya) and may be used in case of life-threatening or uncontrolled bleeding 
(Steffel et al. 2021). However, its availability may be limited.

4-factor Prothrombin complex concentrate (4F-PCC) or Activated prothrombin 
complex concentrate (aPCC) / factor 8 inhibitor bypass activity (FEIBA).
6.9.2
Guidance for Management of Participants who Have Surgery or 
Percutaneous/Endoscopic Procedures
When possible, surgery and percutaneous / endoscopic procedures should be planned and 
delayed for at least 24 hours to allow for a 24-hour washout period after temporary 
discontinuation of randomized study intervention to mitigate risks of bleeding.
For urgent or emergent surgery or percutaneous / endoscopic procedures, when waiting for 
24 hours is not an option to allow for study intervention washout after temporary 
discontinuation, the increased risks of procedural bleeding should be assessed against the 
urgency of the procedure based upon the clinical situation. Peri-procedure management may 
in part depend on the randomized treatment assignment (asundexian or apixaban) and 
unblinding of treatment assignment may be necessary. In general, the treatment 
recommendations should follow the Guidelines for Severe Perioperative Bleeding 
Management (Kozek-Langenecker et al. 2013). The procedure should be conducted in such a 
way to minimize the risk for bleeding.
Treatment of participants receiving asundexian during urgent or emergency procedures may 
be guided by published data regarding patients with an inherited FXI deficiency. Apart from 
giving FXI concentrate as replacement therapy to cover a surgical bleeding event (Ling et al. 
2016), there have been reports in the literature about the successful use of tranexamic acid or 
ε-amino caproic acid for the management of these patients with a FXI deficiency when 
undergoing surgery (Duga and Salomon 2013). If treatment with an alternative open label 


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anticoagulant / antithrombotic is indicated for the procedure, it should be used with caution 
and at the lowest therapeutic dose. More detailed information can be found in the 
Investigator’s Brochure.
Depending on the participant’s risk for bleeding with the procedure, participants receiving 
apixaban who require an invasive or surgical procedure within 24 hours of their last dose may 
be treated with prophylactic peri-procedural FFP (2 units IV every 6 hours) at the discretion 
of the local physician and investigator. In addition, the label instructions for apixaban should 
be followed. If treatment with an alternative open label anticoagulant / antithrombotic is 
indicated for the procedure, it should be used at the lowest therapeutic dose (if at all) in the 12 
hours following last dose of study intervention. Interactions between apixaban and other 
antithrombotics (except for ASA and P2Y12 inhibitors) have not been evaluated.
6.9.3
Guidance for Management of Participants who Experience Ischemic 
Stroke During the Study
For participants who experience an ischemic stroke during the study, a complete diagnostic 
work-up including brain and vascular imaging, at least 24-hour cardiac rhythm monitoring, 
and echocardiography is encouraged. 
The treatment assignment may have to be emergently unblinded if necessary (see 
Section 6.4.1), to facilitate management decisions.
Mechanical clot removal (thrombectomy), if indicated and available, may be performed in 
any case but without preceding thrombolysis. In case thrombolysis is considered, the 
following should be taken into account:
For participants with acute ischemic stroke who are receiving asundexian, the risk for 
bleeding with use of intravenous thrombolysis is unknown and has not been studied; hence a 
clear recommendation in this situation cannot be given. However, it is not recommended that 
a thrombolytic agent be given unless it is known that the study investigational intervention 
has not been taken in the previous 48 hours, and the aPTT is normal. In this case, the risk for 
bleeding associated with thrombolysis is not expected to be increased (and unblinding may 
not be necessary).
No high-quality data are available regarding the use of intravenous thrombolysis for acute 
stroke in participants receiving apixaban. Experienced stroke centers worldwide are using 
thrombolysis for patients who have taken NOAC therapy within 48 hours by applying 
different approaches and selection criteria, including therapy guided by NOAC plasma level 
concentration and reversal of NOAC treatment using specific reversal agents like andexanet 
alfa (Seiffge 2022); therefore, for participants with acute ischemic stroke who are receiving 
apixaban, the use of thrombolytic agents will follow local practice. Based on the half-life of 
apixaban (approximately 12 hours) it may be anticipated that little or no study intervention is 
present in circulation if the last dose of study intervention was given at least 48 hours before. 
The anti-Factor Xa chromogenic assay, when used with validated calibrators and controls and 
where available, may be used to confirm that little or no residual anticoagulant effect is 
present for participants on apixaban. 
For participants who undergo thrombolysis, study intervention should be withheld until at 
least 24 hours after thrombolysis. Interventional thrombectomy may be an option in 
participants experiencing an acute ischemic stroke on study intervention.


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6.9.4
Guidance for Management of Participants who Experience an Acute 
Coronary Syndrome During the Study
For participants who experience a suspected new, acute coronary syndrome requiring 
hospitalization (unstable angina or AMI), standard of care medications should be 
administered according to local practice guidelines and based upon the chosen invasive 
procedure (dual antiplatelet therapy, intravenous / subcutaneous anticoagulants, or intravenous 
antiplatelet therapies such as glycoprotein IIb/IIIa inhibitors or cangrelor). Cardiac ischemic 
event (AMI) endpoint reporting guidelines and processes should be followed for these 
situations.
For participants who undergo urgent or emergent coronary angiography (with or without PCI) 
as treatment for the new ischemic event, the interventional procedure can usually be 
conducted while on study intervention, similar to common practice with NOACs such as 
apixaban (Lane et al. 2019), unless bleeding risk exceeds the expected benefits. Radial access 
is preferable in such situations. If interruption of study intervention for PCI is desired by the 
local study team, the study intervention may be restarted as early as considered safe, e.g. no 
earlier than 24 hours after the arterial sheath has been removed and / or no earlier than 24 
hours after the last dose of intravenous / subcutaneous anticoagulant or intravenous 
antiplatelet agent has been administered; the temporary pause of study intervention might be 
reduced if the radial route is used for PCI. For participants who are treated with urgent or 
emergent CABG surgery for the new ischemic event after coronary angiography, study 
intervention should be restarted no earlier than 24 hours after the post-surgical drains (chest 
tubes) have been removed.
For participants who are receiving asundexian or apixaban, the risk for bleeding related to the 
concomitant use of an intravenous fibrinolytic for acute ST-elevation MI is unknown and has 
not been studied. For participants treated with intravenous fibrinolytics, study intervention 
should therefore be withheld until at least 24 hours after receiving fibrinolytics.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study Intervention 
7.1.1
Permanent Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to be evaluated for safety and efficacy outcome events until the common end of 
treatment visit (CEOT visit). Thus, a permanent discontinuation of study intervention should 
not lead to a stop of participation in the study and further study assessments. See the SoA for 
data to be collected at the time of discontinuation of study intervention and follow-up and for 
any further evaluations that need to be completed up to the CEOT visit.
Study intervention will not be routinely permanently discontinued in participants reaching a 
potential outcome event or in case of unblinding, unless there is a safety concern or a clear 
indication for an alternative antithrombotic therapy as determined by the local investigator.
An early termination (ET) visit is only applicable to participants who prematurely discontinue 
intake of study intervention permanently; such participants should undergo the ET visit as 


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soon as possible, after permanent discontinuation of study intervention. A safety follow-up 
visit (telephone call) will occur 14 days after the day of the premature discontinuation (early 
termination) of study intervention (+7 days window). If the ET visit is conducted ≥ 2 weeks 
after permanent discontinuation of study intervention, an additional safety follow-up visit will 
not be performed.
In this study vital status data, outcome events and information on antiplatelet and 
anticoagulant medications are crucial to the analysis and must be collected until the 
completion of study participation of each individual patient, as participants will still be part of 
the study even if they are no longer taking study medication. Therefore, all efforts shall be 
taken to motivate participants who prematurely discontinue intake of study intervention to 
take part in the remaining study visits, usually by phone, and to continue to be followed until 
the CEOT visit.
Specifically, a permanent discontinuation of study intervention may be required if any of the 
following occurs and will last throughout the expected remaining intervention period. 
Otherwise, a temporary discontinuation of study intervention could be considered for the 
duration:

Pregnancy or breastfeeding of the study participant (see also Section 8.4.5)

Concomitant treatment with any of the following medications has to be taken 
continuously throughout the expected remaining intervention period of the study:

anticoagulation for a different indication than AF (e.g. cardiac ventricular 
thrombus, pulmonary embolism, superficial or deep venous thromboembolism) 

antiplatelet therapy other than permitted (single agent therapy is allowed, as well 
as indicated dual antiplatelet therapy, e.g. in case of a myocardial infarction 
and / or a PCI, symptomatic peripheral artery disease or carotid artery stenting 
occurring during the study)

strong combined inhibitors or inducers of CYP3A4 and P-gp

abnormal liver function if a participant meets one of the conditions outlined in 
Section 10.2.1, or if the investigator believes that it is in best interest of the participant.
See country-specific requirements for the Republic of Korea (KOR-1) in Section 10.12.3.1.
See the SoA for data to be collected at the time of premature intervention discontinuation and 
for any further evaluations that need to be completed. 
After permanent discontinuation of the study intervention, the participant is expected to 
continue the study visits as outlined in the protocol by telephone and will therefore be 
contacted by the study site at the regular follow-up intervals. The remaining outlined visits 
may also be done as site visits if preferred by investigator or participant. The same applies to 
participants of the DCT model in case they would prefer video calls over phone calls after 
discontinuation. Ad hoc additional telephone contacts may also be requested and made to the 
participant themselves or to other contact as provided by the participant.
If it is not possible for any reason to continue the visits, the investigator and participant must 
discuss and determine further follow-up options, as listed below, in descending order of 
preference: 


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1. Participant allows his / her treating physician, e.g. general practitioner or a family 
member, to be contacted or his medical file checked at the regular follow-up interval, 
or at least once at study end (if allowed in respective country) 
2. Participant will be contacted only once at the CEOT visit (at least this visit should be 
performed in all living participants)
After permanent discontinuation of the study intervention, the following information will 
need to be collected at the regular study visits and up to the last scheduled study visit (CEOT 
visit or CEOT SFU visit, as specified under section 4.1), preferentially directly from the 
participant and as agreed to by the participant during the initial informed consent process:

Vital Status

Outcome events (MI, stroke, systemic embolism, death, bleeding)

Antiplatelet and anticoagulant medications
It is of utmost importance for the final study results to make every effort to determine if 
relevant outcome events (e.g. an ischemic stroke) have occurred, regardless of the continued 
intake of study intervention. Based on the participant’s respective consent, information on 
outcome events and vital status may be obtained by reviewing the participant’s medical and 
pharmacy records and health insurance information.
If a participant does not wish to have direct follow-up contacts, sites shall explain to the 
participant why follow-up information on the health status is critical for the evaluation of the 
study results. It should be clarified and documented whether the participant upholds consent 
to collect the above listed follow-up visit information or would at least permit that sites 
contact the participant’s representative, family member or treating physician by telephone or 
by mail to collect the specified follow-up information.
In the event that the participant has explicitly withdrawn consent to collect further non-public 
health information, the participant’s vital status may be obtained from consulting public 
information or public sources (e.g. social media, health insurance, public [death] registry), 
unless this process is not allowed by local regulations.
7.1.2
Temporary Discontinuation of Study Intervention
In the event of a temporary interruption of study intervention for any reason, study 
intervention will be restarted as soon as medically justified in the opinion of the investigator. 
An example would be concomitant treatment with any of the prohibited medications 
mentioned above (in Section 7.1), that has to be taken only for a limited, foreseeable 
timeframe, that is expected to be considerably less than the expected remaining intervention 
period of the study. In such a case, based on medical judgement, a temporary interruption of 
study intervention instead of permanent discontinuation should be considered. The need for a 
temporary interruption might also arise from an adverse event, for instance relating to liver 
dysfunction (refer to Section 10.2.1). There is no predefined maximum limit for temporary 
treatment interruption. See country-specific requirements for the Republic of Korea (KOR-1) 
in Section 10.12.3.1.
In the event of a trial-continuity issue (e.g. caused by a pandemic), the sponsor may provide 
additional guidance in study-specific communication.


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If study intervention is temporarily discontinued, PK / PD blood samples should only be 
obtained if study intervention has been restarted and sustained for at least 4 days before 
PK / PD blood sampling.
7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at the participant’s own 
request, for any reason (or without providing any reason).

A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons. 

At the time of discontinuing from the study, if possible, an early termination visit 
should be conducted, as shown in the SoA. See 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.

The participant will be permanently discontinued from the study intervention and the 
study at that time.

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.

At the time of informed consent, participants will be explained all the options to 
continue in the study after permanent discontinuation of study intervention (see 
Section 7.1). This will be re-discussed at the time of permanent discontinuation of 
study intervention and the participant’s specific agreement will be documented. 
Participants will be asked to agree to be contacted to obtain follow-up information 
should they decide to stop the intervention.

When a participant withdraws consent from study participation before completing the 
study, meaning that the participant does not agree to any kind of follow-up and 
specifically refuses any further contact with the investigator, the reason for consent 
withdrawal is to be documented in the source document. Public information can be 
used to obtain vital status for these participants where allowed by local regulations.

Participants following the DCT model: If the participant withdraws consent for 
continued participation (i.e. follow-up) in the study and if the participant received a 
provisioned device (participation kit), he / she must return the study devices following 
provided shipping instructions. The participation kit does not need to be returned until 
the end of the study, if only study intervention is permanently discontinued, and 
consent is not withdrawn.
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if the participant 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, counsel the participant on the importance of maintaining the assigned visit 


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schedule, and ascertain whether 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 should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study.

In order to reduce risk for lost to follow-up the site should collect 2 alternative means 
of contact for each participant e.g. contact information of family members, caretaker, 
legal representative, or treating physician. The correctness of these contact details 
should be checked regularly at the study visits.

A patient locator service may be used (where allowed by local regulations) to re-
establish contact with a participant in case the site has exhausted all means of 
regaining contact.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

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. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Results from procedures conducted as part of the participant’s routine clinical 
management (e.g. creatinine, eGFR, ECG, vital sign measurement) and obtained 
before signing of the ICF may be utilized for screening and / or baseline purposes, 
provided the procedures met the protocol specified criteria and were performed within 
the timeframe defined in the SoA (if no older than 14 days at randomization for eGFR, 
creatinine and vital signs, or no older than 30 days in case of ECG; refer to annotated 
SoA in Section 1.3). See country-specific requirements for the Republic of Korea 
(KOR-1) in Section 10.12.3.1.

Laboratory / analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.

In the event of a significant trial-continuity issue (e.g. caused by a pandemic), 
alternate strategies for participant visits, assessments, medication distribution and 
monitoring may be implemented by the sponsor or the investigator, as per local health 
authority / ethics requirements.

The maximum blood draw volume for each participant over the duration of the study 
is provided in a separate document (e.g. ICF and laboratory manual).


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
If a participant requires an unscheduled visit to perform additional 
procedures / assessments other than regularly scheduled (e.g. for lab sampling), this 
should be documented in the CRF accordingly. Unscheduled visits may occur any 
time during the study conduct.
8.1
Administrative and Baseline Procedures
Administrative and baseline procedures are summarized in the SoA (Section 1.3).
8.2
Efficacy Assessments 
The efficacy assessments include primary, secondary and exploratory endpoints of the study 
(refer to Section 3). Planned timepoints for all efficacy assessments are provided in the SoA.
8.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is assessed as the time from randomization to the first 
occurrence of the composite of stroke or systemic embolism. 
Definitions of the primary efficacy outcome events are provided as follows. Details on the 
time periods for collecting outcome events information are reported in Section 10.9. 
8.2.1.1
Stroke
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by an 
injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction.
Differentiation is made regarding hemorrhagic stroke and ischemic stroke.
Hemorrhagic stroke is defined as an acute, atraumatic extravasation of blood into the brain 
parenchyma, intraventricular or subarachnoid space with associated neurological symptoms. 
This does not include microbleeds or hemorrhagic transformation of an ischemic stroke.
An ischemic stroke is defined as the rapid onset (or present on awakening) of a new focal 
neurological deficit with clinical (> 24 hours symptoms / signs) or imaging evidence of 
infarction that is not attributable to a non-ischemic cause (i.e. not associated with infection, 
tumor, seizure, severe metabolic disease).
The term undetermined stroke will apply when sudden focal neurological deficits persist for 
24 hours (or if death occurs before 24 hours) but without neuroimaging or autopsy. For the 
purpose of analyzing the endpoints undetermined strokes will be counted as ischemic strokes.
Participants who suffer a stroke of any type during this study should be assessed for their 
resulting disability by the modified Rankin Scale (mRS) as follows:

at day 7 after the event (or at hospital discharge / death, if this occurs before day 7); 
and 

at the next visit (any type of visit is acceptable), but no less than 2 months after the 
event (i.e. between 2 and ~5 months after the stroke). If death occurs in the 
intercurrent period this should be documented according to the scale.
Further details on mRS are available in Section 10.8.


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Transient Ischemic Attack (TIA)
Unlike a stroke, a TIA is defined as transient episode of neurologic dysfunction caused by 
focal brain, spinal cord or retinal ischemia without acute infarction (Easton et al. 2009). 
Differentiating TIA from other mimicking conditions is important. Symptoms of TIA usually 
start abruptly, followed by gradual offset, usually over minutes, and are typically associated 
with a focal neurologic deficit and / or speech disturbance due to underlying cerebrovascular 
disease. Isolated dizziness / vertigo or isolated numbness do not qualify as classical TIA.
8.2.1.2
Systemic Embolism
Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or 
radiological evidence of arterial occlusion in the absence of other likely mechanisms (this 
does not include myocardial infarction, thromboembolism of the pulmonary vasculature or 
venous thrombosis, e.g. pulmonary embolism or deep venous thrombosis).
8.2.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints are assessed as time from randomization to first occurrence of:

Composite of ischemic stroke or systemic embolism

All-cause mortality

Ischemic stroke 

CV death

Composite of CV death, stroke, or myocardial infarction.
Definitions of the secondary efficacy outcome events are provided as follows.
8.2.2.1
Cardiovascular Death
Cardiovascular (CV) death includes death due to stroke, myocardial infarction, heart failure or 
cardiogenic shock, sudden death or any other death due to other cardiovascular causes or CV 
procedures. In addition, death due to non-traumatic cardiovascular hemorrhage will be 
included, e.g. non-stroke intracranial hemorrhage, non-procedural or non-traumatic vascular 
rupture (e.g. aortic aneurysm), or hemorrhage causing cardiac tamponade (Hicks et al. 2015). 
Death for which the cause cannot be determined, so called “undetermined death”, will be 
included in the analysis as cardiovascular death (yet will not be excluded from SAE 
reporting).
8.2.2.2
Myocardial Infarction
The term acute MI is used when there is evidence of myocardial necrosis in a clinical setting 
consistent with acute myocardial ischemia. According to the Universal Definition of MI from 
2018 (Thygesen et al. 2018) the diagnosis of MI requires the combination of:

Presence of acute myocardial injury (changes in cardiac biomarkers) and

Evidence of acute myocardial ischemia derived from the clinical presentation, 
electrocardiographic changes, or the results of myocardial or coronary artery imaging, 
or in case of post-mortem pathological findings irrespective of biomarker values.


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8.2.3
Exploratory Efficacy Assessments
Exploratory efficacy endpoints are assessed as time from randomization to first occurrence of:

Composite of CV death, stroke or systemic embolism

Systemic embolism

Hemorrhagic stroke

Disabling stroke (modified Rankin Scale [mRS] ≥ 3).
Another exploratory efficacy endpoint is: 

EuroQol Group 5-dimension questionnaire (EQ-5D).
8.2.3.1
EuroQol Group 5-dimension questionnaire (EQ-5D)
A health-related quality of life assessment tool, the European Quality of life group 5-
Dimension questionnaire (EQ-5D) will be administered at Day 1 (randomization), every 6 
months, and at the CEOT visit. This is a standardized instrument for use as a measure of 
health outcomes primarily designed for self-completion by patients. The questionnaire is to be 
completed by the participant (questionnaires are provided in local languages). However, if the 
participant has problems completing the questionnaire, an attempt has to be made to explain 
the questions in a neutral and unpersuasive manner. The participant will fill in a paper-based 
version of the questionnaire directly at the site, which is then entered by the study personnel 
into the CRF. Participants in the DCT model will complete an electronic version of the 
questionnaire.
Items and scores derived from EQ-5D the are exploratory endpoints, and consists of 2 parts: 
the EQ-5D descriptive system and a Visual Analogue scale (VAS). The descriptive system 
asks questions across 5 dimensions of health (mobility, self-care, usual activities, 
pain / discomfort, anxiety / depression) with 5 response levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The health state index values 
derived from the descriptive system will be analyzed separately to support health economic 
evaluations (i.e. results will not be included in the CSR). The EQ-5D VAS records the 
participant’s own assessment of his / her health status on a vertical graduated scale, anchored 
on 0 (‘the worst health state you can image’) to 100 (‘the best health state you can imagine’).
8.3
Safety Assessments 
The safety endpoints are primary, secondary and exploratory endpoints of the study. At each 
visit during the study as specified in the SoA, the investigator will evaluate the participant for 
the occurrence of bleeding events. All necessary information to classify bleeding events 
according to the ISTH, and the BARC criteria will be collected in the CRF.
8.3.1
Primary Safety Endpoint
The primary safety endpoint is assessed as time from first intake of study intervention to first 
occurrence of ISTH major bleeding events.


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8.3.1.1
ISTH Major Bleeding
An event that meets at least one of the below criteria for a major bleeding event based on the 
definition given by the ISTH (Schulman and Kearon 2005):

Fatal bleeding, and / or

Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular 
with compromised vision, pericardial, retroperitoneal, intra-articular, or intramuscular 
with compartment syndrome), and / or

Clinically overt* bleeding associated with a recent (within 48 hours) decrease in the 
hemoglobin level of ≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared with the most recent 
hemoglobin value available before the event, and / or

Clinically overt* bleeding leading to transfusion of 2 or more units of packed red 
blood cells or whole blood
* overt bleeding requires the identification of the bleeding location and the 
hemoglobin drop and / or transfusion needs to be related to the bleeding.
8.3.2
Secondary Safety Endpoints
The secondary safety endpoints are assessed as time from first intake of study intervention to 
first occurrence of:

Composite of ISTH major or clinically relevant non-major bleeding

Clinically relevant non-major bleeding (Section 8.3.2.1)

Hemorrhagic stroke (Section 8.2.1.1)

Intracranial hemorrhage (does not include cerebral microbleeds or asymptomatic 
hemorrhagic transformation of an ischemic stroke)

Fatal bleeding

Minor bleeding (Section 8.3.2.2).
8.3.2.1
Clinically Relevant Non-Major Bleeding
Clinically relevant non-major bleeding is considered any sign or symptom of acute or sub-
acute clinically overt* bleeding that does not fit the criteria for the ISTH definition of major 
bleeding, but does meet at least one of the following criteria (based on criteria published by 
the EMA) (EMA 2014):

requiring medical or surgical treatment by a healthcare professional for bleeding

leading to hospitalization or increased level of care for bleeding

a change in antithrombotic therapy (including study intervention) for bleeding
* overt bleeding requires the identification of the bleeding location.
A visit alone at a healthcare professional (without fulfilling any of the above criteria) does not 
suffice. Also an assessment of bleeding as part of a healthcare encounter that is primarily for a 
different health issue does not qualify. Examples of clinically relevant non-major bleeding 
include, but are not limited to: multiple-source bleeding requiring treatment for bleeding; 


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macroscopic (gross, visible) hematuria (spontaneous or lasting > 24 hours if associated with 
an intervention) requiring increased medical care; epistaxis or gingival bleeding that requires 
tamponade or other medical intervention to stop the bleeding; hemoptysis, hematemesis or 
spontaneous rectal bleeding requiring endoscopy or other medical intervention.
8.3.2.2
Minor Bleeding
All other overt bleeding episodes not meeting the above criteria for ISTH major or clinically 
relevant non-major bleeding will be classified as minor bleeding (e.g. bleeding from a minor 
wound that does not prompt a treatment for the bleeding, for instance with surgical 
hemostasis, or epistaxis that does not require a medical treatment for bleeding or a change in 
antithrombotic therapy).
8.3.3
Exploratory Safety Endpoints
Exploratory safety endpoints are assessed as time from first intake of study intervention to 
first occurrence of:

Gastrointestinal bleeding

All bleeding

BARC type 3 and 5 bleeding

BARC type 2, 3 and 5 bleeding

BARC type 1 bleeding.
Another exploratory safety endpoint is:

Total number of ISTH major bleeding events.
8.3.3.1
BARC Bleeding
The BARC bleeding definition encompasses the following bleeding types (type 4: CABG-
related bleeding is not applicable to this study):

Type 0: no bleeding

Type 1: bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a healthcare 
professional; may include episodes leading to self-discontinuation of medical therapy 
by the patient without consulting a healthcare professional

Type 2: any overt, actionable sign of hemorrhage (e.g. more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, or 5 but does meet at least one of the following 
criteria: (1) requiring non-surgical, medical intervention by a healthcare professional, 
(2) leading to hospitalization or increased level of care, or (3) prompting evaluation

Type 3:
Type 3a

Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided 
hemoglobin drop is related to bleed)

Any transfusion with overt bleeding
Type 3b


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
Overt bleeding plus hemoglobin drop ≥ 5 g/dL* (provided hemoglobin drop 
is related to bleed)

Cardiac tamponade

Bleeding requiring surgical intervention for control (excluding 
dental / nasal / skin / hemorrhoid)

Bleeding requiring intravenous vasoactive agents
Type 3c

Intracranial hemorrhage (does not include microbleeds or hemorrhagic
transformation, does include intraspinal); subcategories confirmed by 
autopsy or imaging or lumbar puncture

Intraocular bleed compromising vision

Type 5: fatal bleeding
Type 5a

Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious
Type 5b

Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation
* Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1g/dL
hemoglobin).
8.3.4
Physical Examinations
Height and weight (also referred to as “biometrics” in the SoA) will be measured and 
recorded at screening (see Section 1.3). For participants following the DCT model, height and 
weight will be measured by the home nurse; alternatively, these values can also be measured 
by personnel of a patient service center.
8.3.5
Vital Signs
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
Vital signs will be measured in a semi-supine position preceded by 5 minutes rest for the 
participant in a quiet setting and without distractions (e.g. television, cell phones) and will 
include systolic and diastolic blood pressure, and pulse (i.e. the resting heart rate).
If appropriately and recently conducted (i.e. no older than 14 days at randomization) vital sign 
measurements from routine management are available for the participants, those can be used 
instead of being obtained again at the screening visit. This is not applicable to participants 
following the DCT model. If a previous measurement result for the vital sign parameters is 
available at the randomization visit, the repetition of this measurement at the randomization 
study visit is not required. 
For participants following the DCT model, blood pressure together with resting heart rate 
will be measured by the home nurse; alternatively, these values can also be measured by 
personnel of a patient service center.


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8.3.6
Electrocardiograms
A single 6 (or more)-lead ECG will be obtained as outlined in the SoA (see Section 1.3), 
preferably using an ECG machine that automatically calculates the heart rate.
If an appropriately and recently (i.e. no older than 30 days at randomization) conducted ECG 
as part of routine management is available, this can potentially be used instead of being 
obtained again at the screening visit. This is not applicable to participants following the DCT 
model. If a previous ECG result is available at the randomization visit, the repetition of the 
ECG at the randomization study visit is not necessarily required. Both scenarios of not 
needing to repeat an ECG assessment are only applicable in case the required ECG evidence 
of atrial fibrillation as requested as part of the inclusion criteria (refer to Section 5.1) is 
available. In case the ECGs available either from routine management or obtained during the 
screening and / or randomization visit do not confirm atrial fibrillation, historical proof 
(within the last 12 months) needs to be available prior to randomization in order for the 
patient to move forward to getting randomized. For participants following the DCT model,
the ECG might need to be repeated if not available in sufficient quality in the first place.
8.3.7
Clinical Safety Laboratory Tests

See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
for the timing and frequency.

Creatinine and eGFR values must be available at randomization; if not available from 
screening central lab, the respective values should be determined in local lab prior to 
randomization to be available in time to not delay randomization. Values obtained as 
part of routine management can also be used for this purpose if no older than 14 days 
at randomization. In any case, the full set of protocol-required safety laboratory tests 
for central lab analysis (Table 10–1) needs to be obtained once during the 14 day 
screening period prior to randomization, at the latest at randomization, and at indicated 
visits thereafter. See country-specific requirements for the Republic of Korea (KOR-1) 
in Section 10.12.3.1.

The investigator must review the laboratory results, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
results must be retained with source documents.

Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or the medical monitor.

If clinically significant 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.


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
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA. 

If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification), then the results must be recorded.
8.3.8
Pregnancy Testing
A woman of childbearing potential must have a negative highly sensitive pregnancy test 
within 4 days before the first dose of study intervention. Local urine testing will be standard 
for the protocol unless serum testing is required by local regulation or Institutional Review 
Boards (IRB) / Independent Ethics Committees (IEC). For country-specific requirements for 
the Republic of Korea (KOR-1), please see Section 10.12.3.1.
If a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy 
test is required. In such cases, the participant must be excluded from participation if the serum 
pregnancy result is positive.
Female participants of childbearing potential are scheduled to perform a serum or urine 
pregnancy test at the screening and randomization visit, unless ≤ 4 days lie between the 
screening and randomization visit, in which case a negative test at screening is sufficient 
(refer to SoA). 
In addition a pregnancy test is required at the end of relevant systemic exposure, which is 
either at the early termination visit for participants that prematurely discontinue intake of 
study intervention (unless study intervention has been discontinued since more than 7 days) or 
at the CEOT visit for participants that end the study intervention period regularly. 
Further serum or urine pregnancy tests should be performed in participants of childbearing 
potential as required by national / institutional regulations (e.g. at every site visit). At any time 
during study participation, additional pregnancy testing should be performed upon suspicion 
of pregnancy.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting
The definitions of AEs and SAEs can be found in Section 10.3.
Events that are deemed to be disease-related efficacy outcome events according to the study 
protocol will not be reported as (S)AEs and will only be reported on the dedicated outcome 
event CRFs. A description of these outcome events is covered in Section 8.4.6 and Section 
10.9.
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 all AEs considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention and / or study (see Section 7). This 
includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative).


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Sites following the DCT model: Usually, participants will be reporting AEs to the metasite 
during the scheduled contacts, or ad hoc by contacting the metasite directly. During the home 
nurse (HN) visit or while at the patient service center, the staff (i.e. the home nurse or the 
responsible personnel at service centers) will not actively enquire about or collect (S)AE 
information. However, if an (S)AE is self-evident, occurring during a procedure or 
spontaneously reported by the participant, the staff will capture relevant details which will be 
made available to the investigator immediately upon conclusion of the visit. In addition, in the 
case of suspected SAEs, the staff will immediately contact and inform the investigator. If the 
staff is not able to speak to the investigator or qualified designee directly, he / she is 
responsible for continuing to attempt this until direct contact is made and should ensure this is 
done on the same day that the visit took place. In all cases, the investigator is responsible for 
evaluating potential (S)AEs, ensuring their timely entry into the CRF as well as for SAE 
reporting to the sponsor within the required timeframe (see Section 8.4.1). The 
investigator / designee is then responsible for obtaining further information if needed, e.g. 
contacting the participant, obtaining records from other sources or deciding if an unscheduled 
follow-up visit or referral to another medical practitioner is required.
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
(S)AEs will be collected from the start of study intervention until a participant’s respective 
safety follow-up visit* at the timepoints specified in the SoA (Section 1.3). (S)AEs which are 
related to protocol-required study procedures (e.g. (S)AE related to invasive study 
procedures) will be recorded as (S)AEs from the signing of the ICF.
Any medical occurrences / conditions that begin in the period between signing ICF and the 
start of study intervention, and which are not related to a protocol-required study procedure, 
will be recorded as medical history / current medical conditions, not as AEs.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in 
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 information on AEs or SAEs 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. 
8.4.2
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.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
                                                
* For a participant with premature permanent discontinuation of study intervention, this is the early termination 
safety follow-up visit


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8.4.3
Follow-up of AEs and SAEs
After the initial AE / SAE report, the investigator is required to proactively follow each 
participant at subsequent visits / contacts. All SAEs 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). Further information on follow-up procedures is provided in Section 
10.3. 
8.4.4
Regulatory Reporting Requirements for SAEs

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, IRBs / IECs, and investigators.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB / IEC, if appropriate according to local requirements.

For all studies except those using medical devices, 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.
8.4.5
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 4 days after the last dose intake.

If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
participant pregnancy.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.

Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported as 
such.

The female 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.

Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 


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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 
discontinue study intervention.
8.4.6
Disease-related Events
The following disease-related events (DREs) are part of the efficacy outcome events in 
participants with AF: 
a) Ischemic stroke
b) Systemic embolism
c) Myocardial infarction
d) Cardiovascular death
e) Events indicative of those outcome events listed under a) to d) (e.g. TIA or cardiac 
chest pain requiring hospitalization with increased cardiac enzymes).
Because the above mentioned DREs pertaining to efficacy endpoints are typically associated 
with the disease under study, they will be exempted from reporting as (S)AE by the 
investigator to the sponsor as well as from expedited SUSAR reporting.
Even though these events may meet the definition of an SAE (including life threatening or 
fatal events), they will not be reported according to the standard process for expedited 
reporting of SAEs to the sponsor. Consequently, they will not be subject to systematic 
unblinding and expedited SUSAR reporting to Health Authorities and Independent Ethics 
Committees / Institutional Review Boards (IECs / IRBs). Systematic unblinding of these 
expected efficacy events could compromise the integrity of the clinical study.
Instead, the above mentioned DREs and events indicative of those outcomes [a) to e)] will be 
recorded on the corresponding efficacy outcome / death CRF pages on an ongoing basis. 
Following documentation in the CRF, they will be adjudicated by the CEC and monitored on 
a routine basis by the IDMC as outlined in the respective charters (Section 10.1.6).
In case the diagnosis of a supposed DRE changes and the event no longer fulfills the criteria 
for a disease-related event as described above, the investigator is requested to proceed with 
reporting the event to the sponsor as (S)AE and – if serious – within the timelines required for 
an SAE (Sections 8.4 and 10.3), in addition to deleting the event from the outcome CRF.
In case efficacy outcome events [listed above as a) to e)] are adjudicated by the CEC as not 
meeting the outcome criteria specified in the CEC charter (“refuted”), these events will not be 
reported as SAEs, as the adjudication results will not be shared with the investigators during 
the study. Therefore investigators will not be asked to change the reporting of these events. 
This process will maintain the independence of the CEC. Refuted events will still be part of 
the review by the IDMC and later be summarized in final analyses.
However, if either of the following conditions applies, then the event may be recorded and 
reported as an (S)AE in addition to reporting on the efficacy outcome CRF:

The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant.


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OR

The investigator considers that there is a reasonable possibility that the event was 
related to study intervention.
Safety outcome events (i.e. all bleeding) or efficacy outcome events with a symptomatic 
bleeding component (e.g. hemorrhagic stroke, ischemic stroke with symptomatic hemorrhagic 
transformation, cardiovascular death due to a ruptured aortic aneurysm) are not exempted and 
are therefore to be reported as (S)AE, in addition to reporting them on the respective outcome 
CRF pages.
Events that have already been reported as (S)AEs and eventually result in cardiovascular 
death will not be deleted from the adverse event CRF page (e.g. decompensated heart failure 
leading to death).
Irrespective of that, any death will need to be captured on the death CRF page and classified 
as either cardiovascular, non-cardiovascular or undetermined (refer to Section 8.2.2.1). Table 
8–1 shows an overview of how different events are expected to be reported to the sponsor. 
Please also refer to Section 8.4.1 in relation to reporting of AEs and Section 10.9 for more 
details on reporting in relation to the time of the occurrence of the respective outcome events.
Table 8–1: Reporting of events
Event type
Efficacy 
outcome / 
death CRF
Bleeding 
outcome 
CRF
(S)AE 
CRF*
Timing of 
reporting
Disease-related events pertaining to 
efficacy outcomes#
[detailed as a) to e) in beginning of this 
section]
X
–
–
Ongoing 
basis
Efficacy outcome events with 
symptomatic bleeding component
X
X
X**
SAE ≤ 24 
hours†
Safety outcome events (all bleeding)
–
X
X**
SAE ≤ 24 
hours†
Other (S)AE
–
–
X
SAE ≤ 24 
hours†
Abbreviations: CRF= case report form; (S)AE= (serious) adverse event
# Events leading to non-CV or undetermined death are not disease-related and will need to be reported as SAEs
* Reportable events (i.e. SUSARs) will be unblinded and reported to the competent authorities and Independent
Ethics Committees / Institutional Review Boards (IECs / IRBs) according to legal requirements (Section 8.4.4).
** in case of premature permanent discontinuation of study intervention, (S)AE reporting is not required after the
participant’s early termination follow-up visit (Section 7)
† SAEs will be recorded and reported to the sponsor or designee immediately and under no circumstance should
this exceed 24 hours of the investigator learning of the SAE (Section 8.4.1 and Section 10.3).
8.5
Pharmacokinetics
For the investigation of systemic exposure to asundexian and its relationship with treatment 
effects, the plasma concentrations of asundexian, M-10 (BAY 2826102), and optionally other 
metabolites will be determined at different time points using a sparse sampling approach in all 


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participants of the conventional study model. These analyses will not be performed in 
participants of the DCT model. Details about the collection, processing, storage and shipment 
of samples will be provided separately (e.g. in the laboratory manual). Study personnel 
responsible for bioanalytics will be unblinded and will have access to the randomization list. 
Analysis of samples from participants not treated with asundexian is optional.
Blood samples will be collected at the time points indicated in the SoA (Section 1.3). 
Deviations from the specified sampling intervals will be documented and taken into account 
for the PK analysis. Date and time of the PK sample collection and date and time of most 
recent study intervention intake (i.e. both timepoints on the PK sampling day, and on the day 
before that) must be documented.
At Visit 4 and Visit 7 a trough sample for the determination of asundexian plasma 
concentrations will be collected before intake of study intervention. Study intervention at 
those visits should be taken out of the respective new bottles that participants receive, 
preferably at the study site. Ideally, the study personnel should contact the participants prior 
to Visit 4 and Visit 7 to remind them not to take the study intervention as usual in the morning 
at home.
The PK data and the relationship of the asundexian exposure parameters with treatment 
effects might be evaluated using population approaches including potential influence of 
relevant participant co-variables. Analysis and reporting will be done under a separate cover. 
This evaluation might be started prior to database lock: if this is applicable, appropriate 
measures will be taken to maintain blinding of the study team (refer to Section 6.4.1).
PK samples will be analyzed, using validated analytical methods. Quality control (QC) and 
calibration samples will be analyzed concurrently with study samples. The results of 
calibration samples and QC samples will be reported in the Bioanalytical Report.
8.6
Pharmacodynamics
Blood sampling for PD parameters will be done in a subset of countries / regions, in at least 
(approximately) 5000 of the participants of the conventional study model (not in participants 
of the DCT model), and is scheduled for the time points as given in Table 1–2. PD samples 
should be drawn before intake of study intervention at the respective visits. The actual date 
and time of study intervention intake and of blood sampling will be documented in the CRF. 
All PD parameters will be measured using validated methods.
Quality control and calibration samples will be analyzed concurrently with study samples. For 
selected PD parameters, the results of QC samples will be reported together with analyte 
concentrations in the Bioanalytical Report.
Results of the analysis are calculated according to the method description. Detailed method 
descriptions of all PD methods will be filed with the CSR. Results will be reported under 
separate cover.
The sampling will be done for an exploratory assessment of PD effects and may include but is 
not limited to, baseline assessments of FXI levels (clotting assay), FXII levels (clotting 
assay), and von Willebrand factor activity, as well as aPTT at baseline and after study 
intervention intake.
In addition, blood samples will be taken for exploratory biomarker analyses (see Section 8.8).


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Detailed information about the collection, processing, storage and shipment of the samples 
will be provided separately (e.g. sample handling sheets and / or laboratory manual).
8.7
Genetics 
Genetic as well as non-genetic analyses will be part of the biomarker investigations and 
collected in the same subset of participants as the biomarkers in this study, if approved by 
local ECs / IRBs and competent authorities. See Section 8.8 for details. Biomarker blood for 
pharmacogenetics is generally planned to be collected at the randomization visit (refer to 
Table 1–2), however, it can also be collected at a later visit in case it has not yet been taken,
and can be collected at any time in relation to study intervention intake at the respective visit.
8.8
Biomarkers
Blood sampling for exploratory biomarker analyses will be done only in a subset of 
countries / regions in approximately 5000 of the participants of the conventional study model 
(scheduled for the time points as given in Table 1–2). Biomarker plasma / serum samples 
should be collected before intake of study intervention at the respective visits. The exact 
biomarkers chosen will depend on the outcome of the Phase 2 biomarker analysis: biomarkers 
related to the study intervention, its safety or drugs with similar, e.g. mode-of-action related 
effects may be examined. The same applies to further biomarkers deemed relevant to 
cardiovascular diseases and associated health problems. These investigations may include e.g. 
diagnostic, safety, pharmacodynamic, monitoring, or potentially predictive biomarkers. 
Those additional analyses may include genetic as well as non-genetic biomarkers. Genetic 
investigations may be of any kind, except for whole genome sequencing. Results will be 
reported under separate cover if the evaluations are performed.
Details on the collection, processing, storage, and shipment of biomarker samples will be 
provided in separate documents (e.g. sample handling sheets or lab manual). Samples may be 
stored for a maximum of 15 years (or according to local regulations) following the end of the 
study at a facility selected by the sponsor to enable further analyses.
8.9
Immunogenicity Assessments
Not applicable. 
8.10
Medical Resource Utilization and Health Economics 
Participants will be asked to complete a quality of life questionnaire during the study conduct 
(Section 8.2.3.1). In addition, the use of healthcare resources is going to be collected.
8.10.1
Healthcare Resource Utilization (HCRU)
The use of healthcare resources (hospitalizations) related to all SAEs and outcome events will 
be documented for all participants during the study. The total number of hospitalizations due 
to efficacy or safety outcome events will be assessed as exploratory net clinical benefit 
endpoint based on the investigator reported use of healthcare resources.


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9.
Statistical Considerations 
The first version of the statistical analysis plan (SAP) will be finalized prior to study 
enrollment, with final updates made prior to database lock. The SAP will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.1
Statistical Hypotheses
As described in Section 3, the population-level summary to describe the treatment effects for 
the primary and secondary efficacy and safety endpoints is the cause-specific hazard ratio 
comparing asundexian with apixaban. Let 	
 represent the (cause-specific) hazard 
ratio, i.e. the ratio of the cause-specific hazard for participants assigned to asundexian and the 
cause-specific hazard for participants assigned to apixaban, for the respective estimand. 
The proposed study plans to test several null hypotheses.
The aim related to the first part of the primary efficacy objective is to show that assigning 
asundexian is as least as effective than apixaban in preventing stroke and systemic embolism 
in patients with AF using a non-inferiority margin of 1.5 for the cause-specific hazard ratio. 
The one-sided test problem is:
: primary  efficacy ≥ 1.5  versus  
: primary  efficacy < 1.5
The aim related to the second part of the primary efficacy objective to show that assigning 
asundexian versus apixaban is superior in preventing stroke and systemic embolism in 
patients with AF. The one-sided test problem is:
: primary  efficacy ≥ 1  versus  
: primary  efficacy < 1
For the primary safety objective, the aim is to show that treatment with asundexian is 
associated with less ISTH major bleeding events than treatment with apixaban in patients with 
AF. The one-sided test problem is:
: primary  safety ≥ 1  versus  
: primary  safety < 1
For the net clinical benefit objective, the aim is to show that treatment with asundexian is 
associated with less events of the net clinical benefit endpoint than treatment with apixaban in 
patients with AF. The one-sided test problem is:
: net clinical benefit ≥ 1  versus  
: net clinical benefit < 1
The hypotheses for secondary endpoints follow the same principles as outlined above.
The non-inferiority margin of 1.5 for the primary efficacy composite was chosen to preserve 
at least 50% of the relative reduction in the risk for stroke or systemic embolism associated 
with apixaban. As there is no randomized controlled clinical study with a direct comparison of 
apixaban versus placebo, an indirect comparison was done based on the effect of apixaban 
over warfarin (HR=0.79 CI=0.66;0.95) as shown in the ARISTOTLE study (Granger et al. 
2011) and the effect of placebo over warfarin (HR=2.8 CI=1.88;4.2) as estimated from 6 
previous major randomized controlled studies, that was also used in the ARISTOTLE study. 
Using the extended Bucher method for indirect comparison this provides a lower 95% 
confidence limit of 2.28 for the relative risk with placebo as compared with apixaban 


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(HR=3.54 CI=2.28-5.51) (Bucher et al. 1997, Wells et al. 2009). Half of this value on the log 
scale is 1.509.
9.1.1
Multiplicity Adjustment
The familywise type-I error rate will be controlled at the overall (two-sided) significance level 
α = 5% using the graphical method of (Bretz et al. 2009). The initial graph of the strategy is 
shown in Figure 9–1. 
The graph will be updated with each null hypothesis that is rejected. 
First, the non-inferiority null hypothesis for the primary efficacy outcome will be tested as a 
gatekeeper at the entire available significance level α. If this null hypothesis is rejected, the 
significance level will be split and passed on to the superiority null hypothesis for the primary 
safety outcome (90% of 5% = 4.5%) and to the superiority null hypothesis for the primary 
efficacy outcome (10% of 5% = 0.5%). The weights, 10% and 90%, were chosen by 
balancing the prior expectations about efficacy and safety endpoints. In particular, one aim 
was to ensure that there would be at least 90% power for the testing of the superiority null 
hypothesis for the primary safety endpoint assuming a 30% relative hazard reduction.
If the superiority null hypothesis for the primary safety outcome is rejected, the local 
significance level is first propagated to the superiority null hypothesis for the bleeding 
endpoint ISTH major and clinically relevant non-major bleeding and, if significant, thereafter 
to the superiority null hypothesis for the primary net clinical benefit outcome. If this null 
hypothesis is rejected, the local significance level will be propagated to the superiority null 
hypothesis for the primary efficacy outcome, leading to a local significance level of 5%.
For the primary efficacy outcome, the test for superiority will be performed at a local 
significance level of either 0.5% or 5%. If the null hypothesis can be rejected, all, except for 
an infinitesimally small fraction ε, of the local significance level will be propagated to the 
superiority null hypothesis of the primary safety outcome, if not yet rejected. Further testing 
of null hypotheses associated with other endpoints will be done in case all 5 key null 
hypotheses are rejected. This part is not shown in detail in the figure.
The testing of the null hypotheses for other endpoints will be in hierarchical other, i.e. it stops 
if a null hypothesis cannot be rejected. The following 4 additional hypotheses will be tested in 
the specified order:

Composite of ischemic stroke or systemic embolism,

Composite of ISTH major bleeding, stroke, systemic embolism or all-cause mortality,

All-cause mortality, and

Ischemic stroke.
This reflects the priority to show superiority in both efficacy and safety and, in addition, 
allows testing for the primary net clinical benefit, even in situations where superiority of 
efficacy cannot be shown. No further formal testing is planned.


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Figure 9–1: Graphical testing strategy 
Note: The numbers in the bullets are the local significance levels while the numbers on the arrow reflect the 
proportion of the local significance level transferred to subsequent null hypotheses, once a null hypothesis 
is rejected.
9.2
Analysis Sets
For purposes of analysis, the following analysis sets are defined as displayed below.
Table 9–1: Analysis sets
Participant Analysis Set
Description
Full Analysis Set (FAS)
All participants randomized to study intervention.
Safety Set (SAF)
All participants randomized to study intervention and who took 
at least 1 dose of study intervention.
Unless otherwise specified, the FAS will be used for all analyses addressing efficacy 
estimands.
The SAF will be used for analyses addressing the primary safety estimand and other 
estimands relating to bleeding endpoints, and the net clinical benefit estimands as well as 
analyses of AEs.
9.3
Statistical Analyses
9.3.1
General Considerations
The statistical analyses will be performed using SAS and validated R; the version used will be 
specified in the statistical analysis plan (SAP).
Derivation of time-to-event variables, censoring and incomplete dates
For the key efficacy and safety events, see Section 9.3.2, the variable is the time to first 
occurrence of the outcome event of interest, which can be a single outcome or a composite. In 
general, time-to-event variables will be derived as the number of days from the individual 
participant’s randomization date to the date of onset of the respective endpoint event. The 


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time-to-event variable for participants who have not experienced the respective endpoint 
event will be censored on the date of the last follow-up in the following way:

for participants who reach their CEOT visit without the event of interest, the censoring 
date will be the date of their CEOT visit,

otherwise the censoring date will be based on latest date participants are known to be 
at risk for the event of interest.
For analyses addressing the primary safety estimand and other estimands relating to bleeding 
endpoints, and the net clinical benefit estimands, randomization date will be replaced by the 
date of first intake of study intervention when deriving the time-to-event variable.
Where the “while on treatment” strategy is proposed to address the intercurrent event “early 
discontinuation of treatment”, see estimand definition in Section 3, the occurrence of this 
intercurrent event will be considered a “soft” competing risk in the analysis. I.e. in the 
analysis events of interest will only be counted up to the date of last intake of study 
intervention plus 2 days. Similarly, if the “while alive” strategy is proposed to address the 
intercurrent event “death”, the occurrence of death will be considered a competing risk in the 
analysis, resulting in “technical censoring” at the date of death.
If the date of a key endpoint or of censoring is incomplete following all attempts to get an 
approximate date by the investigator, a day will be imputed using the following algorithm:

If only the month of the event is known, then the 1st day of this month will be imputed.

If only the year of the event is known, then the 1st of January will be imputed.

If year, month and day are unknown, the randomization date will be imputed.
If this imputation rule leads to an implausible date, i.e. before the randomization date the date 
will be imputed as that date.
Descriptive statistics
Study data will be summarized using methods like frequency tables and other descriptive 
statistics. Generally, confidence intervals will be presented as two-sided 95% confidence 
intervals. 
For time-to-event variables, the numbers of participants with an event of interest in defined 
periods of patient follow-up will be presented. Incidence proportions and incidence rates for 
the event of interest as well as potential competing risks will be shown.
Nelson-Aalen estimates of the cumulative hazard for the event of interest by treatment arm 
will be used to explore if the estimated hazards are reasonably constant over time as 
applicable. The cumulative incidence risk, i.e. the expected proportion of participants with an 
event of interest over the course of time taking competing risk into account, will be estimated 
for time-to-event variables using Aalen-Johansen estimators.
In addition, endpoint events after (administrative) censoring will be summarized, as 
applicable. 
Stratification
Regression models or statistical tests for time-to-event outcomes will be stratified (if 
applicable) by 

participation in conventional study model vs. DCT model


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
current use vs. no current use of single agent antiplatelet therapy planned to continue 
for at least 6 months after randomization.
Stratified analyses will only be conducted if there are at least 5 participants with an event in 
each stratum and if there is at least 1 participant with an event in each treatment arm.
Missing data
The aim is to minimize missing observation time as much as possible. Generally, all 
participants, including those who discontinue study intervention, will be followed until death 
or the end of the intervention period. Information of participants discontinuing study 
intervention or participation in study visits will be collected whenever possible and 
meaningful for the analysis. Data that would be meaningful for the analysis of a given 
estimand but were not collected, are considered missing.
For participants who could not be followed up for outcome events on a regular basis, it is 
aimed to at least determine the participants’ status at the end of the intervention period with 
respect to the occurrence and timing of key outcome events, including MI, stroke, systemic 
embolism, death and bleeding. In general, sensitivity analyses will be performed to assess the 
robustness with respect to assumptions that need to be made to handle missing data. Details 
will be described in the SAP.
Handling of missing data for key time-to-event analyses
Regarding time-to-event endpoints censoring for administrative reasons will be assumed to be 
non-informative.
All efforts will be made to reduce incomplete follow-up with regard to the occurrence and 
timing of key outcome events are the end of the study to a minimum.
To keep the main analyses simple and in line with the estimation approaches commonly used, 
the observation time for event-free participants with incomplete follow-up time will be 
censored at the last available point in time for which data on the outcome has been obtained.
As a sensitivity analysis, it is planned to apply statistical methods aligned with the targeted 
estimand in line with ICH E9(R1). When missing follow-up time occurs after the occurrence 
of an intercurrent event, the missing data will be addressed by methods aligned with the 
strategy proposed for the respective intercurrent event and estimand. 
For example, it is assumed that after withdrawal of informed consent (or loss to follow-up) 
participants remain untreated if they have not already discontinued their randomized treatment 
earlier. Thus, when for a given estimand the intercurrent event “treatment discontinuation” is 
addressed by the treatment policy strategy, unobserved follow-up time will be modelled based 
on patient data observed after treatment discontinuation.
Unobserved follow-up time will be multiply imputed using hazard rates estimated from those 
participants who have observed data subsequent to the intercurrent event “treatment 
discontinuation” but who have not experienced the event of interest prior to “treatment 
discontinuation”. The constant hazard rate assumption will be assessed, and if not satisfied, a 
piecewise exponential or other distribution will be used for imputing the missing follow-up 
time. The imputation will include the following steps:
1. Identify participants who have observed follow-up time subsequent to early 
discontinuation of randomized treatment and who have not experienced the event of 
interest prior treatment discontinuation. For these participants, estimate the hazard rate 
for the off-treatment period separately for each treatment group. The off-treatment 


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period is defined as from the date of last intake of randomized treatment + 2 calendar 
days to either the outcome event of interest or the date of censoring due to study 
completion or death. 
2. For each participant with incomplete follow-up for the event of interest who was 
censored without an outcome event of interest, simulate missing follow-up time as 
follows:

Draw (a) parameter(s) [Exponential, Weibull, or other] from the normal 
distribution using the estimates for the hazard rate in step 1 to incorporate 
variability in the estimated hazard rates. 

Simulate a follow-up time from that resulting distribution and add it to the 
observed censoring date to get the imputed time-to-event for that participant. 
If the imputed time-to-event is before a defined cut-off date, the participant 
“experienced” the outcome event at the imputed time; if not, the participant would be 
censored at the cut-off date. The cut-off date will be set to the last CEOT visit date 
over all participants, reflecting the maximal time under risk for these patients.
3. Analyze the time to the outcome event of interest based on the complete time-to-event 
data (observed + imputed). 
4. Repeat steps 2 and 3 multiple times and use Rubin’s rule for combining analysis 
results from multiply imputed datasets using an approximate proper imputation. 
9.3.2
Primary Endpoint(s)/Estimand(s) Analysis
The following subsections describe the planned statistical analyses addressing the primary 
efficacy and safety estimands.
9.3.2.1
Primary Efficacy Estimands
Definition of endpoint
The primary efficacy endpoint is the time from randomization to the first occurrence of the 
composite of stroke or systemic embolism. The outcomes are defined in Section 3, the 
derivation of the time-to-event is described in Section 9.3.1.
Main Analytical Approach
In line with the “while on treatment” (here: “while alive”) strategy proposed to address the 
intercurrent event “death” for the primary efficacy estimand, see Section 3, “death prior to the 
occurrence of a primary efficacy outcome” will be considered a competing risk in the 
analysis. Addressing “premature discontinuation of assigned treatment” with the treatment 
policy strategy means that primary efficacy events occurring after treatment discontinuation 
are used in the analysis.
To estimate the relative change in the instantaneous rate of the occurrence of the primary 
efficacy outcome in participants assigned to asundexian versus apixaban according to the 
defined estimand, cause-specific hazard ratios (csHRs) and their associated confidence 
intervals will be derived from a stratified cause-specific Cox proportional hazards regression 
model. The results will be presented together with estimates of the csHRs for the competing 
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The primary efficacy non-inferiority null hypothesis, see Section 9.1, will be rejected if the 
upper limit of the 95% confidence interval for the csHR does not exceed the non-inferiority 
margin. 
The primary efficacy superiority null hypothesis, see Section 9.1, will be tested using a 
stratified log-rank test. 
Missing follow-up time for the time to the primary efficacy outcome will be addressed as 
described for the main analysis in Section 9.3.1.
Sensitivity Analyses
If Nelson-Aalen estimates of the cumulative hazard for the primary efficacy outcome by 
treatment arm indicate that estimated hazards are not reasonably constant over time, piecewise 
incidence rates, with appropriately chosen cut-points, will be estimated and presented. 
The plausibility of the proportional hazards assumption will be assessed by visually 
examining the plot of the log of the negative log of Aalen-Johansen estimates of the survival 
function versus the log time for evidence of non-parallelism. If there is strong evidence of 
non-proportionality, time-dependent cause-specific hazard ratios will be estimated with the 
model that includes the interaction term. Further details will be specified in the SAP.
Missing follow-up time will be in general handled as described above. In addition, sensitivity 
analyses with regard to the missing follow-up time will be done as described in Section 9.3.1.
Subgroup analyses will be performed without imputation of missing follow-up time. Details 
will be described in the SAP. 
Supplementary Analyses
In a supplementary analysis the primary efficacy objective will be explored from a different 
angle, comparing the probability for the occurrence of a primary efficacy outcome over time 
in contrast to the hazard rates. I.e. the estimand explored in the supplementary analysis is the 
same as the primary efficacy estimand but the population-level summary is the sub-
distribution hazard ratio based on a Fine-Gray model. Since the expected probability of the 
occurrence of a primary efficacy event is less than 20% over the whole duration of study 
follow-up, a sub distribution hazard ratio of x is associated with an x-fold decrease of the odds 
of the occurrence of the primary efficacy outcome when comparing asundexian with 
apixaban. Gray’s test will be used to compare the cumulative incidence functions.
Another supplementary analysis will explore an estimand specifically targeting the non-
inferiority objective to provide additional insights into the understanding of the treatment 
effect. This estimand will use different strategies to address intercurrent events in defining the 
treatment effect of interest. Details will be described in the SAP.
9.3.2.2
Primary Safety Estimand
Definition of endpoint
The primary safety endpoint is the time from randomization to the first occurrence of ISTH 
major bleeding. The bleeding outcome is defined in Section 3, the derivation of the time-to-
event is described in Section 9.3.1.
Main Analytical Approach
In line with the “while on treatment” strategy proposed to address intercurrent events for the 
primary safety estimand, see Section 3, both “death prior to the occurrence of a primary safety 
outcome” and “premature discontinuation of assigned treatment” will be considered 


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competing risks in the analysis. This also implies that only participants who took at least one 
dose of study intervention will be included in the analysis, i.e. the analysis will be performed 
on the SAF.
To estimate the relative change in the instantaneous rate of the occurrence of the primary 
safety outcome in participants taking asundexian versus apixaban according to the defined 
estimand, csHRs and their associated confidence intervals will be derived from a stratified 
cause-specific Cox proportional hazards regression model. The results will be presented 
together with estimates of the csHRs for the associated competing risks.
The primary safety superiority null hypothesis, see Section 9.1, will be tested using a 
stratified log-rank test. 
If applicable, incomplete follow-up for the time to the primary safety outcome will be 
addressed with statistical methods aligned with the targeted estimand. 
Sensitivity Analyses
If Nelson-Aalen estimates of the cumulative hazard for the primary safety outcome by 
treatment arm indicate that estimated hazards are not reasonably constant over time, piecewise 
incidence rates, with appropriately chosen cut-points, will be estimated and presented. 
The plausibility of the proportional hazards assumption will be assessed as described above 
for the primary efficacy outcome.
If applicable, the robustness of the main estimator to deviations from assumptions regarding
incomplete follow-up for the time to the primary safety outcome will be addressed with 
statistical methods aligned with the targeted estimand.
Supplementary Analyses
In a supplementary analysis the objective will be explored from a different angle, comparing 
the probability for the occurrence of the primary safety outcome as compared to the hazard 
rates based on a Fine-Gray model and using Gray’s test to compare the cumulative incidences. 
I.e. the estimand explored in the supplementary analysis is the same as the primary safety 
estimand but the population-level summary is the sub-distribution hazard ratio based on a 
Fine-Gray model.
9.3.2.3
Primary Net Clinical Benefit Estimand
Definition of endpoint
The primary net clinical benefit endpoint is the time to first occurrence of stroke, systemic 
embolism, or ISTH major bleeding (excluding hemorrhagic stroke). The outcomes are defined 
in Section 3, the derivation of the time-to-event is described in Section 9.3.1.
Main Analytical Approach
In line with the “while on treatment” strategy proposed to address intercurrent events for the 
primary net clinical benefit estimand, see Section 3, both “death prior to the occurrence of a 
primary net clinical benefit outcome” and “premature discontinuation of assigned treatment” 
will be considered competing risks in the analysis. This also implies that only participants 
who took at least one dose of study intervention will be included in the analysis, i.e. the 
analysis will be performed on the SAF.
To estimate the relative change in the instantaneous rate of the occurrence of the primary net 
clinical benefit outcome in participants taking asundexian versus apixaban according to the 


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defined estimand, csHRs and their associated confidence intervals will be derived from a 
stratified cause-specific Cox proportional hazards regression model. The results will be 
presented together with estimates of the csHRs for the associated competing risks.
The primary net clinical benefit superiority null hypothesis, see Section 9.1, will be tested 
using a stratified log-rank test. 
If applicable, incomplete follow-up for the time to the primary net clinical benefit outcome 
will be addressed with statistical methods aligned with the targeted estimand. 
Sensitivity Analyses
If Nelson-Aalen estimates of the cumulative hazard for the primary net clinical benefit 
outcome by treatment arm indicate that estimated hazards are not reasonably constant over 
time, piecewise incidence rates, with appropriately chosen cut-points, will be estimated and 
presented. 
The plausibility of the proportional hazards assumption will be assessed as described above 
for the other primary outcomes.
If applicable, the robustness of the main estimator to deviations from assumptions regarding
incomplete follow-up for the time to the primary net clinical benefit outcome will be 
addressed with statistical methods aligned with the targeted estimand.
Supplementary Analyses
In a supplementary analysis the objective will be explored from a different angle, comparing 
the probability for the occurrence of the primary net clinical benefit outcome as compared to 
the hazard rates based on a Fine-Gray model and using Gray’s test to compare the cumulative 
incidences. I.e. the estimand explored in the supplementary analysis is the same as the 
primary net clinical benefit estimand but the population-level summary is the sub-distribution 
hazard ratio based on a Fine-Gray model.
9.3.3
Secondary Endpoint(s)  Analysis 
The analysis of estimands associated with secondary endpoints will follow the principles as 
described for the respective primary efficacy and safety estimands.
For those efficacy composites that include CV death as a component of the endpoint, the 
competing risk death will be reduced to non-CV death and, obviously, death will not be a 
competing risk for the all-cause mortality endpoint.
9.3.4
Exploratory Endpoint Analysis
The analyses of exploratory time-to-event endpoints will follow the principles described 
above. Details around the analyses of exploratory endpoints will be specified in the SAP.
9.3.5
Other Safety Analysis
An overall summary of AEs will be generated by study intervention arm. The number and 
percentage of participants with treatment emergent AEs (TEAEs; i.e. AEs occurring until 2 
days after last study intervention administration), post-treatment AEs (i.e. AEs occurring 
more than 2 days after last intake of study intervention), treatment emergent SAEs, treatment 


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emergent study intervention-related AEs, treatment emergent study intervention-related 
SAEs, TEAEs leading to premature and permanent discontinuation of study intervention, 
treatment emergent non-serious AEs, TEAEs by maximum intensity, drug-related TEAEs by 
maximum intensity will be summarized by treatment group using Medical Dictionary for 
Regulatory Activities (MedDRA) terms grouped by Primary System Organ Class and 
Preferred Term.
The number of participants with treatment emergent abnormal laboratory values above or 
below the normal range will be tabulated by the laboratory parameter and study intervention 
group.
Summary statistics including changes from baseline will be calculated by study intervention 
group and visit for all quantitative laboratory parameters.
9.3.6
Other Analysis
Subgroup analyses of primary and secondary efficacy and safety outcomes will be performed 
to assess consistency of the investigational intervention effect across subgroups.
Key subgroups
The following subgroup considered to be potentially predictive is planned to be analyzed:

Apixaban dosage
As described in Section 6.1, a 2.5 mg dose of apixaban is indicated for participants with any 2 
of the following criteria: age 80 years or older, body weight of 60 kg or less, or serum 
creatinine level of 1.5 mg per dL (133 µmol/L) or more. For each participant, the dose 
selection will be based on the values at the randomization visit. As the apixaban treatment 
will be blinded, all participants will be assigned to one of the apixaban groups according to 
their risk factors. As the lower apixaban dosage might decrease the efficacy treatment effect, 
the “apixaban dosage” factor might be predictive of the treatment effect. Since the aim of the 
study is to show superiority or at least non-inferiority for all participants it seems reasonable 
not to conduct 2 different studies. This holds true since the proportion of participants with 2 
or 3 risk factors for apixaban dosage is estimated to be at about 10%.
The following factors that define subgroups are known or expected to possibly show different 
risks of either efficacy and / or safety events across the different levels of the factor and are 
therefore considered potential prognostic factors:

The stratification factors

Participation in conventional study model vs. DCT model.
Participants in the DCT part might be younger and different compared to  
participants in the conventional study model.

Current use vs. no current use of single agent antiplatelet therapy planned to 
continue for at least 6 months after randomization.
Participants on single agent antiplatelet therapy may have a higher risk of 
bleeding. 

CHA2DS2-VASc score as the most important risk score for stroke

BMI 

eGFR, reflecting the known higher risks for an event and the recommendation of 
lowering the apixaban dose for decreased kidney function 


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
Race, with focus on the known differences in the risk profile for Asian / non-Asian and 
Black / Non-Black participants.

Region, as there are different known risk profiles and medical care standards.
If the number of participants is too small within a subgroup, then the subgroup categories may 
be redefined prior to unblinding the study. For other factors there is no a priori rationale that 
the treatment effect could possibly be modulated. The definition or categorization of 
subgroups will be reflected in the final SAP prior to unblinding.
Exploratory subgroups
Analyses of truly exploratory subgroups will be performed for a spectrum of demographic, 
disease and clinical characteristics, including but not limited to age, gender, geographic 
region, and type of AF, baseline risk factors for stroke and risk factors for bleeding. 
Additional subgroups and details will be pre-specified in the SAP.
Analytical Approach 
Consistency of treatment effects across subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable and the corresponding treatment-
subgroup interaction to the respective stratified Cox proportional hazards model.
The objective of the subgroup analyses is to show the consistency of treatment effects across a 
wide variety of participant groups. As the number of subgroup analyses for baseline 
characteristics may be large, the probability of observing at least one statistically significant 
but spurious interaction is high despite the lack of a biological or pharmacological basis for 
expecting an interaction. Thus any significant interactions will be interpreted as “flags” to 
prompt further investigation.
If the interaction term is significant at the 5% type-I error level in the analysis of the primary 
endpoint, secondary endpoints will be investigated to evaluate the plausibility of such an 
effect. Furthermore, in the analysis of key endpoints if the interaction term is significant at the 
5% type-I error level the likelihood ratio test proposed by Gail and Simon will be performed 
to test the hypothesis that there is no crossover or qualitative interaction at the 1% type-I error 
level (H0: The direction of treatment effect is the same for all levels of a subgroup variable vs. 
H1: The direction of treatment effect is different for at least one level of a subgroup variable).
Following the test of interaction, the hazard ratio summarizing the treatment effect will be 
estimated separately within each level of a subgroup variable using stratified Cox proportional 
hazards models. Results will be presented graphically using forest plots.
9.4
Interim Analysis
An interim analysis is planned when about 85 participants with a primary efficacy event have 
been observed, corresponding to 25% of the target number of participants with a primary 
efficacy event. The interim analysis is for futility; therefore no adjustment of the type 1 error 
is needed.
It is recommended to stop the study before its planned completion for ethical reasons if both 
of the following 2 criteria are fulfilled based on the results of the interim analysis:

The point estimator of the cause-specific hazard ratio for the primary efficacy outcome 
is higher or equal to the non-inferiority margin of 1.5. 


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This guidance corresponds to a setting where based on the results of the interim 
analysis and assuming the point estimate from the interim analysis governing the 
remainder of the study, the chance that the trial will reach its success criterion if it 
continues falls below 1.2%. If the true hazard ratio for the primary efficacy outcome is 
1, the probability to estimate a cause-specific hazard ratio of > 1.5 at this stage is only 
3.1%.

The lower bound of the two-sided 95% confidence interval for the cause-specific 
hazard ratio for all-cause mortality is higher than 1.
The interim analysis will be conducted such that the ongoing study integrity is maintained. 
Only the independent statistical support group, who is responsible for providing the interim 
analysis results to the IDMC will be unblinded to the individual treatment group assignments. 
Interim analysis results will not be shared with investigators, participants, or the study team 
who are involved in the conduct of the study nor will be available for submission before the 
final database lock. 
9.5
Sample Size Determination
A single study with a study-wise type-I error level of 5% is proposed to provide convincing 
evidence on the effect of asundexian vs. apixaban on prevention of stroke and systemic 
embolism in participants with atrial fibrillation. Both the number of participants with primary 
efficacy or safety events and the total sample size must be sufficiently robust to support the 
intended claims for efficacy and safety, respectively. 
To meet these needs approximately 18000 participants will be randomly assigned to study 
intervention, eventually targeting approximately 333 participants with a primary efficacy 
event and 343 participants with a primary safety event (while exposed to intervention). The 
sample size may be increased if planning assumptions are not satisfied. Any decision to 
extend follow-up or increase sample size will be based upon the review of blinded data. 
The target numbers of participants with events were determined based on the primary 
hypotheses (see Section 9.1), the assumption of constant hazard rates for time from 
randomization to the events of interest over the total duration of the study, as well as the 
following assumptions: 

Efficacy

Non-inferiority margin of 1.5 for the cause-specific hazard ratio of asundexian vs. 
apixaban for the primary efficacy endpoint

Type-I error level of 0.05 for a two-sided log-rank test

Power of at least 90% for the non-inferiority test under the assumption that the true 
cause-specific hazard ratio (including effects of treatment discontinuation) is HR = 
1

Power of at least 90% for the superiority test under the assumption that the true 
cause-specific hazard ratio, including effects due to treatment discontinuation, is 
HR = 0.7 and the non-inferiority for efficacy and superiority for safety can be 
shown prior to testing of the superiority.

Safety


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
Type-I error level of 0.045, reflecting the division for superiority testing for safety 
and efficacy, for a two-sided log-rank test

Power of at least 90% for the superiority test under the assumption that the true 
cause-specific hazard ratio is HR = 0.7.

Net Clinical Benefit

Type-I error level of 0.045, reflecting the division for superiority testing for safety 
and efficacy and assuming that at least bleeding superiority endpoint will be met, 
for a two-sided log-rank test

Power of at least 90% for the superiority test under the assumption that the true 
cause-specific hazard ratio is HR = 0.7.
Based on the above assumptions, the required target number of study participants who have 
experienced a primary efficacy event is estimated to be 210 for the non-inferiority test, 333 
(rounded to 340) for the superiority test and the required target number of study participants 
who have experienced a primary safety as well as a net clinical benefit event on treatment is 
estimated to be 343. If the true hazard ratio (including effects of early treatment 
discontinuation) for the primary efficacy endpoint is HR = 0.73, the power to detect a 
treatment difference between asundexian and apixaban is 80% for a target number of 340 
participants with a primary efficacy outcome. For an estimated HR ≤ 0.80 (including effects 
of early treatment discontinuation) for an observed target number of 340 participants with a 
primary efficacy outcome superiority would be achieved at a 5% significance level.
This study will be event-driven, which implies that the study duration depends on when the 
target numbers of participants have experienced primary efficacy or safety events.
The anticipated incidence rates in the apixaban arm are assumed to be constant over time with

1.6 participants with a primary efficacy event per 100–patient years, corresponding to 
a cumulative incidence of 1.58% participants with a primary efficacy event one year 
after randomization

2.8 participants with a primary safety event per 100–patient years, corresponding to a 
cumulative incidence of 2.76% participants with a primary safety event one year after 
randomization

4.3 participants with death per 100–patient years, corresponding to a cumulative 
incidence of 4.21% for all-cause mortality one year after randomization

4.0 participants with net clinical benefit outcome per 100–patient years, corresponding 
to a cumulative incidence of 3.92% for net clinical benefit outcome one year after 
randomization
Furthermore, the total duration of the accrual period is assumed to be approximately 24 
months with a plausible accrual pattern of (0.08%, 0.16%, 0.44%, 0.69%, 1.39%, 1.81%, 
2.64%, 3.61%, 4.83%, 4.72%, 5.28%, 5.39%, 4.83%, 5.39%, 5.39%, 5.56%, 6.11%, 6.11%, 
5.83%, 5.83%, 6.11%, 6.11%, 6.11%, 5.57%) of the total participants in the respective 
months. 
Under these assumptions, assigning approximately 18000 participants randomly to study 
intervention an expected study duration of approximately 33 months will be sufficient to 
achieve the target number of participants with efficacy or safety events. If the pooled 
incidence rate for the primary safety event is indeed higher than the pooled incidence rate for 


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primary efficacy events, the study can be stopped when the required number of participants 
with a primary efficacy outcome is reached. Under the assumptions outlined above, the 
expected follow-up durations for participants assigned to study intervention are 9 to 33 
months after randomization plus safety follow-up. The mean treatment duration is projected 
as 15.5 months (median observation time 16 months). In addition, > 15600 participants are 
expected to be followed for at least 9 months, > 12600 participants for 12 months, > 6600 
participants for 18 months and > 1700 participants for 24 months.
In order to achieve the target number of participants with efficacy or safety events and to 
preserve the target power of the study the incidence rates of the primary endpoints will be 
monitored in a blinded fashion so that adjustments can be made to the number of participants 
to be randomized and / or the duration of follow-up.
Sample size calculations were derived using the software PASS 13.


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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:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines

Applicable ICH GCP guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (e.g. advertisements) must be submitted, reviewed and approved in 
accordance with national legislation and undergo scientific and ethical assessment 
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. Any substantial modification of 
the protocol will be submitted to the competent authorities as substantial amendments 
for approval, in accordance with ICH Good Clinical Practice and national and 
international regulations.

Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants.

The investigator will be responsible for the following, as applicable:

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

Notifying the IRB / IEC of SAEs or other significant safety findings as required by 
IRB / IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB / IEC, and all other applicable local 
regulations
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 
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 the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the potential participants or their legally 
authorized representative and answer all questions regarding the study. 

Potential participants must be informed that their participation is voluntary. They or 
their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the 
IRB / IEC or study center. 

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 participants or their legally authorized 
representative. 

A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 7 days from the previous ICF signature date.

Informed consent must be obtained before initiation of any study-specific procedures. 
The process of obtaining informed consent must be documented in participant’s source 
documentation.

Pharmacogenetic samples will be taken in a subset of participants. Eligible 
participants will be asked to sign a corresponding informed consent.

As part of the DCT model, a secure link will be provided via email to the study 
participant by the study staff to access the electronic consent web portal, along with 
unique login credentials. 

Individuals who agree to take part in the study will be asked to review the consent 
overview information. 

Study investigator / designated staff will complete the informed consent process 
with the participant by telephone / videoconference. 

Individuals who agree to take part in the study will provide their signature 
executed to an electronic record as per local requirements on a computer, 
smartphone, or a tablet in the designated signature block, with the person 
conducting consent countersigning. 

Once consented, a DCT participation kit will be sent out to study participants and 
other operational logistics will be initiated as described in Section 10.10.1.

Participants will be instructed to return all study supplies, including any 
provisioned devices, back to the study site once study participation is completed.
10.1.4
Recruiting Strategy
Detailed description of the recruitment strategy will be provided in country-specific 
documentation as required.


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10.1.5
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or biological samples 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.

Participants must be informed that their 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 who will be required to give consent for their data to be 
used as described in the informed consent 

Participants must be informed that their 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.
10.1.6
Committees Structure
10.1.6.1
Program Leadership Committee (PLC)
There will be a Program Leadership Committee for the overall Phase 3 OCEANIC program. 
The PLC consists of external experts in the areas of neurology and cardiology. It will include 
the Executive Committee heads of the Phase 3 studies with asundexian, as well as sponsor 
representatives, and will ensure the overarching integrity of the studies. The role of the PLC is 
to facilitate communication and alignment and to coordinate the high-level program wide 
strategy across the asundexian Phase 3 program. Details of the Committee will be specified in 
the Committee charter.
10.1.6.2
Executive Committee (EC)
The main task of the Executive Committee for OCEANIC-AF (study 19767), which is 
composed of a panel of experts in the field cardiology, thrombosis / hematology and 
neurology, is to be actively engaged in the protocol development and the conduct, 
interpretation, and reporting of the results of the study. Furthermore it will advise the sponsor 
on clinical, medical, and scientific questions, and support publications surrounding the study 
and the overall program. The EC will work collaboratively with other entities (including the 
sponsor and the Steering Committee) engaged in the relevant clinical study to coordinate 
communication with sites and site investigators. In addition, the EC will make an effort to 
engage and train a next generation of diverse clinical study investigators. Details of the 
Committee will be specified in the Committee charter.
10.1.6.3
Steering Committee (SC)
Each Phase 3 study in the asundexian Phase 3 program will have an independent SC that 
reports to the Executive Committee for the study. Each SC will be made up of national leaders 
from most participating countries. Some countries may have more than one national leader. 
SC members will have relevant expertise in thrombosis, cardiology, neurology, and / or 
clinical studies and / or will be recognized national leaders within their country. The SC will 
provide input into the design and execution of the clinical study, with a focus on issues 
relevant to specific countries. SC members will be in close contact with the sponsor’s local 
operational team in their country. Details of the SC will be specified in the Committee charter.


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10.1.6.4
Independent Data Monitoring Committee (IDMC)
Ongoing safety monitoring during the conduct of the study will be performed by an external 
and unblinded IDMC (efficacy data will also be assessed to determine the risk / benefit ratio 
and futility). An independent statistical analysis center (SAC) will be involved in processing 
unblinded data for the IDMC. Analysis periods and procedures will be defined in an 
operational charter (IDMC Charter) filed in the study file. Following data review, the IDMC 
will provide written recommendations that will be transferred to the sponsor. All other 
definitions will be provided in the IDMC charter.
10.1.6.5
Clinical Events Committee (CEC)
Potential and pre-specified clinical outcome events will be submitted for adjudication to an 
independent CEC. Adjudication of all bleeding events as well as efficacy events will be 
performed by members of the CEC who will review events in a blinded fashion and will 
adjudicate and classify the following events in a consistent and unbiased manner according to 
definitions further specified in the CEC charter. The adjudication will also include algorithmic 
approaches:

Bleeding events according to the following classifications and definitions (refer to 
Section 8.3):

ISTH (major, clinically relevant non-major and minor)

BARC (type 1, 2, 3, 5)

Death (CV death [including death with undetermined cause] or non-CV death)

MI

Stroke (ischemic, hemorrhagic, undetermined)

Systemic embolism.
In addition, events that might be indicative of a potential outcome event will be reported as 
outcome events to ensure that no outcome event is missed. This includes for example TIA and 
hospitalization for cardiac chest pain with increased cardiac enzymes.
Data entry procedures and documentation necessary for case adjudication will also be 
described in the CEC charter. Adjudication results will be the basis for the final analysis.
10.1.7
Dissemination of Clinical Study Data
Bayer fulfills its commitment to publicly disclose study results through posting the result 
studies on public registries in accordance with applicable law and regulations.
Result Summaries of Bayer's sponsored clinical studies in drug development Phases 2, 3 and 
4 and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition results of clinical drug 
studies will be provided on the publicly funded websites ClinicalTrials.gov and EU Clinical 
Trials Register in line with the applicable regulations.
In accordance with the current EU regulation, result summaries will be submitted within one 
year from the end of the studies in adult populations or within 6 months for studies in a 


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pediatric population, in all participating countries. No preliminary data analysis (e.g. on EU 
data only) will be performed, as this might compromise data integrity and the scientific 
validity of the study.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical study data, study-level clinical study data, and protocols from clinical 
studies in patients for medicines and indications approved in the United States (US) and 
European Union (EU) on or after January 01, 2014, as necessary for conducting legitimate 
research.
All Bayer-sponsored clinical studies are considered for publication in the scientific literature 
irrespective of whether the results of the clinical studies are positive or negative.
10.1.8
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g. laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

Guidance on completion of CRFs will be provided in the CRF completion guidelines 
provided to the study sites.

The investigator must permit study-related monitoring, audits, IRB / IEC review, and 
regulatory agency inspections and provide direct access to source documents. 

Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g. risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g. 
contract research organizations).

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. 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. 

In addition to the on-site monitoring, a remote monitoring option is available. All 
study materials, including but not limited to drug accountability records or electronic 
source documentation, will be available for remote monitoring with view-only access, 
with training provided prior to access being granted. Study staff will be available to 
meet via video conference or over the phone. Study monitors will be able to issue 
queries and request resolutions which will be completed by the designated study staff.

Home nurses are expected to record source electronically. The clinical data recorded 
by home nurses is readily visible to the investigator / authorized site personnel and will 


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be referenced when making entries into the CRF. Source data collected electronically 
can also be viewed by study monitors for ongoing source data verification purposes. 
Where patient service centers are utilized, staff may also record source electronically 
in a similar fashion.
10.1.9
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 reported on the CRF or 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.

Definition of what constitutes source data, and its origin can be found in the Source 
Data Location List (SDLL).

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The sponsor or designee will perform monitoring 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.

The site must implement processes to ensure availability of all required source 
documentation (e.g. participant file, local laboratory report). The monitor will work 
with the site to collect key data points by completing the SDLL.

Race and ethnic group may be entered directly into the CRF, without availability of 
corresponding source documentation. Thus, these CRF data will be the source and no 
additional source documentation will be available. For all other data, source 
documentation must be available at the site.
10.1.10
Study and Site Start and Closure
Study Start
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The start of a clinical study in EU is defined as the date on which the first site is declared by 
the sponsor to be ready to enroll in a country and clinical study will be open for recruitment of 
participants.
Study / Site Termination
The sponsor or 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.


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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:
For study termination:

Discontinuation of further study intervention development
For site termination:

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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator

Total number of participants at study level included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs / IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and / or follow-up.
10.1.11
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 

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 multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

Additional information regarding publication policy can be found in the Steering 
Committee charter.


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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 unless 
specifically mentioned. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.

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 Tests
Laboratory 
Assessments
Parameters
Hematology
Red blood cell (RBC) 
count 
White blood cell (WBC) 
count
Platelet 
count
Hemoglobin
Hematocrit
Clinical Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase (AP)
Gamma glutamyl transpeptidase (γGT) 
Bilirubin (total and fractionated)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Blood urea nitrogen (BUN)
Creatinine
eGFR
Sodium
Potassium
Uric acid
Glucose
Cholesterol (total)
Abbreviations: ALT = Alanine aminotransferase, AP = Alkaline phosphatase, AST = Aspartate aminotransferase, 
BUN = Blood urea nitrogen, CK = Creatine kinase, eGFR = estimated glomerular filtration rate, γGT = Gamma 
glutamyl transpeptidase, LDH = Lactate dehydrogenase, RBC = Red blood cell (count), WBC = White blood cell 
(count) 
Investigators must document their review of each laboratory safety report.
The name and address for the central laboratory service provider can be found in the 
documentation supplied by the vendor. In the event of implausible results, the laboratory may 
measure additional parameters to assess the quality of the sample (e.g. clotted or hemolyzed) 
and to verify the results. The results from such additional analyses may neither be included in 
the clinical database of this study nor evaluated further. If the results are relevant, the 
investigator will be informed to determine follow-up activities outside of this protocol. 
All exploratory biomarkers analyzed in a subset of participants (see Section 8.8) are not used 
routinely in practice and will be analyzed in batches. Therefore, timely reporting of the results 
will not be possible during the study and review of the results will not assist participant care.


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10.2.1
Liver Safety: Follow-up Assessments and Suggested Actions
Abnormal laboratory results and / or clinical signs and symptoms indicative of liver injury 
and / or liver dysfunction should be reported as adverse event.
It is important to initiate follow-up immediately upon detection of such an adverse event and 
not to wait until the next scheduled visit. This applies to both abnormalities detected at local 
or central laboratory and might include additional samples for analyses in local laboratories.
Objectives of the follow-up assessments are to ensure participant safety and to identify the 
etiology of the adverse event as far as possible. The assessments are guided by clinical and 
regulatory requirements. The follow-up assessments and documentation of additional 
information as outlined below have to be initiated during intervention period and up to 2 
weeks after last study intervention intake (safety follow-up) if the following criteria are met:
1. Elevation of ALT or AST in comparison to values obtained from central laboratory at 
baseline (either at screening or randomization):
a) Normal value (≤ ULN) at baseline: ALT or AST reaches > 3 x ULN, or 
b) Elevated value (> ULN) at baseline: ALT or AST increases by ≥ 1.5-fold compared to 
the lowest elevated baseline value and reaches > 4 x ULN
AND
2. A confirmatory re-test has been obtained and confirms the prior elevation. A confirmatory 
re-test has to be performed as soon as possible, at the latest within 48-72 hours of the 
investigator becoming aware of the result and includes minimally: AST, ALT, AP and 
bilirubin (total and fractionated) (see Table 10–2).
For participants with AST elevation according to 1. a) or 1. b) and 2. in the context of a 
diagnosis of an AMI, this elevation will not be considered meeting the criteria requiring 
further follow-up, unless judged otherwise by the investigator.
Follow-up assessments

Repeating follow-up samplings for liver enzymes (ALT and AST) and serum total 
bilirubin tests 2 or 3 times weekly. Frequency of re-testing can decrease to once a week or 
less if abnormalities stabilize (details see Table 10–2). Follow-up sampling should also 
include any other relevant abnormal liver parameter observed in prior testing (such as AP, 
albumin, γGT, CK or LDH), as clinically indicated. Follow-up sampling might be 
discontinued earlier than when values return to normal or participant baseline levels in 
case a confirmed clinical diagnosis unrelated to the study intervention has been 
established that explains the elevated liver enzymes and no further normalization is 
expected.

Obtaining additional samples to assess further general chemistry, lipid metabolism and 
liver function parameters and complete blood count. This is part of the central laboratory 
sample (see Table 10–2).
Etiological follow-up assessments

Ruling out acute viral hepatitis, autoimmune or alcoholic hepatitis, nonalcoholic 
steatohepatitis, hypoxic / ischemic hepatitis and biliary tract disease. This may require 
performing additional procedures, e.g. ultrasound examinations. A sample for further 
etiology assessment should be obtained from a participant evaluated at a study site as soon 


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as possible after a positive confirmatory re-test if needed for exploration of the underlying 
cause or if no confirmed diagnosis has yet been established. This sample includes several 
tests for ascertaining the etiology of the elevation; not all of these parameters might need 
to be analyzed if an unambiguous assignment of etiology can be made based on a fraction 
of those parameters (see Table 10–2: further etiology assessment).

Considering gastroenterology or hepatology consultations.
Additional information

Obtaining a detailed history of the symptoms and prior or concurrent diseases and risk 
factors including exposure to environmental chemical agents.

Obtaining a history of concomitant drug use (including nonprescription medications, 
Traditional Chinese medicine and herbal and dietary supplement preparations), alcohol 
use, recreational drug use, and special diets.
Data for follow-up assessments (including relevant local laboratory results) and the additional 
information are to be recorded in the corresponding CRF pages, as applicable. This includes 
an update to the (S)AE report including the reported term(s) and the causality assessment in 
case of relevant findings.
For ALT or AST > 3 x ULN concurrent with a total bilirubin > 2 x ULN, every effort should 
be made to promptly clarify any possible underlying disease(s).
Suggested actions:
Participant management is at the discretion of the treating physician, but study intervention 
may be continued during confirmatory re-testing.
Follow-up assessments including sampling as outlined in Table 10–2 and documentation of 
additional information should be continued as specified above regardless of study intervention 
discontinuation. If follow-up assessments for ALT / AST are not possible, then the participant 
should interrupt and potentially permanently discontinue study medication.
Discontinuation of treatment should be considered if:

ALT or AST > 8 x ULN

ALT or AST > 5 x ULN for more than 2 weeks

ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN or INR > 1.5)

ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and / or eosinophilia (> 5%).


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Table 10–2: Liver Laboratory Monitoring
Sample / Time point
Laboratory Test 
Further aspects
Initial confirmatory re-test*
within 48-72 hours of the 
investigator becoming aware of 
elevation
AST, ALT, AP, Bilirubin (total and 
fractionated)
If not analyzed in prior sample: γGT, CK, LDH
If confirmed: Document 
(S)AE and additional 
information in CRF
Follow-up sampling*
while ALT or AST are > 3 x or > 4 
x ULN#: at least 2-3 times a week
ALT, AST, Bilirubin (total and fractionated) 
Continue observation for 
clinical signs and 
symptoms
Follow-up sampling*
when ALT and AST are ≤ 3 x or 
≤ 4 x ULN#: once a week
ALT, AST 
Follow-up generally ends 
earliest when values 
return to normal or 
participant baseline levels
Central laboratory sample* /**
(after AST or ALT elevation# has 
been confirmed in a re-test) 
includes parameters for etiology 
assessment and should be taken 
as soon as possible (may be 
combined with first follow-up 
sampling)

ALT, AST, AP, Bilirubin (total and 
fractionated), γGT, LDH, CK, CRP

PT / INR

Albumin, Cholinesterase

Glucose, HbA1c

Total cholesterol, Triglycerides

Complete blood count including WBC 
with differentials (absolute and relative 
values), Hemoglobin
Further etiology assessment 

Anti-hepatitis A virus antibodies (total, 
IgM)

Hepatitis B virus surface antigen, Anti-
hepatitis B virus core IgM antibody; if 
positive, the following will be evaluated: 
Anti-hepatitis B virus antibodies (surface,
core total, core IgG), Hepatitis B DNA, 
Anti-hepatitis D virus IgM antibodies 

Hepatitis C RNA, Anti-hepatitis C virus 
IgM antibodies 

Hepatitis E RNA, Anti-hepatitis E virus 
antibodies (IgM and IgG)

IgG

Antinuclear antibodies (ANA)

Anti-smooth muscle antibodies (ASMA)

Cytomegaly virus DNA, Anti-Cytomegaly 
virus IgM antibodies

Epstein-Barr virus DNA, Anti-Epstein-Barr 
virus IgM antibodies

Herpes simplex virus DNA, Anti-herpes 
simplex virus IgM antibodies

Anti-mitochondrial autoantibodies

Ferritin, Iron, Total iron binding capacity, 
Transferrin saturation

Ceruloplasmin

Anti-neutrophil cytoplasmic antibodies /
Anti-neutrophil perinuclear antibodies

Alpha-1 antitrypsin level
Consider update of AE 
reporting terms in case of 
relevant findings
Abbreviations: ALT = Alanine aminotransferase, ANA = Antinuclear antibodies, AP = Alkaline phosphatase, ASMA = Anti-
smooth muscle antibodies, AST = Aspartate aminotransferase, CK = Creatine kinase, CRF = Case report form, CRP = C-
reactive protein, DNA = Desoxyribonucleic acid, γGT = Gamma glutamyl transpeptidase, HbA1c = Hemoglobin A1c, 
IgG = Immunoglobulin G, IgM = Immunoglobulin M, INR = International normalized ratio, LDH = Lactate dehydrogenase, PT = 
Prothrombin time, RNA = Ribonucleic acid, (S)AE = (Serious) adverse events, ULN = Upper limit of normal, WBC = White 
blood cell count.
# refer to criteria for comparison to individual baseline value under 1. a) or 1. b) in Section 10.2.1
* samples to be analyzed preferably via central lab; local lab is also acceptable if a site visit is not possible
** in case the investigator learns about an AE diagnosed by another treating physician, every effort should be made to obtain
the parameters for further elucidation of etiology in a timely fashion, unless a clear etiology has already been established.


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10.3
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, associated 
with the use of study intervention, whether or not considered related to the study 
intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e. not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and / or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE / SAE unless it is an intentional overdose taken with possible suicidal / self-
harming intent. Such overdoses should be reported regardless of sequelae.

Sign, symptoms, or the clinical sequelae of suspected medication errors, misuse and 
abuse of either study intervention or a concomitant medication. Medication errors, 
misuse and abuse per se will not be reported as an AE / SAE, unless it is resulting in 
AE / SAE. Such medication errors, misuse and abuse should be reported regardless of 
sequelae.

Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and / or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE or 
SAE. 
Events NOT Meeting the AE Definition

Any abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition


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
The disease / disorder being studied or expected progression, signs, or symptoms of 
the disease / disorder being studied, unless more severe than expected for the 
participant’s condition

Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that 
leads to the procedure is the AE

Situations in which an untoward medical occurrence did not occur (social and / or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g. hospitalization for signs / symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose, meets the one or 
more of the criteria listed:
a.
Results in death
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 admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and / or treatment 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 treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant 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 (e.g. sprained ankle) that 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:


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
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that 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 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, convulsions, or development of intervention dependency or 
intervention abuse.
10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE / SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE / SAE information.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the AE / SAE CRF page.

There may be instances when copies of medical records for certain cases are requested 
by the sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and / or other clinical information. Whenever possible, the diagnosis (not 
the individual signs / symptoms) will be documented as the AE / SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 

Mild: A type of adverse event that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.

Moderate: A type of adverse event that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm to 
the research participant.

Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
An event is defined as serious when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE / SAE. The investigator will use clinical judgment to 
determine the relationship.

A reasonable possibility of a relationship conveys that there are facts, evidence, 
and / or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

For causality assessment, the investigator will also consult the IB and / or product 
information, for marketed products.

The investigator must review and provide an assessment of causality for each 
AE / SAE and document this in the medical notes. There may be situations in which an 
SAE has occurred, and the investigator has minimal information to include in the 
initial report to the sponsor. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor.

The investigator may change his / her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

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 healthcare 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 post-mortem 
findings including histopathology. 

New or updated information will be recorded in the originally submitted documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to the Sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours.


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
The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form and 
transmit to the sponsor via PV.CaseProcessing@bayer.com.

Contacts for SAE reporting can be found in the Investigator Site File.
SAE Reporting to the Sponsor via Paper CRF

Email transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the sponsor via PV.CaseProcessing@bayer.com.

In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes.

Contacts for SAE reporting can be found in the Investigator Site File.


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10.4
Appendix 4: Contraceptive and Barrier Guidance
10.4.1
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 considered WOCBP (fertile)
1. Following menarche
2. From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below):

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, confirmation with more than one FSH measurement 
(> 40 IU/L [for US only: FSH levels > 40 mIU/mL and estradiol < 20 pg/mL]) is 
required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen 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.

Permanent sterilization methods (for the purpose of this study) include:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g. Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Woman of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
1. Premenopausal female with permanent infertility due to one of the following:
a) Documented hysterectomy
b) Documented bilateral salpingectomy
c) Documented bilateral oophorectomy


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d) For individuals with permanent infertility due to an alternate medical cause other than 
the above (e.g. Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry.
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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement (> 40 IU/L [for US only: FSH levels > 40 mIU/mL and 
estradiol < 20 pg/mL]) is required. 

Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.


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10.4.2
Contraception Guidance
A list of contraceptives allowed during the study is reported as follows:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) c

Bilateral tubal occlusion

Azoospermic partner (vasectomized or due to a medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Highly Effective Methodsb That Are User Dependent Failure rate of < 1% per year when used consistently 
and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable
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) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. 
Male condom and female condom should not be used together (due to risk of failure from friction).


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10.5
Appendix 5: Calculating the Child-Pugh Score
The severity of liver disease (Table 10–3) will determine the Child-Pugh score (Table 10–4).
Table 10–3: Grading of severity of liver disease
Factor
+1
+2
+3
Bilirubin (mg/dL)
< 2
2 – 3
> 3
Albumin (g/dL)
> 3.5
2.8 – 3.5
< 2.8
International Normalized Ratio
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Mild
Moderate / Severe
Encephalopathy
None
Grade I – II
Grade III – IV
Source: adapted from (Pugh et al. 1973)
Table 10–4: Child-Pugh score
Child-Pugh Class
A
B
C
Points
5 – 6
7 – 9
10 – 15
Source: adapted from (Pugh et al. 1973).


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10.6
Appendix 6: Calculating Glomerular Filtration Rate
In accordance with established nephrology practice and guidelines, renal function will be 
assessed by means of the estimated glomerular filtration rate (eGFR), calculated using the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation refit without the 
race variable (Inker et al. 2021).
CKD-EPI equation (Conventional units [serum creatinine level is measured in mg/dL]):
GFR (mL/min/1.73 m2) = 142 x min(Scr/κ, 1)α x max(Scr/κ, 1)-1.200 x 0.9938Age x 
1.012 [if female] 
where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.241 for females 
and -0.302 for males, min indicates the minimum of (Scr/κ or 1.0), and max indicates the 
maximum of (Scr/κ or 1.0), and Age is measured in years.
GFR can be estimated using the calculator provided in the following link: 
https://www.kidney.org/professionals/kdoqi/gfr_calculator
For measurement of renal function in Japan, please refer to Section 10.12.2. 


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10.7
Appendix 7: Calculating CHA2DS2-VASc Score
Table 10–5: CHA2DS2-VASc score 
Letter
Risk factor
Score
C
Congestive heart failure / LV dysfunction
(Clinical HF, or objective evidence of moderate-to-severe LV dysfunction, or HCM)
1
H
Hypertension
(or on antihypertensive therapy)
1
A2
Age ≥ 75
2
D
Diabetes mellitus
(Treatment with oral hypoglycemic drugs and / or insulin or fasting blood glucose 
> 125 mg/dL [7 mmol/L])
1
S2
Stroke / TIA / thromboembolism
(Previous stroke, TIA, or thromboembolism)
2
V
Vascular disease
(Angiographically significant CAD, previous myocardial infarction, PAD, or aortic 
plaque)
1
A
Age 65-74
1
Sc
Sex category (i.e. female sex)
1
C Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even 
if asymptomatic) of moderate-severe LV systolic impairment (LV ejection fraction ≤ 40%) on cardiac imaging; 
HCM confers a high stroke risk and OAC is beneficial for stroke reduction.
H History of hypertension may result in vascular changes that predispose to stroke, and a wellcontrolled BP 
today may not be wellcontrolled over time. Uncontrolled BP - the optimal BP target associated with the lowest 
risk of ischemic stroke, death, and other cardiovascular outcomes is 120 - 129/< 80 mmHg.
A2 Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years 
upwards. Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 
65 - 74 years and 2 points for age ≥ 75 years. Age is a powerful driver of stroke risk, and most population 
cohorts show that the risk rises from age 65 years upwards. Age-related risk is a continuum, but for reasons 
of simplicity and practicality, 1 point is given for age 65 - 74 years and 2 points for age ≥ 75 years.
D Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to 
duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thrombo-
embolism) and presence of diabetic target organ damage, e.g. retinopathy. Both type 1 and type 2 diabetes 
mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients 
aged < 65 years with type 2 diabetes mellitus compared with patients with type 1 diabetes mellitus.
S2 Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischemic stroke, hence 
weighted 2 points. Although excluded from RCTs, AF patients with ICH (including hemorrhagic stroke) are at 
very high risk of subsequent ischemic stroke, and recent observational studies suggest that such patients 
would benefit from oral anticoagulation.
V Vascular disease (PAD or myocardial infarction) confers a 17 - 22% excess risk, particularly in Asian patients. 
Angiographically significant CAD is also an independent risk factor for ischemic stroke among AF patients 
(adjusted incidence rate ratio 1.29, 95% CI 1.08 - 1.53). Complex aortic plaque on the descending aorta, as 
an indicator of significant vascular disease, is also a strong predictor of ischemic stroke.
A See above. Recent data from Asia (Chao et al. 2016) suggest that the risk of stroke may rise from age 50 - 55 
years upwards and that a modified CHA2DS2-VASc (mCHA2DS2-VASc) score may be used in Asian patients 
(mCHA2DS2-VASc assigns 1 point for patients aged 50 - 74 years). This is not applicable to this study.
Sc Recent studies have suggested that female sex, in the absence of other AF risk factors (CHA2DS2-VASc 
score of 0 in males and 1 in females), carries a low stroke risk that is similar to males. The excess risk for 
females was especially evident among those with ≥ 2 non-sex-related stroke risk factors; thus, female sex is 
a risk modifier rather than a risk factor.and is age dependent. Adding female sex to the CHA2DS2-VASc 
score matters for age > 65 years or ≥ 2 non-sex-related stroke risk factors (January et al. 2019).
Abbreviations: AF = atrial fibrillation; BP = blood pressure; CAD = coronary artery disease; CI = confidence 
interval; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFpEF = heart failure 
with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial 
hemorrhage; LV = left ventricular; LVEF = left ventricular ejection fraction; OAC = oral anticoagulant; PAD = 
peripheral artery disease; RCT = randomized controlled trial; TIA = transient ischemic attack
Sources: adapted from (Hindricks et al. 2021, Lip et al. 2010).


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10.8
Appendix 8: Modified Rankin Scale
Table 10–6: Modified Rankin Scale (mRS) and Corresponding Sections of a 
Structured Interview
Scale
Description
0
No symptoms at all
No symptoms at all; no limitations and no symptoms
1
No significant disability despite 
symptoms; despite symptoms, able to 
carry out all usual duties and activities
No significant disability; symptoms present but not other 
limitations. Question: Does the person have difficulty 
reading or writing, difficulty speaking or finding the right 
word, problems with balance or coordination, visual 
problems, numbness (face, arms, legs, hands, feet), 
loss of movement (face, arms, legs, hands, feet), 
difficulty with swallowing, or other symptom resulting 
from stroke?
2
Slight disability; unable to carry out all 
previous activities but able to look after 
own affairs without assistance
Slight disability; limitations in participation in usual 
social roles, but independent for ADL. Questions: Has 
there been a change in the person’s ability to work or 
look after others if these were roles before stroke? Has 
there been a change in the person’s ability to 
participate in previous social and leisure activities? Has 
the person had problems with relationships or become 
isolated?
3
Moderate disability; requiring some help, 
but able to walk without assistance
Moderate disability; need for assistance with some 
instrumental ADL but not basic ADL. Question: Is 
assistance essential for preparing a simple meal, doing 
household chores, looking after money, shopping, or 
traveling locally?
4
Moderately severe disability; unable to 
walk without assistance and unable to 
attend to own bodily needs without 
assistance
Moderately severe disability; need for assistance with 
some basic ADL, but not requiring constant care. 
Question: Is assistance essential for eating, using the 
toilet, daily hygiene, or walking?
5
Severe disability; bedridden, incontinent 
and requiring constant nursing care and 
attention
Severe disability; someone needs to be available at all 
times; care may be provided by either a trained or an 
untrained caregiver. Question: Does the person require 
constant care?
6
Death
Abbreviation: ADL = Activities of daily living
Sources: adapted from (Banks and Marotta 2007, van Swieten et al. 1988, Wilson et al. 2002).


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10.9
Appendix 9: Outcome Events: Data Collection
All outcome events (efficacy and safety) are to be captured and reported from randomization 
until a participant’s last regular scheduled study visits (i.e. follow-up visit for participants 
taking study intervention until the regular end of the intervention period; in case of permanent 
discontinuation of study intervention, until the CEOT visit if the participant is still alive and if 
the participant agrees / as allowed by local regulations). The CRF will contain specific 
outcome event pages to capture the outcome events occurring throughout the study. Refer to 
Section 8.4.6 and Table 8–1 for more details. The following points need to be considered 
when reporting outcome events in relation to the time of their occurrence:

After randomization and before the first intake of the study intervention, outcome 
events should be reported on the respective outcome event CRF page. 

After first intake, if study intervention has not been discontinued permanently
(unless due to reaching the CEOT visit), outcome events should be reported on the 
respective outcome event CRF page and up to the CEOT safety follow-up visit.

After first intake, if study intervention has been prematurely discontinued 
permanently, outcome events should be reported on the respective outcome event 
CRF page through the CEOT visit (unless permanent discontinuation occurred less 
than 2 weeks prior to the CEOT visit, in which case reporting occurs until the CEOT 
safety follow-up visit).
Please also refer to Section 8.4.1 regarding the reporting of AEs.


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10.10
Appendix 10: DCT Model for DCT Sites Only
DCTs are intended to reduce the burden on clinical study participants and make studies more 
visible and accessible to patients independently of referring physicians. There is a growing 
body of evidence supporting the use of broadband internet access, home computing and 
smartphones, as well as digital health technologies enabling remote interactions and robust 
monitoring, support, and management of trial participants. 
In this study, approximately 10-20 sites globally are expected to participate as DCT metasites.
10.10.1
Recruitment, Onboarding, Training in DCT Model
Recruitment
Participants in the DCT model will be recruited by employing digital advertising on social 
media (e.g. Facebook, Google, Instagram) and in banners on patient advocacy and other 
relevant websites. In addition, outreach to the investigator’s network should be used to raise 
awareness of and recruit for the study.
Onboarding and Training
Upon signing informed consent, participants will be onboarded and trained for study-specific 
procedures during the screening period, including operational logistics. Part of this training 
will include confirmation that any devices provided to support participation are working 
appropriately and are fit for use.
Training will be conducted via teleresearch (phone and / or video call as applicable), home 
nurse, and / or by utilizing remote training methods available via the study application and / or 
web portal. 
DCT study site personnel will be trained for the study during the investigator meeting and / or 
during the site initiation process.
Training will be conducted on the smartphone application and / or web portal to access, 
navigate and use the app and / or study platform and on the below listed electronic devices 
used in the DCT model:
Study applications and devices used in the DCT model:

Study app and / or web portal
The study application and / or web portal will give participants access to complete the 
EQ-5D and attend teleresearch visits. Also included are reminders / engagement 
notifications, and the ability to contact the site directly via the app / portal. Training 
materials on how to use the app / portal will be provided to participants. 

Electronic devices
Participants are asked to use their own camera-equipped, web-enabled devices for the 
study. If needed, a smartphone with limited functionality for study use only will be 
provided to the participants.

ECG monitoring device
An ECG monitoring device will be utilized during the screening period to evaluate 
heart rhythm and may be supported by the home nurse.


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Further important topics for onboarding and training are:
Pregnancy Testing

For remote confirmation of the pregnancy test, the pregnancy test results can be 
reviewed and documented by the home nurse, if applicable. Alternately, the results 
should be provided to site staff for visual confirmation (e.g. photo, teleresearch visit). 
The image is not required as source documentation; written confirmation of a negative 
result in source is sufficient. 

If 4 or more days have elapsed between the negative screening pregnancy test and 
receipt of study intervention after randomization, a second negative pregnancy test 
must be obtained prior to the participant starting study intervention.
Direct-to-participant shipments of study intervention

First Dose
The first intake of study intervention will involve a delay due to the time required for 
delivery of study intervention to participant. After receipt of the first DtP shipment, 
but prior to taking the first dose of study medication, site staff will contact the 
participant to ensure the study medication was received in good condition and to 
review dosing instructions. Furthermore, study participants should be instructed to 
take the last dose of their open label NOAC (or non-oral anticoagulant if applicable) 
on the day prior to starting study intervention intake.

Accountability and Compliance
The metasite will be responsible for study medication accountability and will facilitate 
return of the used and unused study medication from the participant via (traceable) 
courier according to the DCT SoA. While a home nurse may conduct a count of study 
medication during a visit, this count is considered to be for use in compliance 
calculations only and is not considered formal accountability.
Respective documentation of DtP shipments will be maintained by Fisher Clinical 
Services and will be made available upon request.


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10.10.2
Schedule of Activities for DCT Model (DCT SoA)
Study periods
Duration
Screening
≤ 4 weeks
before RND
Intervention period
~9 ~33 months*, from RND until Common End of Treatment
(CEOT) visit / Early Termination (ET)
Early Termination period**
ET until CEOT visit
Common End of Treatment period
CEOT visit until 2 weeks after
Visit number / acronym
1 a
 1 b
2ǂ
3
4
5
6
7
8
9
10
11
12*
13*
ET visit ET SFU visit
≥ 3 13*
CEOT visit
CEOT SFU visit† 
Visit type
 / 














()
()
 ()

Visit / Month [M]
Day [D] ± window
Week [W] ± window
SCR a
D -28 
D -14
SCR b
D -14 
D 1
RND / M 0
D 1 ―∆
SI intake
M 1
 30±4
M 3
W 13±1
M 6
26±1
M 9
39±1
M 12
52±1
M 15
65±1
M 18
78±1
M 21
91±1
M 24
104±1
M 27
117±1
M 30
130±1
ET
ET
ET + 2 W
(ET+ 2 W) + 1 W
≥ M 1 M 30
≥ D 30±4 
W 130±1
CEOT
CEOT ± ~3 W
CEOT visit + 2 W 
(CEOT visit + 2 W) + 1 W
Administrative procedures
Remote eConsent
X
Initiate operational logistics
X
Inclusion / exclusion criteria
X
X
   X
Demographics / biometrics
X
Medical history
X
   X
Prior / concomitant meds
====================================continuously==================================
AP / AC only X (AP / AC only)
X
Clinical procedures / assessments
ECG
X
  (X)
Vital signs (BP and RHR)
X
  (X)
Adverse events
only procedure related
events
 ==============================continuously==============================
X†
X
Outcome events
  =================================================continuously=====================================================
HCRU
  =================================================continuously=====================================================
EQ-5D
   X
X
X
X
X
X
X
X†
IRT
Randomization /
Visit registration
X
X 
X
X
X
X
X
X
X
X
Laboratory assessments
Safety blood sampling
X
  (X)
X
X
X
X
X
X†
Pregnancy test (if WOCBP)
X
   X
X
X†
Study intervention (SI) shipment (direct-to-participant SI shipment)
SI delivery
∆X 
X
X
X
X
X
X
SI return / accountability
X
X
X
X
X
X
X
X†


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Annotated Schedule of Activities for DCT Model (DCT Annotated SoA)
Administrative procedures done by remote trial site
Remote eConsent
this includes use of electronic systems to convey information related to the study and also electronic signature of the consent form
Initiate operational logistics operational logistics will be initiated during this visit (home health visit scheduling, device shipment, familiarization with app / web portal and communication functionality) 
Inclusion / exclusion criteria in case SCR and RND are performed on the same calendar day, these criteria need to be assessed only once
Demographics / biometrics
biometrics refers to measurement of height and weight and will only be recorded at screening
Medical history
in case SCR and RND are performed on the same calendar day, this needs to be assessed only once
Prior / concomitant 
medication
in case SCR and RND are performed on the same calendar day, this needs to be assessed only once; in case a participant pretreated with a NOAC (or another antico-
agulant) has already taken the anticoagulant on the planned day of intake of study intervention, intake of SI should be postponed by one day (Section 6.1); if SI is
permanently discontinued ≥ 2W before CEOT visit, only AP / AC need to be reported at scheduled visits, including CEOT visit; otherwise all meds need to be reported
Clinical procedures performed by participant or local provider / assessments performed by remote trial site or local provider in case of events and HCRU, by participant in case of questionnaire
ECG
to display ≥ 6 leads; no need to be repeated once available, unless not available in sufficient quality (Section 8.3.6)
Vital signs (BP and RHR)
no need to be repeated once available (Section 8.3.5)
Adverse events
(S)AEs will be collected from start of SI intake until SFU visit; only study procedure related events will be reported from signing of eConsent onward (Section 8.4.1)
Outcome events
outcome events including all bleeding, death, MI, stroke and systemic embolism, as well as events indicative of a potential outcome (Section 8.4.6) need to be reported
in the CRF continuously until death or last study visit (= CEOT SFU; only if SI is permanently discontinued ≥2 W prior to CEOT visit reporting occurs until CEOT visit)
HCRU
HCRU (within hospitals) in conjunction with SAEs and outcome events needs to be documented, e.g. time points or periods affected (Section 8.10.1)
EQ-5D
at the respective visits participants should complete the questionnaire via smartphone / electronic device at any time during the visit window, preferably in one attempt
IRT operated by remote trial site
Randomization /
Visit registration
SCR and RND can take place on the same calendar day if all information is available (Visits 1b and 2 are combined); SI intake will start as soon as possible after RND 
(day 1); this will involve a delay due to time required for delivery of SI to participant; SI intake is expected to continue until the day prior to the CEOT visit
Laboratory assessments done by local provider (home nurse or service center) or potentially participant (pregnancy test)
Safety blood sampling
creatinine and eGFR values must be available at RND and can be used if done as part of routine management and no older than 14 days at RND (Section 8);
in any case, the full set of safety laboratory tests (Table 10–1) needs to be obtained once during the SCR period, at the latest at RND, and at indicated visits thereafter
Pregnancy test (if WOCBP) a WOCBP must have a negative serum or urine pregnancy test at SCR; a repeat test at RND (before SI intake) is required, unless ≤ 4 days lie between SCR and RND
Study intervention (SI) shipment (direct-to-participant SI shipment)
SI delivery
at each contact participants should be instructed regarding SI compliance; 1st SI shipment will be initiated after RND, and SI intake will start on the day after arrival of SI at
the participant’s home; participants need to be instructed on stopping open label anticoagulant; start of SI has to be confirmed with the participant and documented by site 
SI return / accountability
at the CEOT visit the final SI collection occurs: no SI intake should take place on the day of this visit anymore; the last intake of SI occurs on the previous day 
Abbreviations: AP / AC = antiplatelets / anticoagulants, BP = blood pressure, CEOT = common end of treatment, D = day, ECG = electrocardiogram, EQ-5D = European Quality of Life group 5-Di-
mension questionnaire, ET = early termination, HCRU = healthcare resource utilization, RHR = resting heart rate, IRT = interactive response technology, M = month, RND = randomization, SCR = 
screening, SFU = safety follow-up, SI = study intervention; W = week(s), WOCBP = woman of childbearing potential,  = teleresearch visit, = phone visit, ∆= time for delivery of SI to participant
ǂ procedures and assessments at visit 2 should preferably be conducted prior to RND; SI delivery will be initiated after RND; once participant confirms SI receipt, SI intake will be concluding the visit 
* if applicable (if the number of efficacy outcome events does not accrue until Month 33 as expected) the visit schedule will continue after Month 30 with the respective labelling, e.g. Visit 14, 15.
The duration of the intervention period (~9 to ~33 months) depends on when a participant joins during the course of the study. Displayed timepoints might therefore not be applicable to all participants.
** An early termination visit is only applicable to participants who prematurely discontinue intake of SI permanently; those should undergo an ET visit as soon as possible after discontinuation of SI. An 
ET SFU visit will occur 2 weeks (+ 7 days window) after the day of the discontinuation of SI (Section 7.1), unless permanent discontinuation occurred < 2 W prior to CEOT visit, in which case a CEOT 
SFU will be performed instead. After permanent discontinuation of SI participants should take part in the remaining visits (via phone) as scheduled, until including the CEOT visit (or CEOT SFU).
† if SI permanently discontinued: item not applicable; only if discontinued < 2 W before CEOT visit, CEOT SFU will replace ET SFU; if SI is permanently discontinued a phone call CEOT visit is expected


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10.11
Appendix 11: Tokenization
Participants at study sites in the United States may be invited to take part in voluntary 
tokenization that links their de-identified real-world data (e.g. claims, electronic health 
records, laboratory, pharmacy) to their study data without compromising the privacy of study 
participants. Approval for tokenization must be obtained from each participant, and a separate 
ICF will be provided. Tokenization may allow looking into the vital status and potentially 
cause of death of participants lost to follow-up.
Participation is optional, and participants who decline to take part in tokenization will still be 
able to participate in the clinical study. Non-participation in tokenization will not affect study 
conduct or the clinical care of the participants.
Third-party entities will use dedicated software to encrypt the original patient identification 
information into a new de-identified key (i.e. “token”) that is unique to each participant and 
will verify privacy compliance. No additional compensation will be provided to participants 
for participating in tokenization and linking of their data.


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10.12
Appendix 12: Country/region-specific Requirements 
10.12.1
China
10.12.1.1 CHN: Country/region-specific Changes Valid for China only
Overall Rationale
This section implements modifications of the original protocol to meet local requirements in 
China.
A description of changes and a brief rationale is outlined in the table below:
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities (SoA)
8.8. Biomarkers
Modifications made to specify no biomarker 
sampling will be carried out in China.
Biomarker sampling is not 
applicable to China.
3 Objectives, Endpoints and 
Estimands
Addition of footnotes to specify biomarkers 
will not be collected in China and therefore, 
no data from Chinese participants will be 
available for the analysis of the respective 
endpoints.
Biomarker sampling is not 
applicable to China.
3 Objectives and Endpoints
Footnote added “PK and PD analyses in 
Chinese participants will be performed to 
investigate ethnicity differences in AF 
patients. Blood samples for 
pharmacogenetics (limited to CES1 
genotyping analysis) will be collected in 
China. Other biomarker samples will not be 
collected in China and therefore, no data 
from Chinese participants will be available 
for the analysis of the respective 
endpoints.”
For clarification of the plan 
and purpose of PK, PD, 
and pharmacogenetics in 
China.
8.5 Pharmacokinetics
Text added “PK analyses in Chinese 
participants will be performed to investigate 
ethnicity differences in AF patients.” Text “, 
M-10 (BAY 2826102), and optionally other 
metabolites” replaced by “and its metabolite 
M-10 (BAY 2826102)”.
8.6 Pharmacodynamics
Text added “PD analyses in Chinese 
participants will be performed to investigate 
ethnicity differences in AF patients.
8.7 Genetics
Text added “Blood samples for 
pharmacogenetics (limited to 
Carboxylesterase 1 [CES1] genotyping 
analysis) will be collected in China.”
6.5 Study Intervention 
Compliance 
8 Study Assessments and 
Procedures
Text added “To meet China’s health 
authority expectation, memory aids will be 
dispensed to participants in China to 
support monitoring of participants’ 
interventions adherence and safety.”
To meet China’s health 
authority expectation.
10.12.1.1.1
Changes to the Protocol Text


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Section 1.3 Schedule of Activities
Study periods
Duration
Screening
≤ 2 weeks
before RND
Intervention period
~9 ~33 months*, from RND until Common End of Treatment 
(CEOT) visit / Early Termination (ET)
Early Termination period**
ET until CEOT visit
CEOT period
CEOT visit until 2 weeks after
Visit number / acronym
1
2ǂ
3
4
5
6
7
8
9
10
11
12*
13*
ET visit ET SFU visit
≥ 3 13*
CEOT visit
CEOT SFU visit†
Visit type
site
site

site
site

site

site

site

site
site
(site)
(site)
site ()

Visit / Month [M]
Day [D] / ± allowed windows
Week [W] ± allowed windows
SCR
 D -14 1
RND / M 0
D 1
M 1
 30±4
M 3
W 13±1
M 6
26±1
M 9
39±1
M 12
52±1
M 15
65±1
M 18
78±1
M 21
91±1
M 24
104±1
M 27
117±1
M 30
130±1
ET
ET
ET + 2 W
(ET+ 2 W) + 1 W
≥ M 1 M 30
≥ D 30±4 
W 130±1
CEOT
CEOT ± ~3W
CEOT visit + 2 W 
(CEOT visit + 2 W) + 1 W
[……….]
Laboratory assessments
Safety blood sampling
X
  (X)
X
X
X
X
X
X†
Pregnancy test (if WOCBP)
X
   X
X
X†
PD (a); PK (b) 
Pharmacogenetics (c)
   a, c
a, b
a, b
Study intervention (SI) shipment
SI dispensation / intake
       X
X
X
X
X
X
X
SI collection / accountability
X
X
X
X
X
X
X
X†
Annotated Schedule of Activities (Annotated SoA)
[……….]
Laboratory assessments
Safety blood sampling
creatinine and eGFR values must be available at RND; if not available from SCR central lab, respective values should be determined in local lab prior to RND; values 
obtained as part of routine management can also be used if no older than 14 days at RND (Section 8); in any case, the full set of safety laboratory tests (Table 10–1) 
needs to be obtained once during the SCR period, at the latest at RND, and at indicated visits thereafter
Pregnancy test (if WOCBP)
a WOCBP must have a negative serum or urine pregnancy test at SCR; a repeat test at RND (before SI intake) is required, unless ≤ 4 days lie between SCR and RND
PD (a); PK (b)
Pharmacogenetics (c)
refer to Table 1-2 regarding further details. Pharmacogenetics will be limited to CES1 genotyping analysis.
[……….]


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An overview of the PK, PD, and pharmacogenetics sampling is shown in Table 1–2:
Table 1–2: PK, PD and Pharmacogenetics Sampling
Day 1
(Visit 2)
Month 3
(Visit 4)
Month 12
(Visit 7)
Sample timing*
Pre-dose
Pre-dose
Pre-dose
PK**
-
X
X
PD**
X
X
X
Pharmacogenetics 
(limited to CES1 genotyping)
X
-
-
Abbreviations: CES1 = Carboxylesterase 1; PD = Pharmacodynamic(s), PK = Pharmacokinetic(s)
* at all visits: in order to collect pre-dose samples for PK and PD, participants should take their study intervention 
at the site only after blood sampling. The investigator must record the time when the study intervention is taken 
at the site. A phone call to remind the participants is recommended.
** if study intervention will be temporarily discontinued, PK / PD blood samples should only be obtained if the 
study intervention has been restarted and sustained for at least 4 days, see Section 7.1.2
PK and PD will be collected in all Chinese participants (refer to Sections 8.5 and 8.6). 
Blood for pharmacogenetics is generally planned to be collected at randomization (Day 1), however it can also 
be collected at a later visit in case it has not been taken (refer to Section 8.7).
The exact time of PK and PD sampling needs to be recorded, as well as the time of the most recent / associated 
study intervention intake (i.e. on the PK / PD sampling day, as well as on the day before that).
Section 3 Objectives, Endpoints, and Estimands
Table 3–1 Study objectives and endpoints
Objectives
Endpoints
[…] 
Other
To further investigate the study intervention, 
and drugs with similar, e.g. mode-of-action 
related effects, and to further investigate 
pathomechanisms deemed relevant to 
cardiovascular diseases and associated health 
problems

PK and various biomarkers1 (e.g. diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers)
1 PK and PD analyses in Chinese participants will be performed to investigate ethnicity differences in 
AF patients. Blood samples for pharmacogenetics (limited to CES1 genotyping analysis) will be 
collected in China. Other biomarker samples will not be collected in China and therefore, no data 
from Chinese participants will be available for the analysis of the respective endpoints.
Section 6.5 Study Intervention Compliance 
[…]
To meet China’s health authority expectation, memory aids will be dispensed to participants 
in China to support monitoring of participants’ interventions adherence and safety.
[…]


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Section 8 Study Assessments and Procedures
[…]

To meet China’s health authority expectation, memory aids will be dispensed to 
participants in China to support monitoring of participants’ interventions adherence 
and safety.
[…].
Section 8.5 Pharmacokinetics
[…]
For the investigation of systemic exposure to asundexian and its relationship with treatment 
effects, the plasma concentrations of asundexian and its metabolite M-10 (BAY 2826102) 
will be determined at different time points using a sparse sampling approach in all participants 
of the conventional study model. 
[…]
PK samples will be analyzed, using validated analytical methods. Quality control (QC) and 
calibration samples will be analyzed concurrently with study samples. The results of 
calibration samples and QC samples will be reported in the Bioanalytical Report.
PK analyses in Chinese participants will be performed to investigate ethnicity differences in 
AF patients.
[…]
Section 8.6 Pharmacodynamics
[…]
Quality control and calibration samples will be analyzed concurrently with study samples. For 
selected PD parameters, the results of QC samples will be reported together with analyte 
concentrations in the Bioanalytical Report.
PD analyses in Chinese participants will be performed to investigate ethnicity differences in 
AF patients.
[…]
Section 8.7 Genetics 
Blood samples for pharmacogenetics (limited to CES1 genotyping analysis) will be collected 
in China.
[…]
Section 8.8 Biomarkers
This section is not applicable to China, as no biomarker samples will be collected in China. 
[…].


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10.12.2
Japan
10.12.2.1 JPN: Country/region-specific Changes Valid for Japan only
Overall Rationale
This section implements modifications of the original protocol to meet local requirements in 
Japan.
A description of changes and a brief rationale is outlined in the table below:
Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
The name of the formula 
used for the estimated 
glomerular filtration rate was 
modified.
The modified formula has been 
the standard for the local clinical 
practice in Japan and frequently 
used in other clinical studies with 
the Japanese population. Please 
note that the eGFR threshold for 
exclusion of participants from the 
study remains the same 
(< 25 mL/min/1.73 m2).
10.6 Calculating glomerular 
filtration rate
The formula for calculating 
the estimated glomerular 
filtration rate was modified 
according to the 
recommendation by 
Japanese Society of 
Nephrology for the Japanese 
population.
10.12.2.1.1
Changes to the Protocol Text
Section 5.2 Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
[…]
8. Estimated glomerular filtration rate (eGFR) < 25 mL/min/1.73 m2 within 14 days prior to 
randomization, calculated by Japanese Equation (see Section 10.6), or on dialysis or 
expected to be started on dialysis within the next 12 months starting from randomization
[…]
Section 10.6 Appendix 6: Calculating glomerular filtration rate
In accordance with the recommendation by the Japanese Society of Nephrology, renal 
function at baseline and throughout the study will be assessed by means of the estimated 
glomerular filtration rate (eGFR), calculated using the Japanese Equation (JSN 2012, Matsuo 
et al. 2009).
Conventional units (serum creatinine level is measured in mg/dL)
GFR (mL/min/1.73 m2) = 194 x (serum creatinine)-1.094 x (Age)-0.287 x (0.739 if female).


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10.12.3
Republic of Korea
10.12.3.1 KOR-1: Country/region-specific Changes Valid for the Republic of 
Korea only
KOR-1 (06 JAN 2023)
Overall Rationale
This section implements modifications of the original protocol to meet local requirements in 
the Republic of Korea.
10.12.3.1.1
Overview of Changes
A description of changes and a brief rationale is outlined in the table below:
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA)
Inclusion of ALT, AST, total bilirubin,
hemoglobin and platelet count assessments
Changes 
requested by
MFDS to account 
for the safety 
characteristics of 
the study 
interventions 
Only serum pregnancy testing is allowed. It 
will be performed at all site visits.
5.1 Inclusion Criteria
Only serum pregnancy testing is allowed
5.2 Exclusion Criteria
ALT / AST > 2.5 x ULN added to the 
exclusion criteria
Uncontrolled hypertension (e.g. systolic BP 
> 180 mmHg or diastolic BP > 100 mmHg) 
added to the exclusion criteria
Platelet count ≤ 100000/ mm3 or 
hemoglobin < 9 g/dL added to the exclusion 
criteria
Antiphospholipid syndrome and participants 
who have undergone significant resection 
of relevant gastrointestinal tract added as 
examples of contraindications listed in the 
local label of Apixaban
6.1 Study Intervention(s) 
Administered
Inclusion that study intervention should be 
used with caution in participants with mild 
hepatic impairment (Child Pugh A) or 
participants with ALT / AST > 2 x the upper 
limit of normal (ULN) or total bilirubin ≥ 1.5 
x ULN
6.9 Prior and Concomitant 
Therapy
Other platelet aggregation inhibitors listed 
as prohibited medications
7.1.1 Permanent 
Discontinuation of Study 
Intervention
Inclusion of discontinuation rule for severe 
thrombocytopenia
7.1.2 Temporary
Discontinuation of Study 
Intervention
Inclusion of further clarification for 
temporary discontinuation of study 
intervention
8 Study Assessments and 
Procedures
Inclusion of ALT, AST, total bilirubin, 
hemoglobin and platelet count assessments
8.3.7 Clinical Safety Laboratory 
Tests
Inclusion of ALT, AST, total bilirubin, 
hemoglobin and platelet count assessments
8.3.8 Pregnancy Testing
Only serum pregnancy testing is allowed.
10.2.2 Thrombocytopenia: 
Follow-up Assessments and 
Suggested Actions
Inclusion of follow-up assessment and 
suggested actions in case of
thrombocytopenia


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10.12.3.1.2
Changes to the Protocol Text
Section 1.3 Schedule of Activities (SoA)
Study periods
Duration
Screening
≤ 2 weeks
before RND
Intervention period
~9 ~33 months*, from RND until Common End of Treatment
(CEOT) visit / Early Termination (ET)
Early Termination period**
ET until CEOT visit
CEOT period
CEOT visit until 2 weeks after
Visit number / acronym
1
2ǂ
3
4
5
6
7
8
9
10
11
12*
13*
ET visit ET SFU visit
≥ 3 13*
CEOT visit
CEOT SFU visit†
Visit type
site
site

site
site

site

site

site

site
site
(site)
(site)
site ()

Visit / Month [M]
Day [D] / ± allowed windows
Week [W] ± allowed windows
SCR
 D -14 1
RND / M 0
D 1
M 1
 30±4
M 3
W 13±1
M 6
26±1
M 9
39±1
M 12
52±1
M 15
65±1
M 18
78±1
M 21
91±1
M 24
104±1
M 27
117±1
M 30
130±1
ET
ET
ET + 2 W
(ET+ 2 W) + 1 W
≥ M 1 M 30
≥ D 30±4 
W 130±1
CEOT
CEOT ± ~3 W
CEOT visit + 2 W 
(CEOT visit + 2 W) + 1 W
[..]
Laboratory assessments
Safety blood sampling
X
  (X)
X
X
X
X
X
X†
Pregnancy test (if WOCBP)
X
   X
X
X
X
X
X
X
X
X†
[…]
Annotated Schedule of Activities (Annotated SoA)
[…]
Vital signs (BP§ and RHR)
can also be used if done as part of routine management and no older than 14 days at RND; no need to be repeated once available (Section 8.3.5)
[…]
Laboratory assessments
Safety blood sampling
creatinine, eGFR, ALT, AST, total bilirubin, hemoglobin, and platelet count values must be available at RND; if not available from SCR central lab, respective values 
should be determined in local lab prior to RND; values obtained as part of routine management can also be used if no older than 14 days at RND (Section 8); in any 
case, the full set of safety laboratory tests (Table 10-1) needs to be obtained once during the SCR period, at the latest at RND, and at indicated visits thereafter
Pregnancy test (if WOCBP)
a WOCBP must have a negative serum pregnancy test at SCR; a repeat test at RND (before SI intake) is required, unless ≤ 4 days lie between SCR and RND
[…]
Abbreviations: AP / AC = antiplatelets / anticoagulants, BP = blood pressure, CEOT = Common End of Treatment, D = day, ECG = electrocardiogram, EQ-5D = European Quality of Life group 5-
Dimension questionnaire, ET = early termination, HCRU = healthcare resource utilization, RHR = resting heart rate, ICF = informed consent form, IRT = interactive response technology, M = month,
PD, PK = pharmacodynamic(s), -kinetic(s), RND = randomization, SCR = screening, SFU = safety follow-up, SI = study intervention, W = week(s), WOCBP = woman of childbearing potential
ǂ procedures and assessments at visit 2 should preferably be conducted prior to RND; SI dispensation / intake will usually be concluding the visit 
* if applicable (if the number of efficacy outcome events does not accrue until Month 33 as expected) the visit schedule will continue after Month 30 with the respective labelling, e.g. Visit 14, 15.
The duration of the intervention period (~9 to ~33 months) depends on when a participant joins during the course of the study. Displayed timepoints might therefore not be applicable to all 
participants.
$ Blood pressure measurements can be repeated if medically justified (e.g. in order to avoid suspected “white-coat hypertension”).


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Section 5.1 Inclusion Criteria
[…]
Sex and Contraceptive / Barrier Requirements
4. Male or female
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Male participants: there are no measures required for the study
Female participants: a female participant is eligible to participate if she is not 
pregnant or breastfeeding, and one of the following conditions applies:

is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 4
OR

is a woman of childbearing potential (WOCBP) and using a contraceptive method 
that is highly effective, with a failure rate of < 1%, as described in Appendix 4 
during the study intervention period and for at least 4 days after the last dose of 
study intervention. The investigator should evaluate the potential for contraceptive 
method failure (e.g. noncompliance, recently initiated) in relationship to the first 
dose of study intervention.
A WOCBP must have a negative serum pregnancy test within 4 days before the 
first dose of study intervention, see Section 8.3.8.
[…]
Section 5.2 Exclusion Criteria
[…]
7.
Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) 
or known hepatic insufficiency classified as Child-Pugh B or C or ALT / AST > 2.5 x 
ULN at randomization.
[…]
11.
Any contraindication for the use of an anticoagulant or listed in the local labelling for 
apixaban (e.g. antiphospholipid syndrome or participants who have undergone 
significant resection of relevant gastrointestinal tract).
[…]
Additional Medical conditions
20.
Persistent (confirmed by two measurements, at least 1 hour apart) uncontrolled 
hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg).
21.
Platelet count ≤ 100000/mm3 or hemoglobin < 9 g/dL.
[…].


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Section 6.1 Study Intervention(s) Administered
[…]
Study intervention should be used with caution in participants with mild hepatic impairment 
(Child Pugh A) or participants with ALT / AST > 2 x the upper limit of normal (ULN) or total 
bilirubin ≥ 1.5 x ULN.
Matching placebos for asundexian and both strengths of apixaban are supplied in the same 
way. 
[…].
Section 6.9 Prior and Concomitant Therapy
[…]
Prohibited concomitant medications:
Concomitant therapy with any of the following drugs is prohibited from 14 days (or at least 
five half-lives of the active substance, whatever is longer) before randomization and first 
study intervention administration, until at least 48 hours after last study intervention 
administration:

Strong combined inhibitors of CYP3A4 and P-gp, e.g. human immunodeficiency virus 
protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir, or telaprevir), 
systemically used azole antimycotic agents (ketoconazole, itraconazole, or 
posaconazole), clarithromycin, nefazodone

Strong / moderate combined inducers of CYP3A4 and P-gp, e.g. phenytoin, 
carbamazepine, phenobarbital, rifampicin, or St. John’s wort

Other platelet aggregation inhibitors (e.g. GPIIb/IIIa receptor antagonists, 
dipyridamole, dextran or sulfinpyrazone).
[…].
Section 7.1.1 Permanent Discontinuation of Study Intervention
[…]
Specifically, a permanent discontinuation of study intervention may be required if any of the 
following occurs and will last throughout the expected remaining intervention period. 
Otherwise, a temporary discontinuation of study intervention could be considered for the 
duration:

[…]

severe thrombocytopenia (i.e. platelet count < 50000 / mm3; refer to Section 10.2.2).
[…].


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Section 7.1.2 Temporary Discontinuation of Study Intervention
[…]
The need for a temporary interruption might also arise from an adverse event, for instance 
relating to liver dysfunction or platelet count decrease (refer to Section 10.2.1 and Section 
10.2.2). If the investigator believes that for safety reasons it is in the best interest of the 
participant to interrupt treatment, study intervention can be stopped at any time. There is no 
predefined maximum limit for temporary discontinuation of study intervention.
[…].
Section 8 Study Assessments and Procedures

[…]

Results from procedures conducted as part of the participant’s routine clinical 
management (e.g. creatinine, eGFR, ALT, AST, total bilirubin, hemoglobin, platelet 
count, ECG, vital sign measurement) and obtained before signing of the ICF may be 
utilized for screening and / or baseline purposes, provided the procedures met the 
protocol specified criteria and were performed within the timeframe defined in the 
SoA (if no older than 14 days at randomization for eGFR, creatinine, ALT , AST, total 
bilirubin, hemoglobin, platelet count, and vital signs, or no older than 30 days in case 
of ECG; refer to annotated SoA in Section 1.3).

[…].
Section 8.3.7 Clinical Safety Laboratory Tests

[…]

Creatinine, eGFR, ALT, AST, total bilirubin, hemoglobin, and platelet count values 
must be available at randomization; if not available from screening central lab, the 
respective values should be determined in local lab prior to randomization to be 
available in time to not delay randomization. Values obtained as part of routine 
management can also be used for this purpose if no older than 14 days at 
randomization. In any case, the full set of protocol-required safety laboratory tests for 
central lab analysis (Table 10-1) needs to be obtained once during the 14 day 
screening period prior to randomization, at the latest at randomization, and at indicated 
visits thereafter.

[…].
Section 8.3.8 Pregnancy Testing
A woman of childbearing potential must have a negative serum pregnancy test within 4 days 
before the first dose of study intervention. 
Female participants of childbearing potential are scheduled to perform a serum pregnancy test 
at the screening and randomization visit, unless ≤ 4 days lie between the screening and 
randomization visit, in which case a negative test at screening is sufficient (refer to SoA). 


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In addition a serum pregnancy test is required at the end of relevant systemic exposure, which 
is either at the early termination visit for participants that prematurely discontinue intake of 
study intervention (unless study intervention has been discontinued since more than 7 days) or 
at the CEOT visit for participants that end the study intervention period regularly. 
Further serum pregnancy tests should be performed in participants of childbearing potential at 
every site visit. At any time during study participation, additional pregnancy testing should be 
performed upon suspicion of pregnancy.
Section 10.2.2 Thrombocytopenia: Follow-up Assessments and Suggested Actions
Follow-up assessments
If platelet count is decreased < 100000 / mm3, close monitoring is required through follow-up 
sampling to repeatedly monitor its value, as clinically appropriate (e.g. every 1 to 4 weeks, 
depending on the platelet count as well as its development). 
Suggested actions
Participant management is at the discretion of the treating physician, and study intervention 
may be continued during confirmatory re-testing. 
Temporary discontinuation of study intervention should be considered if platelet count is 
< 50000 / mm3, which should be accompanied by more frequent monitoring; permanent 
discontinuation of study intervention should be considered if platelet count is < 20000 / mm3.
When thrombocytopenia has sufficiently recovered (i.e. platelet count ≥ 100000 / mm3 at 
follow-up laboratory tests), the investigator may consider re-starting study intervention based 
on medical judgement (e.g. resolving reversible cause such as radiotherapy to that might have 
led to the decrease in platelet count).


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11.
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van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement 
for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-7.
Verhamme P, Yi BA, Segers A, Salter J, Bloomfield D, Büller HR, et al. Abelacimab for 
Prevention of Venous Thromboembolism. N Engl J Med. 2021 Aug 12;385(7):609-17.
Visser M, Heitmeier S, Ten Cate H, Spronk HMH. Role of Factor XIa and Plasma Kallikrein 
in Arterial and Venous Thrombosis. Thromb Haemost. 2020 Jun;120(6):883-993.
Wang X, Cheng Q, Xu L, Feuerstein GZ, Hsu MY, Smith PL, et al. Effects of factor IX or 
factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J 
Thromb Haemost. 2005 Apr;3(4):695-702.
Weitz JI, Bauersachs R, Becker B, Berkowitz SD, Freitas MCS, Lassen MR, et al. Effect of 
Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing 
Knee Arthroplasty: The FOXTROT Randomized Clinical Trial. JAMA. 2020 Jan 
14;323(2):130-9.
Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, et al. Milvexian for the 
Prevention of Venous Thromboembolism. N Engl J Med. 2021 Nov 15.
Wells G, Sultan S, Chen L, Khan M, Coyle D. Indirect Evidence: Indirect treatment 
comparison in Meta-Analysis. 2009.
Wilke T, Groth A, Mueller S, Pfannkuche M, Verheyen F, Linder R, et al. Incidence and 
prevalence of atrial fibrillation: an analysis based on 8.3 million patients. Europace. 
2013 Apr;15(4):486-93.


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Wilson JT, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, et al. Improving the 
assessment of outcomes in stroke: use of a structured interview to assign grades on the 
modified Rankin Scale. Stroke. 2002 Sep;33(9):2243-6.
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: 
the Framingham Study. Stroke. 1991 Aug;22(8):983-8.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A multicenter, international, randomized, active comparator-
controlled, double-blind, double-dummy, parallel group, 2-arm 
Phase 3 study to compare the efficacy and safety of the oral FXIa 
inhibitor asundexian (BAY 2433334) with apixaban for the 
prevention of stroke or systemic embolism in male and female 
participants aged 18 years and older with atrial fibrillation at risk 
for stroke 
NCT Number: 
NCT05643573 
Document Date: 
08-Feb-2024 
 


CONFIDENTIAL 
Statistical Analysis Plan 
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Version 1.0 
Page:  1 of 66 
Title Page 
Protocol Title: A multicenter, international, randomized, active comparator-controlled, 
double-blind, double-dummy, parallel group, 2-arm Phase 3 study to compare the efficacy and 
safety of the oral FXIa inhibitor asundexian (BAY 2433334) with apixaban for the prevention 
of stroke or systemic embolism in male and female participants aged 18 years and older with 
atrial fibrillation at risk for stroke 
Protocol Number:  19767 
Compound Number: Asundexian (BAY 2433334) 
Short Title: Phase 3 study to investigate the efficacy and safety of the oral factor XIa (FXIa) 
inhibitor asundexian (BAY 2433334) compared with apixaban in participants with atrial 
fibrillation at risk for stroke (OCEANIC-AF) 
Sponsor Name: Bayer AG 
Legal Registered Address:  
Non-US: Bayer AG, 51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, US 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
141805 
EudraCT 
2022-000758-28 
Date: 08 FEB 2024 
Version: 2.0 
Statistical Analysis Plan template version: 4.0 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate signature document. 


 
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Table of Contents 
Title Page --------------------------------------------------------------------------------------------------- 1 
Table of Contents ----------------------------------------------------------------------------------------- 2 
Table of Tables -------------------------------------------------------------------------------------------- 4 
Table of Figures ------------------------------------------------------------------------------------------ 4 
Version History ------------------------------------------------------------------------------------------- 5 
List of Abbreviations ------------------------------------------------------------------------------------ 6 
1. 
Introduction ------------------------------------------------------------------------------------ 8 
1.1 
Objectives, Endpoints, and Estimands ------------------------------------------------------ 8 
1.1.1 
Estimands Associated with the Primary Efficacy Objective ---------------------------- 11 
1.1.2 
Estimands Associated with the Primary Safety Objective ------------------------------ 15 
1.1.3 
Estimands Associated with the Primary Net Clinical Benefit Objective -------------- 18 
1.1.4 
Secondary Estimands ------------------------------------------------------------------------- 20 
1.2 
Study Design ----------------------------------------------------------------------------------- 20 
1.2.1 
Decentralized Clinical Trial Model --------------------------------------------------------- 22 
2. 
Statistical Hypotheses ----------------------------------------------------------------------- 23 
2.1 
Multiplicity Adjustment ---------------------------------------------------------------------- 23 
3. 
Analysis Sets ---------------------------------------------------------------------------------- 24 
4. 
Statistical Analyses -------------------------------------------------------------------------- 25 
4.1 
General Considerations ----------------------------------------------------------------------- 25 
4.1.1 
Definitions and data handling rules --------------------------------------------------------- 25 
4.1.1.1 
Baseline values ----------------------------------------------------------------------- 25 
4.1.1.2 
Repeated measurements at the same visit ---------------------------------------- 25 
4.1.1.3 
Pre-specified and investigator reported events ---------------------------------- 25 
4.1.1.4 
Missing data -------------------------------------------------------------------------- 25 
4.1.1.5 
Date of last contact and study completion --------------------------------------- 27 
4.1.1.6 
Treatment emergent period --------------------------------------------------------- 28 
4.1.1.7 
Adjudication and classification of investigator reported bleeding ------------ 28 
4.1.1.8 
Death/Fatal AEs ---------------------------------------------------------------------- 29 
4.1.1.9 
Disease-related events, (S)AEs and Outcome events --------------------------- 29 
4.1.1.10 
Blind Review of important deviations and validity findings ------------------ 29 
4.1.1.11 
Classification of regions ------------------------------------------------------------ 29 
4.1.1.12 
Prohibited medications -------------------------------------------------------------- 31 
4.1.1.13 
CHA2DS2-VASc Score for Atrial Fibrillation ----------------------------------- 31 
4.1.1.14 
CHADS2 Score for Atrial Fibrillation -------------------------------------------- 32 
4.1.1.15 
ORBIT-AF and HAS-BLED Score ----------------------------------------------- 32 
4.1.1.16 
Disabling Stroke --------------------------------------------------------------------- 33 
4.1.2 
Derivation of time-to-event variables, censoring and incomplete dates --------------- 33 
4.1.3 
Descriptive statistics -------------------------------------------------------------------------- 35 
4.1.4 
Stratification ----------------------------------------------------------------------------------- 36 
4.2 
Primary Endpoints/Estimands Analysis---------------------------------------------------- 36 
4.2.1 
Primary Efficacy Estimand ------------------------------------------------------------------ 37 
4.2.1.1 
Definition of Endpoint -------------------------------------------------------------- 37 


 
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4.2.1.2 
Main Analytical Approach --------------------------------------------------------- 37 
4.2.1.3 
Sensitivity Analyses ----------------------------------------------------------------- 38 
4.2.1.4 
Supplementary Analyses ----------------------------------------------------------- 38 
4.2.2 
Primary Safety Estimand --------------------------------------------------------------------- 40 
4.2.2.1 
Definition of Endpoint -------------------------------------------------------------- 40 
4.2.2.2 
Main Analytical Approach --------------------------------------------------------- 40 
4.2.2.3 
Sensitivity Analyses ----------------------------------------------------------------- 40 
4.2.2.4 
Supplementary Analyses ----------------------------------------------------------- 41 
4.2.3 
Primary Net Clinical Benefit Estimand ---------------------------------------------------- 41 
4.2.3.1 
Definition of Endpoint -------------------------------------------------------------- 41 
4.2.3.2 
Main Analytical Approach --------------------------------------------------------- 41 
4.2.3.3 
Sensitivity Analyses ----------------------------------------------------------------- 42 
4.2.3.4 
Supplementary Analyses ----------------------------------------------------------- 42 
4.3 
Secondary Endpoints/Estimands Analysis ------------------------------------------------ 42 
4.3.1 
Secondary Efficacy Endpoints -------------------------------------------------------------- 42 
4.3.1.1 
Definition of Secondary Efficacy Endpoints ------------------------------------ 42 
4.3.1.2 
Main Secondary Efficacy Analytical Approach --------------------------------- 42 
4.3.1.3 
Sensitivity Secondary Efficacy Analyses ---------------------------------------- 42 
4.3.1.4 
Supplementary Secondary Efficacy Analyses ----------------------------------- 42 
4.3.2 
Secondary Safety Endpoints ----------------------------------------------------------------- 43 
4.3.2.1 
Definition of Secondary Safety Endpoints --------------------------------------- 43 
4.3.2.2 
Main Secondary Safety Analytical Approach ----------------------------------- 43 
4.3.2.3 
Sensitivity Secondary Safety Analyses ------------------------------------------- 43 
4.3.2.4 
Supplementary Secondary Safety Analyses ------------------------------------- 43 
4.3.3 
Secondary Net clinical benefit Endpoints ------------------------------------------------- 43 
4.3.3.1 
Definition of Secondary Net clinical benefit Endpoints ----------------------- 43 
4.3.3.2 
Main Secondary Net clinical benefit Analytical Approach -------------------- 44 
4.3.3.3 
Sensitivity Secondary Net clinical benefit Analyses --------------------------- 44 
4.3.3.4 
Supplementary Secondary Net clinical benefit Analyses ---------------------- 44 
4.4 
Exploratory Endpoints Analysis ------------------------------------------------------------ 44 
4.4.1 
Definition and Analytical Approach for Exploratory Efficacy Endpoints ------------ 44 
4.4.2 
Definition and Analytical Approach for Exploratory Safety Endpoints -------------- 45 
4.4.3 
Definition and Analytical Approach for Exploratory Net clinical benefit Endpoints
 --------------------------------------------------------------------------------------------------- 46 
4.5 
Other Safety Analyses ------------------------------------------------------------------------ 46 
4.5.1 
Extent of Exposure ---------------------------------------------------------------------------- 46 
4.5.2 
Adverse Events -------------------------------------------------------------------------------- 47 
4.5.3 
Additional Safety Assessments-------------------------------------------------------------- 48 
4.5.3.1 
Laboratory Data ---------------------------------------------------------------------- 48 
4.5.3.2 
Vital Signs ---------------------------------------------------------------------------- 49 
4.5.3.3 
Electrocardiogram ------------------------------------------------------------------- 49 
4.5.3.4 
Analyses of liver events according to protocol ---------------------------------- 49 
4.5.3.5 
Screening and analyses of potential drug-induced liver injuries -------------- 49 
4.6 
Other Analyses -------------------------------------------------------------------------------- 52 
4.6.1 
Pharmacokinetics ------------------------------------------------------------------------------ 52 
4.6.2 
Pharmacodynamics---------------------------------------------------------------------------- 52 
4.6.3 
Genetics and / or Pharmacogenomics ------------------------------------------------------ 52 
4.6.4 
Biomarker -------------------------------------------------------------------------------------- 52 


 
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4.6.5 
Subgroup Analyses ---------------------------------------------------------------------------- 52 
4.7 
Interim Analyses ------------------------------------------------------------------------------ 55 
4.8 
Changes to Protocol-planned Analyses ---------------------------------------------------- 56 
5. 
Sample Size Determination ---------------------------------------------------------------- 57 
6. 
Supporting Documentation ---------------------------------------------------------------- 60 
6.1 
Participant disposition ------------------------------------------------------------------------ 60 
6.2 
Demography and other baseline characteristics ------------------------------------------ 61 
6.3 
Medical history -------------------------------------------------------------------------------- 61 
6.4 
Prior and concomitant medication ---------------------------------------------------------- 62 
6.4.1 
Drug groupings -------------------------------------------------------------------------------- 63 
7. 
Document history and changes in the planned statistical analysis ---------------- 64 
8. 
References ------------------------------------------------------------------------------------- 65 
 
 
 
Table of Tables 
Table 1-1: Study objectives and endpoints ................................................................................ 8 
Table 3-1 Definition of Analysis Sets ...................................................................................... 24 
 
Table of Figures 
Figure 1–1: Study design overview .......................................................................................... 20 
 


 
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Version History 
This Statistical Analysis Plan (SAP) for Study 19767 is based on the protocol Version 1.0 
dated 01 SEP 2022. 
 
SAP Version 
Date 
Change 
Rationale 
1.0 
01 DEC 2022 
Not applicable 
Original version 
2.0 
08 FEB 2024 
See change log 
Final version 


 
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List of Abbreviations 
 
AE 
Adverse Event 
AF 
Atrial fibrillation 
AG 
Joint stock company, Aktiengesellschaft 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
ATC 
Anatomical Therapeutic Chemical 
ASA 
Acetylsalicylic acid 
AST 
Aspartate aminotransferase 
BARC 
Bleeding Academic Research Consortium 
BAS 
Biomarker analysis set 
BDG 
Bayer Drug Grouping 
BID 
Twice a day, Bis in die 
BMI 
Body mass index 
CABG 
Coronary artery bypass graft 
CEC 
Clinical Events Committee 
CEOT 
Common End of Treatment 
CHADS2 
Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, prior Stroke or 
transient ischemic attack 
CI 
Confidence interval 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case report form 
CRNM 
Clinically relevant non-major 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
csHR 
Cause-specific hazard ratio 
CV 
Cardiovascular 
DCT 
Decentralized clinical trial 
DRE 
Disease-related event 
DTOI 
Drug Topics Of Interest 
EAIR 
Exposure-Adjusted Incidence Rate 
e.g. 
For example, exempli gratia 
EC 
Executive Committee 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
ePRO 
Electronic Patient Reported Outcomes 
EQ-5D 
European Quality of Life group 5-Dimension questionnaire 
ET 
Early termination 
EudraCT 
European Clinical Trials Database 
FAS 
Full Analysis Set 
GFR 
Glomerular filtration rate 
i.e. 
That is, id est 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISTH 
International Society on Thrombosis and Hemostasis 
M 
Month 
MCDA 
Multi-criteria Decision Analysis 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 


 
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mRS 
Modified Rankin Scale 
N 
Total number of participants 
NJ 
New Jersey 
NOAC 
Non-Vitamin K oral anticoagulant 
NSAID 
Nonsteroidal anti-inflammatory drug 
OAC 
Oral anticoagulant 
OD 
Once a day 
P2Y12 
Gi-coupled platelet receptor for adenosine diphosphate 
PD 
Pharmacodynamic(s) 
PDS 
Pharmacodynamic analysis set 
PH 
Proportional Hazards 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetic analysis set 
PROs 
Patient Reported Outcomes 
PT 
Preferred term 
RND 
Randomization 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical analysis software 
SDG 
Standard Drug Grouping 
sdHR 
Sub-distribution Hazard Ratio 
SFU 
Safety follow-up 
SoA  
Schedule of activities 
SOC 
System organ class 
SSRI 
Selective serotonin reuptake inhibitors 
TBL 
Total bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TIA 
Transient ischemic attack 
ULN 
Upper limit of normal 
US / USA 
United States / United States of America 
VAS 
Visual Analog Scale 
vs. 
As compared to, versus 
W 
Week 
WHODrug / 
WHODrug 
Global 
WHODrug Dictionary is an international classification of medicines created by the WHO 
Programme for International Drug Monitoring, managed by the Uppsala Monitoring Centre, 
and licensed at Bayer as subscription service called WHODrug Global. 
 


 
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1. 
Introduction 
The SAP describes the final analysis of the study following the common end of treatment 
(CEOT). Table, figure and listing specifications are contained in a separate document. 
Asundexian is a direct, potent inhibitor of activated coagulation factor XI (FXIa) developed 
for 2 main indications: 
1. Prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) 
(cardioembolic stroke prevention).  
2. 
 
 
  
OCEANIC-AF (study 19767) will be an event-driven Phase 3 study (expected treatment 
duration of 9-33 months; refer to Section 5 for more details) and will test asundexian against 
apixaban, a FXa inhibitor (NOAC), in participants with AF. 
 
 
 
 
Each individual study will have its own study objectives to further characterize safety and 
efficacy of asundexian in the respective indications. 
On 19 November 2023, the sponsor followed a recommendation of the IDMC to stop the 
study early due to lack of efficacy. Therefore, all analyses are of exploratory nature. 
1.1 
Objectives, Endpoints, and Estimands 
Objectives and endpoints (primary, secondary and exploratory) are reported in Table 1-1. 
Table 1-1: Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
Efficacy 
 
To demonstrate that asundexian is superior (at 
least non-inferior) when compared with apixaban 
for prevention of stroke and systemic embolism 
in participants with atrial fibrillation at risk for 
stroke 
• 
Composite of stroke or systemic embolism* 
Safety 
 
To demonstrate that asundexian is superior to 
apixaban as assessed by ISTH major bleeding 
in participants with atrial fibrillation at risk for 
stroke 
• 
ISTH major bleeding* 
Net clinical benefit 
 
To demonstrate that asundexian is superior to 
apixaban with respect to benefit and risk 
• 
Composite of stroke, systemic embolism, or 
ISTH major bleeding* 
CCI
CCI


 
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Objectives 
Endpoints 
Secondary 
 
Efficacy 
 
To compare the effects of asundexian and 
apixaban with respect to composite and 
individual efficacy endpoints 
• 
Composite of ischemic stroke, or systemic 
embolism* 
• 
All-cause mortality* 
• 
Ischemic stroke* 
• 
CV death* 
• 
Composite of CV death, stroke, or 
myocardial infarction* 
Safety 
 
To compare asundexian and apixaban with 
respect to composite and individual bleeding 
endpoints 
• 
Composite of ISTH major or clinically 
relevant non-major bleeding* 
• 
Clinically relevant non-major bleeding* 
• 
Hemorrhagic stroke* 
• 
Intracranial hemorrhage* 
• 
Fatal bleeding* 
• 
Minor bleeding* 
Net clinical benefit 
 
To compare the benefit and risk of asundexian 
and apixaban with respect to a composite of 
efficacy and safety endpoints 
• 
Composite of stroke, systemic embolism, 
ISTH major bleeding, or all-cause mortality* 
• 
Composite of disabling stroke (mRS ≥ 3), 
critical bleedingǂ, or all-cause mortality* 
Exploratory 
 
Efficacy 
 
To further investigate the efficacy of the study 
intervention  
• 
Composite of CV death, stroke, or systemic 
embolism* 
• 
Systemic embolism* 
• 
Hemorrhagic stroke* 
• 
Disabling stroke (mRS ≥ 3)* 
To investigate the effect of the study 
interventions on quality of life 
• 
EQ-5D 
Safety 
 
To further investigate the safety of the study 
intervention 
• 
Total number of ISTH major bleeding events 
• 
Gastrointestinal bleeding* 
• 
All bleeding* 
• 
BARC type 3 and 5 bleeding* 
• 
BARC type 2, 3 and 5 bleeding* 
• 
BARC type 1* 


 
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Objectives 
Endpoints 
Net clinical benefit 
 
To further investigate the benefit and risk of the 
study intervention  
• 
Total number of hospitalizations due to 
efficacy or safety outcome events 
Other exploratory 
 
To further investigate the study intervention, and 
drugs with similar, e.g. mode-of-action related 
effects, and to further investigate 
pathomechanisms deemed relevant to 
cardiovascular diseases and associated health 
problems 
• 
PK and various biomarkers (e.g. diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers) 
Abbreviations: BARC = Bleeding Academic Research Consortium, CV = cardiovascular, EQ-5D = European 
Quality of Life group 5-Dimension questionnaire, ISTH = International Society on Thrombosis and Hemostasis, 
MI = myocardial infarction, mRS = modified Rankin Scale, PK = Pharmacokinetic(s). 
* Time to first occurrence 
ǂ Critical bleeding is defined as symptomatic bleeding in either of the following critical locations (intracranial, 
intraspinal, pericardial, intra-articular, or retroperitoneal) or as intraocular bleeding with compromised vision or 
intramuscular bleeding with compartment syndrome 
 
The estimands for the primary efficacy, safety and net clinical benefit objectives are 
described as follows: 
 
 


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1.1.1 
Estimands Associated with the Primary Efficacy Objective 
 
Primary Efficacy Objective: to demonstrate that asundexian is superior (at least non-inferior) when compared with apixaban for prevention 
of stroke and systemic embolism in participants with atrial fibrillation at risk for stroke 
Efficacy estimands for non-inferiority and for superiority assessment are described by the following attributes: 
 
Primary Efficacy Estimand  
Supplemental 
Efficacy 
Estimand 1 
Supplemental Efficacy Estimand 2  
Supplemental 
Efficacy 
Estimand 3 
Population 
Adult individuals with AF at risk for 
stroke 
Same as primary 
Adult individuals with AF at risk for 
stroke exposed to at least one dose of 
assigned treatment. 
Same as 
Supplemental 
Efficacy 
Estimand 2  
Treatment 
condition 
Investigational: once daily oral 
administration of 50 mg of asundexian  
Control: twice daily oral administration of 
5 mg of apixaban (or reduced dose of 2.5 
mg). 
Same as primary 
Same as primary 
Same as primary 
Endpoint 
Time to first occurrence of stroke or 
systemic embolism from day of treatment 
assignment  
Same as primary 
Same as primary except from day of 
first intake of assigned treatment  
Same as 
Supplemental 
Efficacy 
Estimand 2 
Population-
level 
summary 
Cause-specific hazard ratio (i.e. ratio of 
cause-specific hazard rates of the primary 
endpoint) comparing the two treatment 
conditions 
Sub-distribution 
hazard ratio 
(sdHR) comparing 
the two treatment 
conditions 
Same as primary 
Same as 
Supplemental 
Efficacy 
Estimand 1  


 
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Primary Efficacy Objective: to demonstrate that asundexian is superior (at least non-inferior) when compared with apixaban for prevention 
of stroke and systemic embolism in participants with atrial fibrillation at risk for stroke 
Efficacy estimands for non-inferiority and for superiority assessment are described by the following attributes: 
Intercurrent 
events and 
strategies  
 
• Early discontinuation of assigned 
treatment: addressed by the 
treatment policy strategy, i.e. the 
treatment effect including effects 
of treatment discontinuation is of 
interest and primary efficacy 
endpoint events and observation 
time will be used regardless of 
treatment discontinuation  
• Death: addressed by the “while 
alive” strategy, i.e. primary 
endpoint events and observation 
time up until death will be used  
• Treatment with dual antiplatelet 
therapy: addressed by the treatment 
policy strategy, i.e. the treatment 
effect includes the effect of dual 
antiplatelet therapy 
• Other intercurrent events related to 
COVID-19: will be handled 
according to the treatment policy 
strategy, i.e. the treatment effect 
includes the effect of intercurrent 
events related to COVID-19 (other 
than the mentioned intercurrent 
events). 
Same as primary 
Same as primary except 
• Early discontinuation of 
assigned treatment: addressed 
by the “while on-treatment” 
strategy, i.e. primary efficacy 
endpoint events and 
observation time up until 
premature discontinuation of 
assigned treatment will be 
used. 
 
Same as 
Supplemental 
Efficacy 
Estimand 2 


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Rationale for the estimands associated with the primary efficacy objective: 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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CCI


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1.1.2 
Estimands Associated with the Primary Safety Objective 
 
Primary Safety Objective: to demonstrate that asundexian is superior to apixaban in participants with atrial fibrillation as assessed by ISTH 
major bleeding  
Estimands for safety assessment are described by the following attributes: 
 
Primary Safety Estimand  
Supplemental 
Safety Estimand 1 
Supplemental Safety Estimand 2  
Supplemental 
Safety 
Estimand 3 
Population  
 
Adult individuals with AF at risk for stroke 
exposed to at least one dose of treatment. 
Same as primary 
Adult individuals with AF at risk for 
stroke 
As Supplemental 
Safety Estimand 
2 
Treatment 
condition 
Investigational: once daily oral 
administration of 50 mg of asundexian  
Control: twice daily oral administration of 
5 mg of apixaban [or reduced dose of 2.5 
mg] 
Same as primary 
Same as primary 
Same as primary 
Endpoint: 
Time to first occurrence of ISTH major 
bleeding from day of first intake of 
compared treatment  
Same as primary 
Same as primary safety estimand 
except from day of treatment 
assignment  
As Supplemental 
Safety Estimand 
2 
Population-
level 
summary 
Cause-specific hazard ratio (i.e. ratio of 
cause-specific hazard rates of the primary 
safety endpoint) comparing the two 
treatment conditions 
Sub-distribution 
hazard ratio 
(sdHR) comparing 
the two treatment- 
conditions 
Same as primary 
As Supplemental 
Safety Estimand 
1  


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Primary Safety Objective: to demonstrate that asundexian is superior to apixaban in participants with atrial fibrillation as assessed by ISTH 
major bleeding  
Estimands for safety assessment are described by the following attributes: 
Intercurrent 
events and 
strategies:  
 
• Early discontinuation of assigned 
treatment: addressed by the “while 
on-treatment” strategy, i.e. primary 
safety events and observation time 
prior to the occurrence of the 
intercurrent event (i.e. up to the date 
of last intake of assigned treatment 
plus 2 calendar days) will be used  
• Death: addressed by the “while 
alive” strategy, i.e. primary safety 
events and observation time up until 
death will be used  
• Treatment with dual antiplatelet 
therapy: addressed by the treatment 
policy strategy, i.e. the treatment 
effect includes the effect of dual 
antiplatelet therapy 
• Other intercurrent events related to 
Covid-19: will be handled according 
to the treatment policy strategy, i.e. 
the treatment effects include the 
effect of intercurrent events related 
to Covid-19 (other than the 
mentioned intercurrent events) 
Same as primary 
Same as primary except 
Early discontinuation of assigned 
treatment: addressed by the 
treatment policy strategy, i.e. the 
treatment effect including effects of 
treatment discontinuation is of 
interest and primary safety endpoint 
events and observation time will be 
used regardless of treatment 
discontinuation  
As Supplemental 
Safety Estimand 
2 


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Rationale for the estimands associated with the primary safety objective: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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1.1.3 
Estimands Associated with the Primary Net Clinical Benefit Objective 
 
Primary Net Clinical Benefit Objective: To demonstrate that asundexian is superior when compared to apixaban with respect to benefit and 
risk  
Estimands for net clinical benefit assessment are described by the following attributes: 
 
Primary Net Clinical Benefit 
Estimand  
Supplemental Net 
Clinical Benefit 
Estimand 1 
Supplemental Net Clinical Benefit 
Estimand 2  
Supplemental Net 
Clinical Benefit 
Estimand 3 
Population  
Adult individuals with AF at risk for 
stroke exposed to at least one dose of 
treatment 
Same as primary 
Adult individuals with AF at risk for 
stroke 
As Supplemental 
Net Clinical 
Benefit Estimand 2 
Treatment 
condition 
Investigational: once daily oral 
administration of 50 mg of asundexian  
Control: twice daily oral administration 
of 5 mg of apixaban [or reduced dose of 
2.5 mg] 
Same as primary 
Same as primary 
Same as primary 
Endpoint: 
Time to first occurrence of stroke 
(including hemorrhagic stroke), 
systemic embolism, or ISTH major 
bleeding (excluding hemorrhagic 
stroke) from day of first intake of 
compared treatment  
Same as primary 
Same as primary net clinical benefit 
estimand except from day of treatment 
assignment  
As Supplemental 
Net Clinical 
Benefit Estimand 2 
Population-
level 
summary 
Cause-specific hazard ratio (i.e. ratio of 
cause-specific hazard rates of the net 
clinical benefit endpoint) comparing the 
two treatment conditions 
Sub-distribution 
hazard ratio 
(sdHR) comparing 
the two treatment 
conditions 
Same as primary 
As Supplemental 
Net Clinical 
Benefit Estimand 1  


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Primary Net Clinical Benefit Objective: To demonstrate that asundexian is superior when compared to apixaban with respect to benefit and 
risk  
Estimands for net clinical benefit assessment are described by the following attributes: 
Intercurrent 
events and 
strategies:  
 
• Early discontinuation of assigned 
treatment: addressed by the “while 
on-treatment” strategy, i.e. events of 
the net clinical benefit endpoint and 
observation time prior to the 
occurrence of the intercurrent event 
(i.e. up to the date of last intake of 
assigned treatment plus two 
calendar days) will be used  
• Death: addressed by the “while 
alive” strategy, i.e. net clinical 
benefit events and observation time 
up until death will be used  
• Treatment with dual antiplatelet 
therapy after treatment assignment 
(i.e. randomization): addressed by 
the treatment policy strategy, i.e. the 
treatment effects include the effect 
of dual antiplatelet therapy 
• Other intercurrent events related to 
COVID-19: will be handled 
according to the treatment policy 
strategy, i.e. the treatment effects 
include the effect of intercurrent 
events related to Covid-19  
• Same as 
primary 
Same as primary except 
• Early discontinuation of assigned 
treatment: addressed by the 
treatment policy strategy, i.e. the 
treatment effect including effects 
of treatment discontinuation is of 
interest and primary net clinical 
benefit endpoint events and 
observation time will be used 
regardless of treatment 
discontinuation  
• As 
Supplemental 
Net Clinical 
Benefit 
Estimand 2 
 


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Rationale for the estimands associated with the primary net clinical benefit objective: 
 
 
 
 
1.1.4 
Secondary Estimands 
Estimands for secondary efficacy, safety and net clinical benefit endpoints are defined 
following the same approach as done for their respective primary estimands. 
Please refer to Section 4 for a description how data is handled in the statistical analysis to 
estimate the defined estimands. 
 
1.2 
Study Design 
Study 19767 is a multicenter, randomized, active comparator-controlled, double-blind, 
double-dummy, parallel group, Phase 3 study. The overall study design is depicted in Figure 
1–1.  
Approximately 18000 participants ≥ 18 years of age, will be randomized to 1 of the 2 arms 
(approximately 9000 participants per arm), as follows: 
• 
1 investigational study intervention arm (asundexian) or  
• 
1 active comparator arm (apixaban), 
in addition to their potential background therapy (see Section 6.9 of the CSP 19767). 
 
Figure 1–1: Study design overview 
 
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Abbreviations: BID = bis in die (twice a day), CEOT = common end of treatment, M = month, N = total number of participants, 
OD = once a day, RND = randomization, SFU = safety follow-up, W = weeks 
 
*  if applicable visits will continue after Month 30 in the same way as before until CEOT visit 
ǂ the usual dose of apixaban is 5 mg BID, reduced to 2.5 mg BID for participants with 2 or more of the following criteria:  
age 80 years or older, body weight ≤ 60 kg, or serum creatinine level ≥ 1.5 mg/dL 
Notes: Participants receiving asundexian will also receive the apixaban matching placebo.  
Participants receiving apixaban will also receive the asundexian matching placebo. 
After discontinuation of study intervention, further anticoagulation therapy (e.g. NOAC) is at discretion of the investigator. 
 
Decentralized clinical trial participants will have the screening visit split in a “part a”  
to initiate operational logistics and a “part b” to perform screening procedures.  
 
Patients will be eligible for the study based on their CHA2DS2-VASc risk score, among other 
criteria. With a score of ≥ 3 if male or ≥ 4 if female, patients can get enrolled straight into the 
study. Patients with a CHA2DS2-VASc score of 2 if male or 3 if female can participate in the 
study by meeting at least one of the following enrichment criteria in addition: 
• age ≥ 75 
• previous stroke, transient ischemic attack, or systemic embolism 
• renal dysfunction with eGFR < 50 ml/min/1.73 m2 within 14 days prior to 
randomization 
• prior episode of non-traumatic major bleeding 
• current single agent antiplatelet therapy planned to continue for at least 6 months after 
randomization 
• ≤ 6 consecutive weeks of treatment with oral anticoagulant prior to randomization 
 
In order to offer study participation to patients who might be unwilling or unable to 
participate in a conventional, on-site study, a fully remote decentralized clinical trial (DCT) 
model may be implemented in select countries where feasible and local laws / regulations 
allow (refer to Section 10.10 of the CSP 19767, if applicable). For sites participating in the 
DCT model, remote visit activities are completed in place of on-site visits. 
Randomization will be first stratified by participation in the conventional study model vs. the 
DCT model. This will be succeeded by stratification for current use vs. no current use of 
single agent antiplatelet therapy planned to continue for at least 6 months after randomization. 
Following stratification, participants will be assigned randomly via IRT to one of the two 
arms, in a 1:1 ratio. The randomization ratio will be controlled by blocks dynamically 
allocated by region/country. 
This is an event-driven study, and the sponsor will request termination of the intervention 
period once about 340 participants have experienced a primary efficacy endpoint event and 
about 340 have experienced a primary safety endpoint event, whichever occurs latest. The 
planned individual study duration is expected to be 10-34 months; however, the timelines may 
vary (i.e. shorter or longer than planned) depending on enrollment rate and incidence rate in 
the study. Please refer to the CSP 19767 for the study design, however in summary the study 
will consist of the following study periods: 
• Screening period (from visit 1 until visit 2).  


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• Intervention period (from visit 2 until the Common End of Treatment (CEOT) 
visit): The intervention period will be of variable length depending on when the 
participant entered the study. The shortest participant intervention period is expected 
to be 9 months (amongst those last to enter the study) and the longest 33 months 
(amongst those first to enter the study). 
The last day of intake of study intervention will be on the day before the CEOT visit. 
For an individual participant the CEOT visit marks the end of the intervention period 
The CEOT visit should occur as close as possible to the CEOT date, which is an actual 
calendar date at which time it is projected that the required number of primary 
endpoint events will have accrued (see Section 5 for details). If the number of events 
does not accrue as quickly as expected, then visits in the intervention period might 
need to be continued longer than anticipated. 
• Common End of treatment period (from CEOT visit until CEOT SFU visit).  
In the case that participants permanently discontinue study intervention earlier than planned: 
• Early termination (ET) period (ET until CEOT visit): Participants discontinuing 
study intervention should continue with study visits until their CEOT visit. Further 
details on premature discontinuation of the study intervention are given in Section 7.1 
of the CSP 19767. 
Details of study procedures and their timing are summarized in the SoA (Section 1.3 of the 
CSP 19767). 
1.2.1 
Decentralized Clinical Trial Model 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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2. 
Statistical Hypotheses 
Due to the early termination of the study on 19th November 2023 all testing is exploratory; no 
separate non-inferiority testing will be done. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1 
Multiplicity Adjustment 
Due to the early termination of the study, all testing is exploratory and no multiplicity 
adjustment will be done. 
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3. 
Analysis Sets 
For purposes of analysis, the analysis sets are defined in Table 3-1. 
Table 3-1 Definition of Analysis Sets 
Participant Analysis Set 
Description 
Full Analysis Set (FAS) 
All participants randomized to study intervention (including 
participants who did not receive study intervention). 
Adjusted Full Analysis Set (aFAS) 
All participants in the Full Analysis Set excluding participants 
randomized in Site 20076 
Safety Set (SAF) 
All participants randomized to study intervention and who took 
at least 1 dose of study intervention. In case a participant 
received study intervention and was not randomized, whether 
to include them in the SAF will be assessed and confirmed 
prior to unblinding. 
Adjusted Safety Set (aSAF) 
All participants in the Safety Set excluding participants 
randomized in Site 20076  
In September 2023, the Japanese Ministry of Health, Labour and Welfare (MHLW) detected 
GCP violations at the site management organization Medipharma. Medipharma was involved 
in the study at one site (site 20076). The ministry recommended not to use any of the data 
from the affected site. 
Unless otherwise specified (e.g. Supplemental Efficacy Estimands 2 and 3), the aFAS will be 
used for analyses addressing efficacy estimands. Analysis using the aFAS will utilize the 
randomized study intervention group. 
Unless otherwise specified (e.g. Supplemental Safety Estimands 2 and 3), the aSAF will be 
used for analyses addressing the primary safety estimand, other estimands relating to bleeding 
endpoints, the net clinical benefit estimands and analyses of AEs.  
In general summary tables will only be produced for either the aFAS or the aSAF depending 
on the type of data to be summarized. 
Final decisions regarding the assignment of participants to analysis sets will be made during 
the blinded review of study data and documented in the final list of important deviations, 
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4. 
Statistical Analyses 
4.1 
General Considerations 
The statistical evaluation will be performed by using the software SAS (release 9.4 or higher; 
SAS Institute Inc., Cary, NC, USA) and ValidR (version 3.5.2 or higher).  
All data will be presented in the participant data listing as they are recorded on the Case 
Report Form (CRF), i.e. partially missing data will appear as such.  
Data will be displayed by randomized study intervention arm. Tables will be shown by study 
intervention arm and overall.  
Adjudicated data (events and event dates) will be used unless otherwise stated.  
4.1.1 
Definitions and data handling rules 
4.1.1.1 
Baseline values 
Baseline values will be the measurements from Visit 2 (or the respective visit as per SoA) 
regardless of the clock time in relationship to the first intake of study intervention. The 
rationale for not taking the time of measurement into account is that a measurement from 
Visit 2 shortly post study intervention intake is considered more appropriate as baseline than a 
measurement from several days/weeks previously. 
If the Visit 2 (or the respective visit as per SoA) values are not available, then the latest values 
taken before first administration of study intervention will be considered (e.g., values between 
randomization and first study intervention or values taken on Visit 1). In case of more than 
one available value before first administration of study intervention, the non-missing value 
before and closest to first study intervention will be taken. In case no study intervention was 
taken, baseline values are defined as the latest value taken before randomization. Subgroup 
definitions will be done only on central lab assessment. 
4.1.1.2 
Repeated measurements at the same visit 
If more than one measurement is available for a given visit and no special reason for the 
additional observation was provided in the eCRF, the last observation will be used pre-
randomization and the first observation will be used post-randomization in the analysis.  
4.1.1.3 
Pre-specified and investigator reported events 
If more than one entry exists for pre-specified medical history or procedures terms, the 
investigator reported term will overwrite any pre-specified term of the name, i.e. the 
occurrence of that medical history or procedure will be a yes. 
4.1.1.4 
Missing data 
The aim is to minimize missing observation time as much as possible. Generally, all 
participants, including those who discontinue study intervention, will be followed until death 
or the end of the study (CEOT). Information of participants discontinuing study intervention 
or study participation will be collected whenever possible and meaningful for the analysis. 
Data that would be meaningful for the analysis of a given estimand but were not collected, are 
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For participants who could not be followed up for outcome events on a regular basis, it is 
aimed to at least determine the participants’ status at the end of the study (CEOT) with respect 
to the occurrence and timing of key outcome events, including MI, stroke, systemic 
embolism, death and bleeding. Assumptions made to handle missing data will be assessed for 
robustness via sensitivity analyses. 
If a key endpoint event occurrence date, AE start date or censoring date is incomplete 
following all attempts to get an approximate date by the investigator, a date will be imputed 
using the following algorithm: 
• If only the month and year of the event are known, then the day will be imputed as the 
first day of the month. 
• If only the year of the event is known, then the 1st of January will be imputed. 
• If year, month and day are unknown, then the date will be imputed as date of first 
intake of study medication. In case the date of first intake of study medication is 
missing (i.e. for in the FAS who never initiated treatment), the date randomization will 
be used instead. 
If this imputation rule leads to an implausible date (e.g. earlier than the first intake of study 
medication or the randomization), then the date will be imputed as the earliest plausible date 
(e.g., the randomization date) but not earlier than the last date where the participant is known 
event free. 
If any exposure date is incomplete following all attempts to get an approximate date by the 
investigator, a date will be imputed using the following algorithm: 
• If only the month and year of the exposure are known, then the day will be imputed as 
the first day of the month. 
• If only the year of the event is known, then the 1st of January will be imputed. 
• If year, month and day are unknown, then the date will be imputed as date of first 
intake of study medication. In case any date of intake of study medication is missing 
(i.e. for in the FAS who never initiated treatment), no date will be used. 
If this imputation rule leads to an implausible date (e.g. earlier than the first intake of study 
medication or the randomization), then the date will be imputed as the earliest plausible date 
(e.g., the start date of the exposure) but not earlier than the last date where it is known that the 
participant took drug. 
If a prior/concomitant medication start date is incomplete and following all attempts to get an 
approximate date by the investigator, a date will be imputed or ongoing assumed using the 
following algorithm: 
• If only the month and year of the event are known, then the day will be imputed as the 
1st day of the month. 
• If only the year of the event is known, then the 1st of January will be imputed. 
• If year, month and day are unknown, then the date will be imputed by the min (date of 
signed informed consent, imputed medication end date). 
If a medication end date exists and the imputed start date is after the start date, then the end 
date of the medication will be imputed as start date instead. 


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If a prior/concomitant medication end date is incomplete, and the medication is not marked as 
ongoing then following all attempts to get an approximate date by the investigator, a date will 
be imputed or ongoing assumed using the following algorithm: 
• If only the month and year of the end date are known, then the day will be imputed as 
the last day of that month (i.e. 28, 29, 30 or 31). 
• If only the year of the event is known, then the 31st December will be imputed. 
• If year, month and day are unknown and the participant died, then the end date will be 
imputed as the date of death. 
• If year, month and day are unknown and the participant did not die, then the 
medication will be assumed to be ongoing. 
If the imputation rules for partial end dates leads to an implausible date (e.g., after date of 
death), then the date will be imputed as the last plausible date. 
For study intervention, the time under risk will be handled in a conservative matter, i.e., 
missing study intervention end date will be imputed by the latest date known the study 
intervention was taken. 
To keep the main analyses simple and in line with the estimation approaches commonly used, 
the observation time for event-free participants with incomplete follow-up time will be 
censored at the last available point in time for which data on the outcome has been obtained, 
as described in Section 4.1.2. 
4.1.1.5 
Date of last contact and study completion 
The date of last contact will be defined as the latest of the following dates 
• last available subject visit date for the participant (this will be set to the latest of the 
individual randomization date and study intervention intake date for participants 
without any data after randomization or first day of study intervention.) 
• last available date on the participant’s study drug exposure 
• last available date of any known date patient has to be alive before the event, for 
example adverse event, date of clinical outcome event or hospitalization or procedure, 
including death dates 
• the date information about the participant was provided and the participant was alive 
at that time (subject status page)  
• the date of withdrawal of consent 
Note the last contact date cannot be later than the date of death if it exists. Some participants 
may have a date of death after withdrawal of consent, because this is permitted to be collected 
for some regions. 
A participant will be counted as a study completer if the date of last contact is after the date of 
request of termination of the study intervention period by the sponsor or if the participant died 
prior to then. In all other cases the participant will be considered a study non-completer. For a 
participant not completing the study for reason withdrawal of consent there will be data on the 
CRF page “Withdrawal from Informed Consent(s)/Informed Assent”, otherwise the reason for 
non-completion will be imputed as “Lost to follow-up”. These reasons may not match CRF 
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The date of request of termination of the study intervention period is set to the date of the 
decision to terminate the study, the 19th November 2023. 
In parallel, completion and non-completion (including reasons) of study epochs will be 
presented as reported by the investigator.  The number of participants completing epochs will 
not necessarily match the numbers for study (non-)completion. 
4.1.1.6 
Treatment emergent period 
For the treatment emergent period all events starting from first intake of study intervention up 
until 2 days after the last intake of study intervention will be counted.  
Events starting on the day of first study intervention intake will be counted as treatment 
emergent if the time of occurrence is later than the time of first study intervention intake. If 
the event is on the same date as the first study intervention intake but the time of the adverse 
event start cannot be compared to the time of first intake (e.g. adverse event time not 
collected), then the event will be assumed as treatment emergent. 
4.1.1.7 
Adjudication and classification of investigator reported bleeding 
Potential and pre-specified clinical outcome events will be submitted for adjudication to an 
independent clinical event committee (CEC). Adjudication of all bleeding events as well as 
efficacy events will be performed by members of the CEC who will review events in a 
blinded fashion and will adjudicate and classify the following events in a consistent and 
unbiased manner according to definitions further specified in the CEC charter. The 
adjudication will also include algorithmic approaches: 
• Bleeding events according to the following classifications and definitions: 
• According to ISTH bleeding will be classified as  
• ISTH Major Bleeding (defined in Section 8.3.1.1 of the CSP 19767), 
• Clinically Relevant Non-Major Bleeding (defined in Section 8.3.2.1 of the 
CSP 19767), 
• Minor Bleeding (defined in Section 8.3.2.2 of the CSP 19767). 
• According to BARC criteria bleeding will be classified as follows: (defined in 
Section 8.3.3.1 of the CSP 19767; Note: type 4: CABG-related bleeding is not 
applicable to this study)  
• BARC type 3 and 5 bleeding 
• BARC type 2, 3 and 5 bleeding 
• BARC type 1 bleeding. 
• Death (CV death [including death with undetermined cause] or non-CV death) 
• Myocardial Infarction (MI) 
• Stroke (ischemic, hemorrhagic, undetermined) 
• Systemic embolism 
• Potential outcome event (e.g. TIA and hospitalization for cardiac chest pain with 
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Data entry procedures and documentation necessary for case adjudication will also be 
described in the CEC charter. Adjudication results will be the basis for the final analysis. 
4.1.1.8 
Death/Fatal AEs 
There may be deaths captured on the CRF page “Death” that do not have corresponding AE 
or outcome event entries. Deaths that do not have a corresponding AE/outcome event page 
will be included/considered for the estimands, as well as fatal adverse events. 
4.1.1.9 
Disease-related events, (S)AEs and Outcome events 
Event type 
For this study some disease-related events (DREs) (see 8.4.6 of the CSP for further details) 
are part of the efficacy outcome events in participants with AF. Because the DREs pertaining 
to efficacy endpoints are typically associated with the disease under study, they will not be 
reported as (S)AEs by the investigator but will be reported as outcome events. If an efficacy 
outcome event is in the investigator’s opinion worse (e.g. in intensity, frequency or duration) 
than expected for a participant or possible related to study intervention then it may be reported 
as an (S)AE as well as an outcome event. Safety outcome events (i.e. all bleeding) or efficacy 
outcome events with a symptomatic bleeding component are not exempted and will be 
reported as (S)AEs, in addition to outcome events (see 8.4.6 of the CSP for further details). 
Timeframe for event reporting 
(S)AEs will be collected from the start of study intervention until a participant’s respective 
safety follow-up visit (see 8.4.1 of the CSP 19767 for further details). Therefore, for 
participants discontinuing study intervention early, adverse events will not be collected during 
the period from the safety follow up visit (approximately 2 weeks after last study 
intervention) until the CEOT visit. In contrast outcome events (efficacy and safety) will be 
collected, until the CEOT visit if the participant is no longer taking study intervention (see 
10.9 of the CSP 19767 for further details) and until the CEOT safety follow up visit if the 
participant completed study intervention less than 2 week before the CEOT visit.  
4.1.1.10 
Blind Review of important deviations and validity findings 
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis sets. Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an SAP 
amendment and, if applicable, in an additional analysis plan. 
4.1.1.11 
Classification of regions 
The countries in the study will be classified in the following regions 
Country 
Region 
Argentina  
South America 
Australia 
Western Europe, Australia and Israel 
Austria 
Western Europe, Australia and Israel 


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Belgium 
Western Europe, Australia and Israel 
Brazil 
South America 
Bulgaria 
Eastern Europe 
Canada 
North America 
China 
Asia 
Czechia 
Eastern Europe 
Denmark 
Western Europe, Australia and Israel 
Estonia 
Eastern Europe 
Finland 
Western Europe, Australia and Israel 
France 
Western Europe, Australia and Israel 
Germany 
Western Europe, Australia and Israel 
Greece 
Western Europe, Australia and Israel 
Hungary 
Eastern Europe 
India 
Asia 
Israel 
Western Europe, Australia and Israel 
Italy 
Western Europe, Australia and Israel 
Japan 
Asia 
Latvia 
Eastern Europe 
Lithuania 
Eastern Europe 
Malaysia 
Asia 
Netherlands 
Western Europe and Australia and Israel  
Norway 
Western Europe, Australia and Israel 
Poland 
Eastern Europe 
Portugal 
Western Europe, Australia and Israel 


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Romania 
Eastern Europe 
Singapore 
Asia 
Slovakia 
Eastern Europe 
South Korea 
Asia 
Spain 
Western Europe, Australia and Israel 
Sweden 
Western Europe, Australia and Israel 
Switzerland 
Western Europe, Australia and Israel 
Taiwan 
Asia 
Turkey 
Asia 
United Kingdom 
Western Europe, Australia and Israel 
USA 
North America 
4.1.1.12 
Prohibited medications 
Prohibited medications will be identified based on Bayer specific drug groupings. Prohibited 
medications include: 
• Medications with a combination of level 2 groups “Strong CYP3A4 inducers” and 
“Clinical P-gp inducers”  
• Medications with a combination of level 2 groups “Strong CYP3A4 inhibitors” and 
“Clinical P-gp inhibitors”  
4.1.1.13 
CHA2DS2-VASc Score for Atrial Fibrillation 
To support the patient demographics and for use as a subgroup the CHA2D S2-VASc score 
will be calculated at randomization/baseline.  
The CHA2D S2-VASc score is calculated based on  
• Congestive heart failure, increases score by 1, use medical history pre-specified 
terms “Chronic Heart Failure”, or “Hypertrophic cardiomyopathy”, or corresponding 
Preferred Terms "Cardiac failure chronic", or "Hypertrophic cardiomyopathy"; 
• Hypertension, increases score by 1, use medical history pre-specified term “Arterial 
Hypertension”, or corresponding Preferred Term "Hypertension";  
• Age 75 years or older, increases score by 2; 
• Diabetes mellitus, increases score by 1, use medical history pre-specified term 
“Diabetes Mellitus”, or corresponding Preferred Term "Diabetes mellitus"; 


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• Stroke / TIA / thromboembolism, increases score by 2, use medical history pre-
specified terms “Stroke”, “Transient Ischemic Attack”, or “Systemic embolism”, or 
corresponding Preferred Terms "Cerebrovascular accident", "Transient ischaemic 
attack", or "Embolism arterial"; 
• Vascular disease, increases score by 1, use medical history pre-specified terms 
“Myocardial Infarction”, “Coronary Artery Disease”, “Peripheral arterial occlusive 
disease”, “Complex Aortic plaque”, “Pulmonary embolism”, or “Deep Vein 
Thrombosis”, or corresponding Preferred Terms "Myocardial infarction", "Coronary 
artery disease", "Peripheral arterial occlusive disease", "Aortic arteriosclerosis", 
"Pulmonary embolism", or "Deep vein thrombosis" 
, and medical procedures history pre-specified terms “Coronary Artery bypass 
Grafting” or “Percutaneous Coronary Intervention”, or corresponding Preferred Terms 
"Coronary artery bypass", "Percutaneous coronary intervention";  
• Age 65-74, increases score by 1; 
• Sex Category, increases score by 1 for female sex.  
 Missing values will lead to an implicit “no” answers to a specific question, i.e. only 
confirmed risk factor will be counted for the score. 
4.1.1.14 
CHADS2 Score for Atrial Fibrillation 
To support the patient demographics and for use as a subgroup the CHADS2 score [10] will be 
calculated at randomization/baseline.  
The CHADS2 score is calculated based on  
• Congestive heart failure, increases score by 1, use medical history pre-specified term 
“Chronic Heart Failure”, or corresponding Preferred Term "Cardiac failure chronic"; 
• Hypertension, increases score by 1, use medical history pre-specified term “Arterial 
Hypertension”, or corresponding Preferred Term "Hypertension";  
• Age 75 years or older, increases score by 1; 
• Diabetes mellitus, increases score by 1, use medical history pre-specified term 
“Diabetes Mellitus”, or corresponding Preferred Term " Diabetes mellitus"; 
• Stroke / TIA, increases score by 2, use medical history pre-specified terms “Stroke” 
or “Transient Ischemic Attack”, or corresponding Preferred Terms "Cerebrovascular 
accident" or "Transient ischaemic attack"; 
 Missing values will lead to an implicit “no” answers to a specific question, i.e. only 
confirmed risk factor will be counted for the score. 
4.1.1.15 
ORBIT-AF and HAS-BLED Score 
To support the patient demographics, the Outcomes Registry for Better Informed Treatment 
of Atrial Fibrillation (ORBIT-AF) bleeding score [14] and modified HAS-BLED score [15] 
will be calculated at randomization/baseline.  
The ORBIT-AF bleeding score is calculated based on  
• Older, Score 1 for 75 years or older; 


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• Reduced hemoglobin (<13 g/dL in men and <12 g/dL in women), or hematocrit 
(<40% in men and <36% in women) or history of anemia (Score 2);  
• Bleeding history, Score 2 for any history of all major or gastrointestinal bleeding 
documented at the baseline visit; 
• Insufficient kidney function, Score 1 for eGFR < 60 ml/min/1.73 m2 ; 
• Treatment with an antiplatelet agent, Score 1. 
Missing values will lead to an implicit “no” answers to a specific question, i.e. only confirmed 
risk factor will be counted for the score.  
The modified HAS-BLED score is calculated based on the sum of  
• Hypertension, Score 1 for uncontrolled hypertension (as per medical history term 
“Hypertension”) with a baseline systolic BP > 160 mmHg (0/1); 
• Abnormal renal or liver function, Score 1 represented by for serum creatinine ≥ 2.26 
mg/dL (200 µmol/L) AND Score 1 represented by for bilirubin > 2x ULN with 
AST/ALT/AP > 3x ULN (0/1/2); 
• Stroke, Score 1 for history of stroke (0/1); 
• Bleeding, Score 1 for prior major bleeding and medical history of anemia (0/1); 
• Labile INR, not collected for this study (0/1); 
• Elderly, Score 1 for > 65 years (0/1); 
• Drugs, Score 1 for antiplatelet agents or NSAIDs (also score 1 for alcohol use 
however this is not collected for this study) (0/1/2). 
Missing values will lead to an implicit “no” answers to a specific question, i.e. only confirmed 
risk factor will be counted for the score. 
Antiplatelet agents and NSAIDs assessed in ORBIT-AF bleeding score and modified HAS-
BLED score will be identified by use of Standard Drug Groupings  
4.1.1.16 
Disabling Stroke 
Participants with a stroke will be assessed for their resulting disability using the modified 
Rankin Scale (mRS) 7 days after the event and at the next visit, at least 2 months post the 
stroke (see Section 8.2.1.1 and 10.8 of the CSP 19767 for further details). A disabling stroke 
is defined as a stroke, of any type, associated with a mRS of ≥ 3 at the 2nd mRS assessment 
(i.e. between 2 and 5 months after the stroke). An exploratory endpoint of short-term 
disabling stroke will also be analyzed based on the mRS score from 7 days after the stroke. 
4.1.2 
Derivation of time-to-event variables, censoring and incomplete dates 
As reported in Sections 4.2 and 4.3, for efficacy, safety and net clinical benefit time-to-event 
outcomes, the variable is the time to first occurrence of the outcome event of interest, which 
can be a single outcome or a composite.  
For estimands using the treatment policy strategy to address early discontinuation of assigned 
treatment time-to-event variables will be derived as the number of days from the individual 
participant’s randomization date (planned at Visit 2) to the date of onset of the respective 
endpoint event.  


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Date of Event – Date of randomization + 1. 
Due to the early termination of the study it was decided that the main analyses for the 
treatment regimen will not stop on the individual date of CEOT visit, but at the time of the 
request of study termination.  Therefore, the time-to-event variable for participants who have 
not experienced the respective endpoint event will be censored on the earlier of: 
1. 19th November 2023 (the date of the decision of the study stop), 
2. the date of last contact as defined in Section 4.1.1.5.  
As a second supplementary time frame, the original planned time frame will be used. For this 
purpose, the time-to-event variable for participants who have not experienced the respective 
endpoint event until their CEOT visit (as available) will be censored as follows: 
• for participants who reach their CEOT visit without the event of interest, the censoring 
date will be the date of their CEOT visit, 
• for participants without a CEOT visit, the censoring date will be their date of last 
contact as defined in Section 4.1.1.5.  
For estimands using the while exposed to assigned treatment strategy, the start date for the 
time to event interval will be the date of first intake of study intervention (rather than 
randomization date).  
Date of Event – Date of first intake of study intervention + 1. 
Note that for participants using the DCT model there will be a lag between randomization and 
first study intervention intake due to direct to participant supply. This difference will be 
accounted for in the analysis within the stratification by study type (DCT vs conventional). 
Regarding time-to-event endpoints censoring for administrative reasons will be assumed to be 
non-informative. 
All efforts will be made to reduce incomplete follow-up with regard to the occurrence and 
timing of key outcome events to a minimum.  
For those estimands where the “while on-treatment” strategy is proposed to address the 
intercurrent event of “early discontinuation of treatment”, see estimand definition in Section 
1.1.2 for example, the occurrence of this intercurrent event will be considered a “soft” 
competing risk in the analysis, i.e. events of interest will be counted up to the date of last 
intake of study intervention plus 2 days. Also, in case the study intervention is taken up to the 
planned end date (day before the CEOT visit), the event of interest will be counted up to the 
date of last intake of study intervention plus 2 days. 
For all estimands, the “while alive” strategy is proposed to address the intercurrent event 
“death”. The occurrence of death will be considered a competing risk in the analysis, resulting 
in “technical censoring” at the date of death. 
For estimands using the “while on-treatment” strategy (i.e. analyses using the aSAF) events 
occurring on the same day as first study intervention intake will be considered an outcome 
event of interest if either the time of occurrence is later than the time of first study 
intervention intake or if the time of first study intervention intake or time of the event is 
missing. 


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4.1.3 
Descriptive statistics 
All variables will be analyzed by descriptive statistical methods. Generally, confidence 
intervals will be presented as two-sided 95% confidence intervals. 
Metric data 
The number of data available and missing data, mean, standard deviation, minimum, quartiles, 
median, and maximum will be calculated for metric data.  
Categorical data 
Frequency tables will be generated for categorical data.  
Time-to-event data 
• For time-to-event variables, the observed numbers of participants with an event of 
interest and, if applicable, the competing event, will be reported together with the 
proportion by study intervention and overall.  
• Incidence rate estimates for the time to event endpoints and, if applicable, the 
competing event, will be displayed with 95% confidence intervals by study 
intervention and overall. 
Incidence rates will be estimated as number of participants with the respective event of 
interest divided by the cumulative at-risk time in the reference population, where a 
participant is no longer considered at risk once the event-of-interest or a competing 
event, whichever comes first, occurred. 
For the primary efficacy, safety and net clinical benefit endpoints Nelson–Aalen 
estimates of the cumulative hazard for the event of interest by study intervention arm 
will be used to explore if the hazards are reasonably constant over time as applicable. 
The (cause-specific) Nelson-Aalen estimator for event E at time t is defined as: 
𝛬̂𝐸(𝑡) = ∑#𝑃𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎𝑛 𝑒𝑣𝑒𝑛𝑡 𝐸 𝑎𝑡 𝑡𝑗
#𝑃𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠 𝑢𝑛𝑑𝑒𝑟 𝑟𝑖𝑠𝑘 𝑎𝑡 𝑡𝑗
𝑡𝑗≤𝑡
, 
[2]. If Nelson–Aalen estimates of the cumulative hazard for an event-of-interest by 
intervention arm indicate that the hazards are not reasonably constant over time, 
piecewise incidence rates, with appropriately chosen cut-points, will be estimated and 
presented.  
• The cumulative incidence risk for the event-of-interest, i.e. the proportion of 
participants with an event of interest over the course of time taking competing risk 
into account, and, if applicable, the cumulative incidence risk for the competing risk 
will be estimated for time-to-event variables using Aalen-Johansen estimators by 
study intervention. Estimates will be displayed using plots and complementary tables.  
The Aalen-Johansen estimator is a non-parametric estimator based on the cause-
specific Nelson-Aalen estimator and the Kaplan-Meier (KM) estimator 𝑆̂(𝑡) and is 
defined as: 
𝐴𝐽𝐸
̂ (𝑡) = ∑𝑆̂(𝑡𝑗−1)(𝛬̂𝐸(𝑡𝑗) −𝛬̂𝐸(𝑡𝑗−1)) 
𝑡𝑗≤𝑡
. 
To derive the Aalen-Johansen estimators for the cumulative incidence with the 
corresponding confidence intervals, SAS program code corresponding to the following 
will be used: 


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ods output cif=cif; 
 
PROC LIFETEST DATA = <dataset> ALPHA=0.05 ERROR=AALEN; 
  STRATA  / GROUP=trtgrpn; 
  TIME ttevalue * status(0)/eventcode=1;  
                      /* CIF for event of interest type 1 (e.g. bleeding) */ 
RUN; 
PROC LIFETEST DATA = <dataset> ALPHA=0.05 ERROR=AALEN; 
  STRATA  / GROUP=trtgrpn; 
  TIME ttevalue * status(0)/eventcode=2;  
                                   /* CIF for (competing) event of type 2 */ 
RUN; 
 
/* 
where 
dataset  = name of dataset  
trtgrpn  = variable coding randomized antithrombotic treatment group 
           (0 = apixaban control group, 1 = asundexian treatment 
ttevalue = time to first occurrence of outcome event or competing event or  
           censoring 
status   = status of the participant at event time (0 = right-censored, 
           1 = event of interest, 2 = competing event) 
alpha has been set as 0.05 in this example 
*/ 
 
 
4.1.4 
Stratification 
In general, unless there are problems with convergence or too few events in a stratum, 
statistical models will be stratified by  
• Study type (conventional study model vs. DCT model) 
• Single agent antiplatelet therapy planned to continue for at least 6 months after 
randomization (Current use vs. No current use). 
These two baseline covariates are the randomization strata (and not re-derived).   
Models that are by study type or single agent antiplatelet therapy will not use the 
corresponding factor as a covariate in the model.  
When assessing a model across subgroups if a stratification factor has to be removed from at 
least one subgroup category model then, to allow comparisons across the subgroup categories, 
it will be removed from all subgroup category models. 
4.2 
Primary Endpoints/Estimands Analysis 
The following subsections describe the planned statistical analyses addressing the primary 
efficacy, safety and net clinical benefit estimands. 


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4.2.1 
Primary Efficacy Estimand 
4.2.1.1 
Definition of Endpoint 
The primary efficacy endpoint is the time from randomization to the first occurrence of the 
composite of stroke or systemic embolism. The estimand is defined in Section 1.1.1 and 
further details of the derivation of time to event endpoints are described in Section 4.1.2. 
4.2.1.2 
Main Analytical Approach 
Data for the primary efficacy endpoint will be summarized using the set of descriptive 
statistics for time-to-event endpoints (see Section 4.1.3).  
In line with the “while alive” strategy proposed to address the intercurrent event “death” for 
the primary efficacy estimand, see Section 1.1.1, “death prior to the occurrence of a primary 
efficacy outcome” will be considered a competing risk in the analysis. Addressing “premature 
discontinuation of assigned treatment” with the treatment policy strategy means that primary 
efficacy events occurring after treatment discontinuation are used in the analysis. 
To estimate the relative change in the instantaneous rate of the occurrence of the primary 
efficacy outcome in participants assigned to asundexian versus apixaban according to the 
defined estimand, cause-specific hazard ratios (csHRs) and their associated confidence 
intervals for participants assigned to asundexian versus apixaban will be derived from a 
stratified cause-specific Cox proportional hazards regression model. The results will be 
presented together with estimates of the csHRs for the competing risk “death”. 
To derive the cause-specific hazard ratios and the corresponding confidence intervals, SAS 
program code corresponding to the following will be used: 
 
ODS OUTPUT ParameterEstimates = cshr modelANOVA=cspval;  
 
PROC PHREG DATA = <dataset>; 
   MODEL ttevalue*status(0,2)=trtgrpn / RL ALPHA=0.05 TYPE3(SCORE); 
   STRATA dct saap; 
RUN; 
 
/* modeling event of interest and all competing events where status ≠ 0 */ 
 
/* 
where 
dataset  = name of time-to-event-dataset  
trtgrpn  = variable coding randomized antithrombotic treatment group 
ttevalue = time to first occurrence of outcome event or competing event or  
           censoring 
status   = status of the participant at event time (0 = right-censored, 
           1 = event of interest, 2 = competing event) 
dct      = binary strata, participants in conventional study model (=0) vs.  
           participants in DCT model (=1) 
saap     = binary strata, Current use single agent antiplatelet therapy (=1) 
           vs. No current use single agent antiplatelet therapy (=0) 
 
alpha has been set as 0.05 in this example 
 
*/ 
 


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All efficacy hypotheses, see Section 2, will be tested in an exploratory manner using a two-
sided stratified log-rank test, based on the score test from the Cox PH model.  
All analyses described in this section will be repeated for the subgroups in Section 4.6.5. 
4.2.1.3 
Sensitivity Analyses 
If Nelson-Aalen estimates of the cumulative hazard for the primary efficacy outcome by study 
intervention arm indicate that estimated hazards are not reasonably constant over time, 
piecewise incidence rates, with appropriately chosen cut-points, will be estimated and 
presented. 
The plausibility of the proportional hazards assumption will be visually assessed via plots of 
the scaled Schoenfeld residuals over time and via the Chi-Square test of the residuals [7]. 
For the main analysis, missing follow-up time will be handled by censoring at the last 
available timepoint for which data on the outcome exists. 
4.2.1.4 
Supplementary Analyses 
Supplemental Efficacy Estimand 1 
In a supplementary analysis the primary efficacy objective will be explored from a different 
angle, comparing the probability for the occurrence of a primary efficacy outcome over time 
in contrast to the hazard rates. This estimand is the Supplemental Efficacy Estimand 1 (see 
Section 1.1.1) with the population-level summary of the sub-distribution hazard ratio (sdHR) 
based on a Fine-Gray model [5]. Since the expected probability of the occurrence of a primary 
efficacy event is less than 20% over the whole duration of study follow-up, a sub distribution 
hazard ratio of x is associated with an x-fold decrease of the odds of the occurrence of the 
primary efficacy outcome when comparing asundexian with apixaban.  
The estimated sub-distribution hazard ratios (sdHRs) and their associated confidence intervals 
comparing participants assigned to asundexian versus apixaban with respect to the primary 
efficacy outcome will be presented together with estimates of the sdHRs for the competing 
risk “death”. The model will be stratified by study model (DCT vs conventional study) and 
single agent antiplatelet therapy (Current use vs No current use).  
The SAS code for the Fine-Gray model is as below 
 
ODS OUTPUT ParameterEstimates = fg1; 
PROC PHREG DATA = <dataset>; 
   CLASS trtgrpn; /* modeling for event of interest type 1 */ 
   MODEL ttevalue*status(0) = trtgrpn / EVENTCODE(FG) = 1 RL; 
   STRATA dct saap; 
RUN;  
 
ODS OUTPUT ParameterEstimates = fg2; 
PROC PHREG DATA = <dataset>; 
   CLASS trtgrpn;             /* modeling for competing event type 2 */ 
   MODEL ttevalue*status(0) = trtgrpn / EVENTCODE(FG) = 2 RL; 
   STRATA dct saap; 
RUN;  
 
/*  where 
dataset  = name of dataset 


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trtgrpn  = variable coding randomized intervention groups 
ttevalue = time to first occurrence of outcome event or competing  
           event or censoring 
status   = status of participant at event time (0 = right-censored, 
           1 = event of interest, 2 = competing event, ...)  
dct      = binary strata, participants in conventional study model (=0)  
           vs. participants in DCT model (=1) 
saap     = binary strata, Current use single agent antiplatelet therapy  
          (=1) vs. No current use single agent antiplatelet therapy (=0) 
*/ 
 
/* Combine (sub-distribution) HR estimates and confidence intervals from 
datasets fg1 and fg2 for the models for the event of interest and the 
competing events in one table. */ 
 
Gray’s [9] test for equivalence of the cumulative incidence functions, stratified by the two 
stratum variables, will be performed. The SAS code for Gray’s test is as below 
 
ODS OUTPUT GrayTest = Gtest; 
 
PROC LIFETEST DATA = <dataset> ERROR = AALEN; 
  TIME ttevalue*status(0) / EVENTCODE = 1;  
                                      /* for event of interest type 1 */ 
  STRATA dct saap / GROUP=trtgrpn; 
RUN; 
 
/*  where 
dataset  = name of dataset 
trtgrpn  = variable coding randomized intervention groups 
ttevalue = time to first occurrence of outcome event or competing event  
           or censoring 
status   = status of participant at event time (0 = right-censored, 
           1 = event of interest, 2 = competing event, ...)  
dct      = binary strata, participants in conventional study model (=0)  
           vs. participants in DCT model (=1) 
saap     = binary strata, Current use single agent antiplatelet therapy 
          (=1) vs. No current use single agent antiplatelet therapy (=0) 
*/ 
/* Take p-value from Gtest and combine with other results in the 
table.*/ 
 
Supplemental Efficacy Estimands 2 and 3  
Data for the supplemental efficacy estimands 2 and 3 will be summarized as in Section 4.1.3. 
In line with the “while on-treatment” strategy proposed to address intercurrent events for 
these estimands, see Section 1.1.1, both “death” and “premature end of exposure to assigned 
treatment” will be considered competing risks in the analysis. This also implies that only 
participants who took at least one dose of study intervention will be included in the analysis, 
i.e. the analysis will be performed on the aSAF. 
For the supplemental efficacy estimand 2 as described in 4.2.1.2 for the primary efficacy 
estimand the csHRs and their associated confidence intervals for participants taking 
asundexian versus apixaban will be derived. The results will be presented together with 


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estimates of the csHRs for the associated competing risk “death or premature end of exposure 
to assigned treatment”.  
For the supplemental efficacy estimand 3 the sub-distribution hazard ratios (sdHRs) and their 
associated confidence intervals for participants assigned to asundexian versus apixaban will 
be derived from a Fine-Gray model as described for the supplemental efficacy estimand 1 
earlier in this section. The results will be presented together with estimates of the sdHRs for 
the associated competing risk. 
The csHR and results of the two-sided stratified log-rank test, based on the score test from the 
Cox PH model will supplement the results from the primary efficacy estimand analysis.  
4.2.2 
Primary Safety Estimand 
4.2.2.1 
Definition of Endpoint 
The primary safety endpoint is the time from first intake of study intervention to the first 
occurrence of ISTH major bleeding. The primary safety estimand is defined in Section 1.1.2 
and different bleeding classifications in Section 4.1.1.7, the derivation of time to event 
endpoints is described in Section 4.1.2. 
4.2.2.2 
Main Analytical Approach 
In line with the “while on-treatment” strategy proposed to address intercurrent events for the 
primary safety estimand, see Section 1.1.2, both “death prior to the occurrence of a primary 
safety outcome” and “premature discontinuation of assigned treatment” will be considered 
competing risks in the analysis. This also implies that only participants who took at least one 
dose of study intervention will be included in the analysis, i.e. the analysis will be performed 
on the aSAF. 
Data for the primary safety endpoint will be summarized using the set of descriptive statistics 
for time-to-event endpoints (see Section 4.1.3).  
For the primary safety estimand as described in 4.2.1.2 for the primary efficacy estimand the 
csHRs and their associated confidence intervals for participants taking asundexian versus 
apixaban will be derived. The results will be presented together with estimates of the csHRs 
for the associated competing risk “death or premature end of exposure to assigned treatment”.  
The primary safety superiority null hypothesis, see Section 2, will be tested using a stratified 
two-sided log-rank test, based on the score test from the Cox PH analysis.  
All analyses described in this section will be repeated for the set of subgroups defined for the 
baseline variables: risk factors for apixaban dose; current use of single agent anti platelet 
therapy; study model; AF; weight; age group; eGFR; sex; race; region; stroke or TIA prior to 
randomization; treated with moderate CYP3A inhibitors + inducers at randomization and 
CHA2DS2-VASc Score.  
4.2.2.3 
Sensitivity Analyses 
 
 
 
 
 
CCI


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4.2.2.4 
Supplementary Analyses 
Supplemental Safety Estimand 1 
For the supplemental safety estimand 1 the sub-distribution hazard ratios (sdHRs) and their 
associated confidence intervals for participants assigned to asundexian versus apixaban will 
be derived from a Fine-Gray model as described for the supplemental efficacy estimand 1 in 
Section 4.2.1.4. The results will be presented together with estimates of the sdHRs for the 
associated competing risks of “death or premature discontinuation of study intervention”. 
Supplemental Safety Estimands 2 and 3 
The supplemental safety estimand 2 will be summarized as in Section 4.1.3, these summary 
statistics will also apply for supplemental safety estimand 3. 
For the supplemental safety estimand 2 as described in 4.2.1.2 for the primary efficacy 
estimand the csHRs and their associated confidence intervals for participants taking 
asundexian versus apixaban will be derived. The results will be presented together with 
estimates of the csHRs for the associated competing risk “death”.  
For the supplemental safety estimand 3 the sub-distribution hazard ratios (sdHRs) and their 
associated confidence intervals for participants assigned to asundexian versus apixaban will 
be derived from a Fine-Gray model as described for the supplemental efficacy estimand 1 in 
Section 4.2.1.4. The results will be presented together with estimates of the sdHRs for the 
associated competing risk.  
The csHR and results of the two-sided stratified log-rank test, based on the score test from the 
Cox PH model will supplement the results from the primary safety estimand analysis.  
4.2.3 
Primary Net Clinical Benefit Estimand 
4.2.3.1 
Definition of Endpoint 
The primary net clinical benefit endpoint is the time from start of study intervention to first 
occurrence of stroke (including hemorrhagic stroke), systemic embolism, or ISTH major 
bleeding (excluding hemorrhagic stroke). The primary net clinical benefit estimand is defined 
in Section 1.1.3 and different bleeding classifications in Section 4.1.1.7, the derivation of time 
to event endpoints is described in Section 4.1.2. 
4.2.3.2 
Main Analytical Approach 
The analysis of the primary net clinical benefit endpoint will be as the main analyses of the 
primary safety endpoint, see Section 4.2.2.2. 
The primary net clinical benefit superiority null hypothesis, see Section 2, will be tested using 
a stratified log-rank test based on the score test from the Cox PH analysis.  
All analyses described in this section will be repeated for the set of subgroups: Risk factors 
for apixaban dose (0-1, 2-3); current use of single agent anti platelet therapy (yes/no); study 
model (DCT vs. conventional study).  
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4.2.3.3 
Sensitivity Analyses 
No sensitivity analyses are planned for the primary net clinical benefit endpoint. 
4.2.3.4 
Supplementary Analyses 
Supplemental Net Clinical Benefit Estimand 1 
For the supplemental net clinical benefit estimand 1 the analysis will follow that of the 
supplemental safety estimand 1 in Section 4.2.2.4.  
 
Supplemental Net Clinical Benefit Estimands 2 and 3 
The supplemental net clinical benefit estimands 2 and 3 will follow the principles described 
for the supplemental safety estimands 2 and 3, see Section 4.2.2.4. 
4.3 
Secondary Endpoints/Estimands Analysis 
The analysis of estimands associated with secondary endpoints will follow the principles as 
described for the respective primary efficacy, safety and net clinical benefit estimands. 
4.3.1 
Secondary Efficacy Endpoints 
4.3.1.1 
Definition of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are time to first occurrence from randomization of: 
• Composite of ischemic stroke or systemic embolism (Secondary Efficacy Estimand 1) 
• Ischemic stroke 
• Composite of CV death, stroke and myocardial infarction 
• CV death 
• All-cause mortality 
4.3.1.2 
Main Secondary Efficacy Analytical Approach 
The analysis of the secondary efficacy endpoints will follow the principles described for the 
main analyses of the primary efficacy endpoint, see Section 4.2.1.2. 
For those efficacy composites that include CV death as a component of the endpoint, the 
competing risk death will be reduced to non-CV death, and death will not be a competing risk 
for the all-cause mortality endpoint. 
4.3.1.3 
Sensitivity Secondary Efficacy Analyses 
No sensitivity analyses are planned for the secondary efficacy endpoints. 
4.3.1.4 
Supplementary Secondary Efficacy Analyses 
The supplementary analysis of the secondary efficacy endpoints will follow the principles 
described for the supplementary analyses of Supplemental Efficacy Estimand 1, see Section 
4.2.1.4.  


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4.3.2 
Secondary Safety Endpoints 
4.3.2.1 
Definition of Secondary Safety Endpoints 
The secondary safety endpoints are time to first occurrence from first study intervention 
intake of: 
• Composite of ISTH major or clinically relevant non-major bleeding  
• Clinically relevant non-major bleeding  
• Hemorrhagic stroke 
• Symptomatic intracranial hemorrhage 
• Fatal bleeding 
• Minor bleeding 
4.3.2.2 
Main Secondary Safety Analytical Approach 
The analysis of the secondary safety endpoints will follow the principles described for the 
main analyses of the primary safety endpoint, see Section 4.2.2.2. For the endpoint “fatal 
bleeding” death will not be considered as competing event. 
4.3.2.3 
Sensitivity Secondary Safety Analyses 
No sensitivity analyses are planned for the secondary safety endpoints. 
4.3.2.4 
Supplementary Secondary Safety Analyses 
The supplementary analysis of the secondary safety endpoints will follow the principles 
described for Supplemental Safety Estimand 1, see Section 4.2.2.4.  
For the ISTH and BARC bleeding events the observed number of participants with individual 
classifications will be reported together with the proportion. In addition, the incidence rate 
will be displayed with a 95% confidence interval. The classifications displayed will be ISTH 
major bleeding, CRNM bleeding, minor bleeding and BARC bleedings type 1, 2, 3a, 3b, 3c, 
5a and 5b. 
The number of participants with bleeding events in the treatment emergent data scope by 
bleeding site (e.g. ear, eye, GI etc.) will be summarized by study intervention and overall. The 
table by bleeding site will be repeated for ISTH major bleeding, CRNM bleeding and minor 
bleeding.  
The number of participants with bleeding (separately for both ISTH definition and BARC 
bleeding definition) according to investigator reported outcome and after adjudication (cross 
classification) will be reported. The details of participants with ISTH major bleeding, CRNM 
bleeding, and minor bleeding will be listed. 
4.3.3 
Secondary Net clinical benefit Endpoints 
4.3.3.1 
Definition of Secondary Net clinical benefit Endpoints 
The Secondary Net Clinical Benefit Endpoints are time from first study intervention intake to 
first occurrence of: 
• Composite of ischemic stroke (including hemorrhagic stroke), systemic embolism, 
ISTH major bleeding (excluding hemorrhagic stroke), or all-cause mortality 


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• Composite of disabling stroke (mRS ≥ 3), critical bleeding or all-cause mortality 
See Section 4.1.1.7 for the definition of ISTH major bleeding. 
4.3.3.2 
Main Secondary Net clinical benefit Analytical Approach 
The analysis of the secondary net clinical benefit endpoints will follow the principles 
described for the main analyses of the primary safety endpoint, see Section 4.2.2.2. 
4.3.3.3 
Sensitivity Secondary Net clinical benefit Analyses 
No sensitivity analyses are planned for the secondary net clinical benefit endpoints. 
4.3.3.4 
Supplementary Secondary Net clinical benefit Analyses 
The supplementary analysis of the secondary net clinical benefit endpoints will follow the 
principles described for the supplementary analyses of Supplemental Safety Estimand 1, see 
Section 4.2.2.4. 
4.4 
Exploratory Endpoints Analysis 
4.4.1 
Definition and Analytical Approach for Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are: 
• Composite of CV death, stroke and systemic embolism * 
• Systemic embolism * 
• Hemorrhagic stroke * 
• Disabling stroke (modified Rankin Scale [mRS] ≥ 3 at next visit (at least 2 months 
after stroke)) * 
• Short-term disabling stroke (modified Rankin Scale [mRS] ≥ 3 at day 7) * 
• Fatal ischemic stroke 
• Composite of non-fatal ischemic stroke and systemic embolism * 
• Composite of fatal ischemic stroke and systemic embolism * 
• Composite of all-cause mortality, stroke and myocardial infarction * 
• Ischemic disabling stroke (modified Rankin Scale [mRS] ≥ 3 at next visit (at least 2 
months after stroke)) * 
• Hemorrhagic disabling stroke (modified Rankin Scale [mRS] ≥ 3 at next visit (at least 
2 months after stroke)) * 
• Composite of stroke and systemic embolism, up to 7 days after last study intervention 
@ (Exploratory Efficacy Estimand 1) 
• Composite of stroke and systemic embolism, up to 30 days after last study 
intervention @ (Exploratory Efficacy Estimand 2) 
• EuroQol Group 5-dimension questionnaire (EQ-5D). 
* Time from randomization to first occurrence. 


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@ Time from first study intervention intake to first occurrence. 
The analyses of the time to first occurrence exploratory efficacy endpoints will follow the 
principles described for the main and supplementary analyses of the primary efficacy 
endpoint, see Section 4.2.1.2, and Section 4.2.1.4.  
The health state index values derived from the EQ-5D descriptive system will be analyzed 
separately to support health economic evaluations. For the CSR a categorical summary of the 
EQ-5D questions will be produced by visit together with summary statistics for the VAS 
score also by visit. 
4.4.2 
Definition and Analytical Approach for Exploratory Safety Endpoints 
The exploratory safety endpoints are time from first intake of study drug to first occurrence 
of: 
• Gastrointestinal bleeding 
• All bleeding 
• BARC type 3 and 5 bleeding 
• BARC type 2, 3 and 5 bleeding 
• BARC type 1 bleeding 
• ISTH non-fatal major bleeding 
• ISTH major bleeding, up to 7 days after last study intervention (Exploratory Safety 
Estimand 1) 
The total number of ISTH major bleeding events per participant and number of subjects with 
more than one bleeding event are also exploratory safety endpoints. 
The analysis of the time to event exploratory safety endpoints will follow the principles 
described for the main and supplementary analyses of the primary safety endpoint, see 
Section 4.2.2.2, and Section 4.2.2.4. 
Major bleedings will be also described by localization (e.g., intracranial and extra-cranial and 
outcome (e.g.: resulting in death; resulting in disability; recovered without sequels).  
The total number of ISTH major bleeding events per participant will be displayed by means of 
descriptive statistics and a categorical (0, 1, 2, 3, 4, 5-6, 7-9, ≥10) frequency table. On 
treatment ISTH major bleeding events will be displayed using the aSAF and on-study ISTH 
major bleeding events will be displayed using the aFAS. Tables for on-study CRNM bleeding 
and minor bleeding events will also be included. 
Number of subjects with more than one bleeding event will be counted while alive and 
exposed to treatment and displayed using the aSAF. 
 


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4.4.3 
Definition and Analytical Approach for Exploratory Net clinical benefit 
Endpoints 
The exploratory net clinical benefit endpoints are: 
• Total number of hospitalizations due to efficacy or safety outcome events per 
participant. 
The total number of hospitalizations per participant will be displayed by means of descriptive 
statistics and a categorical (0, 1, 2, 3, 4, 5-6, 7-9, ≥10) frequency table. On-treatment 
hospitalizations will be compared using the aSAF and on-study hospitalizations will be 
compared using the aFAS. On – study hospitalizations are defined as all hospitalizations 
starting on the day of randomization or after randomization until last scheduled visit. On-
treatment hospitalizations are defined as all hospitalizations from first intake of study 
intervention up until 2 days after last intake of study intervention. 
 
4.5 
Other Safety Analyses 
4.5.1 
Extent of Exposure 
Treatment duration will be defined as the number of days from the day of first study 
intervention intake up to and including the day of last study intervention intake, ignoring 
temporary study invention interruptions, and will be summarized using descriptive statistics 
by study intervention arm and overall.  
Treatment duration
= Date of last intake of study intervention
−Date of first intake of study intervention + 1 day 
The treatment dose of asundexian or apixaban will be summarized as the average dose in mg 
per day using descriptive statistics by study arm and overall. In addition, the treatment dose 
for asundexian or apixaban will be categorized into 6 groups, ≤ 2 mg, >2 to 3 mg, >3 to 6 mg, 
>6 to 25 mg, >25 to 55 mg and > 55 mg and will be summarized by study arm and overall.  
The compliance (as percentage) will be calculated as: 
100 × Number of tablets taken
Number of planned tablets
 
The number of planned tablets is calculated as: 
(days from first to last intake of study intervention +  1) × 
< number of planned tablets per day >  
All tablets, including the placebo tablets, will be counted. For participants who withdraw 
prematurely from the study intervention, compliance will be calculated up to the time of last 
dose. Compliance values will be reviewed for plausibility and extreme values (e.g. > 200 %) 
may be adjusted. For example if bottles are not returned then assuming all dispensed tablets 
were taken could lead to implausibly large compliance values. In this study tablets not 
returned can be recorded as lost if not taken so it is hoped compliance values will be in a 
plausible range however a review will be done to check this. 


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The compliance for asundexian/placebo-asundexian and apixaban/placebo-apixaban will be 
summarized descriptively by study arm and overall. In addition, percent of compliance will be 
categorized into 3 groups, ≤ 80%, >80 to 120%, and > 120 %, and the categories will be 
summarized by study arm and overall.  
 
4.5.2 
Adverse Events 
All AEs will be summarized using the Medical Dictionary for Regulatory Activities 
(MedDRA, the version defined in SDTM domain TS) preferred terms (PTs) grouped by 
system organ class (SOC).  
Any AEs related to study procedures recorded from signing of informed consent but prior to 
first study intervention intake will be considered as pre-treatment AEs. AEs that occurred or 
worsened after the first dose of study intervention up to 2 days after the last dose of study 
intervention will be considered as treatment-emergent AEs (TEAEs).  
AEs that started 3 days or later after last dose will be considered as post-treatment AEs. 
Determination of whether an event is treatment-emergent will be derived after the missing or 
incomplete AE start date is imputed. Imputation rules for missing and incomplete AE start 
data are described in Section 4.1.2.  
AEs starting before but worsening at or after the date of first study intervention and before or 
at the date of last study intervention + 2 days will be considered as two events, a pre-treatment 
AE and a TEAE. The pre-treatment AE will stop at the time of worsening and the new TEAE 
will start at the time of worsening. Same applies in case an AE starts at or after the date of 
first study intervention, but before the date of last study intervention + 2 days and worsens 
afterwards, then e.g. leading to a TEAE and a post-treatment AE. 
Reasons for worsening of an AE: 
• AE intensity/grade is worsened (e.g.: moderate to severe) 
• AE changed to a serious event 
• AE ends with death  
• AE changed to drug-related 
In case of premature permanent discontinuation of study intervention, (S)AE reporting is not 
required after the participant’s early termination follow-up visit (see Section 7 of the CSP 
19767 for further details), therefore there may be safety and efficacy outcome events that are 
not reported as AEs. 
Certain disease-related events (DREs) do not need to be reported as AEs but are documented 
as efficacy outcome events, regardless of when they occurred, see Section 4.1.1.9 for 
summary definition and Section 8.4.6 of 19767 CSP for detailed definition. 
Overall summaries of the number of participants with any AEs, pre-treatment AEs, TEAEs, 
and post-treatment AEs will be generated by study intervention arm and overall.  
The number of participants with  
• TEAEs,  
• study intervention-related TEAEs, 


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• TEAEs resulting in discontinuation of study intervention,  
• TEAEs by maximum intensity,  
• study intervention-related TEAEs by maximum intensity,  
• non-serious TEAEs,  
• SAEs,  
• serious TEAEs,  
• study intervention-related serious TEAEs,  
• serious TEAEs resulting in discontinuation of study intervention,  
• AEs with fatal outcome,  
• TEAEs with fatal outcome, and  
• post-treatment AEs  
will be summarized by study arm and overall using PTs grouped by SOC. Listings of serious 
TEAEs, AEs with fatal outcome, and deaths not attributed to AEs will be provided.  
In case of events with different intensity within a participant, the maximum reported intensity 
will be used. If intensity is missing, the event will be considered as severe. If the same event 
is reported as both unrelated and related to the study intervention within a participant, the 
event will be considered as related to study intervention. If the study intervention relationship 
is missing, the event will be considered as being related to the study intervention. 
4.5.3 
Additional Safety Assessments 
4.5.3.1 
Laboratory Data 
The number of participants with treatment-emergent high or low abnormal laboratory values 
will be summarized for each laboratory parameter by study intervention arm and overall. For 
summaries of abnormal laboratory values the measurements from both scheduled / 
unscheduled visits, as well as measurements from both central and local laboratory will be 
considered. 
Continuous laboratory parameter values (from Table 10-1 of the CSP 19767) including the 
change from baseline will be summarized by visit and by study arm and overall. For the by 
visit laboratory parameter summaries the measurements from scheduled visits and the central 
laboratory will be considered, unless specified otherwise. For all other analyses only central 
laboratory values will be used. 
If for laboratory parameters results are reported as below or above a quantification limit (i.e. if 
LBSTRESC starts with a “<” or “>”) then the respective numerical value of the quantification 
limit will be used and the DTYPE will be set to “LLOQ” or “ULOQ” respectively.  
The laboratory parameter eGFR from the central lab will be derived based on the CKD-EPI 
formula with the exception for sites from Japan. For Japanese sites, a Japanese Equation 
formula will be used. For the statistical analyses, eGFR derived from both formulas will be 
analyzed together.  
The laboratory tables will be repeated for the subgroups DCT and conventional study (only 
for the aSAF). 


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4.5.3.2 
Vital Signs 
Vital sign (systolic and diastolic blood pressure, heart rate) values will be summarized by 
study intervention arm and overall.  
The vital signs tables will be repeated for the subgroups DCT and conventional study. 
4.5.3.3 
Electrocardiogram 
The baseline mean ventricular rate will be summarized using descriptive statistics by study 
intervention arm and overall.  
The number of participants with electrocardiograms findings will be summarized by primary 
diagnostic category. 
The ECG tables will be repeated for the subgroups DCT and conventional study. 
4.5.3.4 
Analyses of liver events according to protocol  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
4.5.3.5 
Screening and analyses of potential drug-induced liver injuries 
  
 
 
 
 
  
 
 
 
 
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4.6 
Other Analyses 
4.6.1 
Pharmacokinetics 
The PK analyses will be presented separately from the CSR and will be described in a 
separate analysis plan. 
4.6.2 
Pharmacodynamics 
The pharmacodynamic analyses will be presented separately from the CSR and will be 
described in a separate analysis plan. 
4.6.3 
Genetics and / or Pharmacogenomics 
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study, if approved by local ECs / IRBs and competent authorities. See Section 8.8 of the CSP 
19767 for details. 
4.6.4 
Biomarker 
The biomarker analyses will be presented separately from the CSR and will be described in a 
separate analysis plan. 
4.6.5 
Subgroup Analyses 
Subgroup analyses of primary efficacy outcome will be performed to assess consistency of the 
investigational intervention effect across subgroups. 
The following factor is considered a potential predictive factor: 
• Risk factors for apixaban dosage at randomization (utilized for the primary efficacy, 
safety and net clinical benefit estimands) 
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As described in Section 6.1 of the CSP 19767, a 2.5 mg dose of apixaban is indicated for 
participants with any 2 of the following criteria: age 80 years or older, body weight of 60 kg 
or less, or serum creatinine level of 1.5 mg per dL (133 µmol/L) or more. For each 
participant, the dose selection will be based on the values at the randomization visit. As the 
lower apixaban dosage might decrease the efficacy treatment effect, the “apixaban dosage” 
factor (apixaban higher dosage group (0-1 risk factor) versus apixaban lower dosage group (2-
3 risk factors)) might be predictive of the treatment effect. Since the aim of the study is to 
show superiority or at least non-inferiority for all participants it seems reasonable not to 
conduct two different studies. This holds true since the proportion of participants with 2 or 3 
risk factors for apixaban dosage is to be estimated at about 10%. Whether a participant has 0-
1 or 2-3 risk factors at time of randomization will be re-derived based on the data collected for 
the 3 factors. 
The following factors that define subgroups are known or expected to possibly show different 
risks of efficacy events across the different levels of the factor and are therefore considered 
potential prognostic factors will be utilized for the primary efficacy estimand. 
• The stratification factors  
o Participation in conventional study model vs. DCT model. 
Participants in the DCT might be different (e.g. in age or socio-economic 
group) compared to conventional study participants. 
o Current use vs. no current use of single agent antiplatelet therapy planned to 
continue for at least 6 months after randomization. 
Participants on single agent antiplatelet therapy may have a higher risk of 
bleeding.  
• CHA2DS2-VASc score (2&3 vs. > 3 for male participants, 3&4 vs. >4 for female 
participants) (utilized for the primary efficacy and safety estimands) 
• BMI (< 25; ≥ 25 to < 30; ≥ 30 kg/m2) (utilized for primary efficacy estimand) 
• eGFR (<50; 50-80; >80 ml/min/1.73 m2), reflecting the known higher risks for an 
event and the recommendation of lowering the apixaban dose for decreased kidney 
function (utilized for the primary efficacy and safety estimands) 
• Race (White, Black, Asian, other), with focus on the known differences in the risk 
profile for Asian / non-Asian and Black / Non-Black participants (utilized for the 
primary efficacy and safety estimands). 
• Region: North America; South America; Western Europe, Australia and Israel; 
Eastern Europe; Asia (utilized for the primary efficacy and safety estimands) 
If the number of participants is too small within a subgroup, then the subgroup categories may 
be redefined prior to unblinding the study. 
 
Exploratory subgroups 
 
 
 
 
 
 
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Analytical Approach  
Consistency of treatment effects across subgroups, both in magnitude and direction, will be 
assessed by adding a covariate for the subgroup variable and the corresponding treatment-
subgroup interaction to the respective stratified Cox proportional hazards model. 
The objective of the subgroup analyses is to show the consistency of treatment effects across a 
wide variety of participant groups. As the number of subgroup analyses for baseline 
characteristics may be large, the probability of observing at least one statistically significant 
but spurious interaction is high despite the lack of a biological or pharmacological basis for 
expecting an interaction. Thus, any significant interactions will be interpreted as “flags” to 
prompt further investigation. 
If the interaction term is significant at the 5% type I error level in the analysis of the primary 
endpoint, secondary endpoints will be investigated to evaluate the plausibility of such an 
effect. Furthermore, in the analysis of key endpoints if the interaction term is significant at the 
5% type I error level the likelihood ratio test proposed by Gail and Simon [6] will be 
performed to test the hypothesis that there is no crossover or qualitative interaction at the 1% 
type I error level (H0: The direction of treatment effect is the same for all levels of a subgroup 
variable vs. H1: The direction of treatment effect is different for at least one level of a 
subgroup variable). 
Following the test of interaction, the hazard ratio summarizing the treatment effect will be 
estimated separately within each level of a subgroup variable using stratified Cox proportional 
hazards models. Results will be presented in a table and graphically using forest plots. 
The cumulative Aalen-Johansen probability over time will be reported by subgroup in tables 
and plots, apart from for exploratory subgroups. 
4.7 
Interim Analyses  
Due to the early stopping of the trial, the interim analysis did not take place. 
 
 
 
  
 
 
 
  
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4.8 
Changes to Protocol-planned Analyses 
No changes to protocol planned analyses have been made. However, there are some additional 
analyses compared to the protocol. Some additional exploratory endpoints were added in 
response to Scientific Advice from the EMA (Doc Ref: EMADOC-360526170-1176060). 
Some additional exploratory subgroups have been added that may be required for the PMDA 
submission. The protocol suggested producing the plot of the log of negative log of estimated 
survivor functions versus the log of time, this has been updated to a plot of the Schoenfeld 
residuals. The baseline ORBIT-AF bleeding score, HAS-BLED score and CHADS2 score 
have been added to the demographic summary. 
Due to a request of the Japanese Ministry of Heath, Labour and Welfare, the data of the site 
number 20076 is not used in the main analysis. The analysis set is for the main analysis is for 
that reason re-defined as aFAS and aSAF. 
After the decision to end the trial due to lack of efficacy early, the planned analyses are now 
considered exploratory. Formal testing procedures as well as sensitivity analyses were 
deleted. In particular, all analyses on weighted net clinical benefit were deleted. In addition, 
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the time of the decision (19 NOV 2023) will be used as censoring date for the time under 
risk/censoring date. 
5. 
Sample Size Determination 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sample size calculations were derived using the software PASS 13. 


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6. 
Supporting Documentation 
6.1 
Participant disposition 
The number of participants enrolled, randomized and valid for the analysis sets will be 
summarized for each study site by study intervention arm and overall and by study site.  
The number of participants randomized will further be summarized by region and country and 
by study arm and overall.  
The number of sites will be summarized by country.  
The number of participants with important protocol deviations and the number of screen 
failures will be summarized overall and by study arm, country/region and study site. 
The number of participants per important deviation category and validity finding will be 
presented by study arm and overall.  
A disposition summary for each study period (Screening period, Intervention period and 
ET/CEOT period) will be presented summarizing the number of participants starting and 
completing the respective study period, the number of participants discontinuing each period 
and the primary reason for discontinuation. This will be presented overall and for each study 
arm. 
The number of participants completing the overall study will be provided by study 
intervention arm and overall. See Section 4.1.1.5 for the definition of participants who 
completed the study.  
The number and proportion of participants still in the study by visit will be reported. 
Similarly, the number and proportion of participants still on-treatment by visit will be 
reported. 
The distribution of the variables 
• time from randomization to the date of last contact (see Section 4.1.1.5) for 
participants in the aFAS 
• time from first intake of study intervention to the date of last double-blind dose of 
study intervention for participants in the aSAF 
will be summarized using descriptive statistics. The cumulative incidence risk will be 
estimated using cause-specific Aalen-Johansen estimators and reported via both figures 
displaying the cumulative incidence curves and tables containing the cumulative probability 
for the relative days and its 95% CI. 
For the time in study follow-up, the competing risks “death” and “loss to follow-
up/withdrawal of consent” will be accounted for.  
For the time to the date of last double-blind dose of study intervention, the competing risks 
“death”, “early discontinuation of assigned treatment” and “loss to follow-up/withdrawal of 
consent” will be accounted for. 
In addition, the duration of study intervention (treatment) and duration of follow up will be 
reported using standard summary statistics. 
Other details regarding visit adherence (e.g., visit completed in person, by telephone, through 
third party) and completion may be summarized using frequency tables by visit and study 
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6.2 
Demography and other baseline characteristics  
Demographic and baseline data as collected in the CRF will be evaluated descriptively for the 
FAS, by study intervention arm and overall. In the case that the aFAS is a different subgroup 
of participants to the aSAF a subset of tables may be repeated on the aSAF. No statistical tests 
will be performed to compare these characteristics across study arms. 
Demographics and baseline characteristics will also be displayed by risk factors for apixaban 
dosage, current use of single use antiplatelet therapy (vs no current use), and DCT vs. 
conventional study. 
The baseline categories used for subgroup analysis (see Section 4.6.5) will be displayed as 
part of the demographics and baseline characteristics.  
In addition, the following variables will be displayed: 
• Moderate to severe renal dysfunction with eGFR 25-50 ml/min/1.73 m2 (yes/no) 
• Time from AF diagnosis to randomization (≤30 days; >30 days to 3 months; > 3 months) 
• Chronic Kidney Disease (yes/no) 
• Coronary Artery Disease (yes/no) 
• Tobacco/nicotine use (never; former; current) 
• Baseline ORBIT-AF bleeding score (see Section 4.1.1.7) 
• Baseline modified HAS-BLED score (see Section 4.1.1.7) 
• Baseline CHADS2 score (see Section 4.1.1.13, will be used for Japanese Eldercare 
subgroup) 
6.3 
Medical history 
Medical history data will be evaluated by frequency tables, showing the number and 
percentage of participants with medical history findings (i.e., previous diagnoses, diseases, or 
surgeries) that started before signing of the informed consent using MedDRA Primary System 
Organ Class / Preferred Term. This frequency table will be produced for all findings and for 
findings that are considered relevant for the participant’s study eligibility. 
Number and percentages of participants with different AF patterns (Paroxysmal, Persistent, 
Long-standing persistent, Permanent), and of participants in the apixaban dosage groups (0-1 
risk factor vs 2-3 risk factors) will be shown separately. The AF pattern table will be repeated 
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6.4 
Prior and concomitant medication 
For prior and concomitant medications, the following definitions apply: 
• Prior medication: Medication taken before start of the study intervention intake, 
(regardless of when it ended). 
• Concomitant medication at baseline is defined as medication taken at day of 
randomization 
• Concomitant medication: Medication taken during treatment period, i.e., between first 
and last study intervention intake (regardless of when it started or ended).  
Prior and concomitant medication will be coded to Anatomical Therapeutic Chemical (ATC) 
classification codes according to the World Health Organization Drug Dictionary (WHO-
Drug,). 
 
. The number of participants 
taking prior and concomitant medication will be presented by study intervention arm and 
overall using ATC classes and subclasses. All tables will be reported for the aSAF only. The 
concomitant medication table will be repeated for the risk factors for apixaban dosage (0-1, 2-
3) and DCT vs conventional model. The concomitant table will be repeated including 
prohibited medications only. 
Tables in similar format to the concomitant medication table will be produced for the aSAF 
and the three sets of medications below: 
• ongoing prior/concomitant medication at start of study intervention (medications 
stopping on day of first intervention will be excluded), 
• concomitant medication started during the treatment period (medications starting on 
the first day of intervention are included, but medications starting on the last day of 
study intervention are excluded). 
• medications that started after stop of study intervention (medications starting on the 
last day of study intervention will be included). 
Separate tables will be provided for anticoagulants, antiplatelet therapy used and for CYP3A 
inhibitors and inducers for the aSAF. These tables will be repeated for ongoing at start of 
treatment period, started during treatment period and started after treatment period. The 
anticoagulant/antiplatelet table will be repeated for those medications used during the 7 days 
prior to an ISTH major or CRNM or minor bleeding. 
Drugs will be grouped using standardized drug groupings. 
A table of number and percentage of participants on anticoagulants and antiplatelets at 
specific days during the study will be reported, this table will be for the overall study 
intervention arm (i.e., not split by intervention group) and only include participants that 
completed treatment. The study days that will be reported are days 1, 15, 30, 60, 90, 180, and 
365. 
A participant will be defined being on dual antiplatelet therapy at a day if the participant takes 
ASA and any other antiplatelet inhibitor as defined by the respective drug grouping at that 
day. Dosages higher than 325 mg for ASA and routes of administration besides oral 
administration will not be counted for antiplatelet use. The following medications will not 
count as antiplatelet therapy: alprostadil, beraprost and limaprost. 
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6.4.1 
Drug groupings 
Medications of interest are identified by using Drug Groupings and Bayer DTOIs.  
 
 
 
 
 
 
 
  
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7. 
Document history and changes in the planned statistical analysis 
• SAP Version 1.0 completed 01 DEC 2022 
• SAP Version 2.0: The following changes have been made: 
• Analysis using the SAF will utilize the planned study intervention group.  
o Renal dysfunction with eGFR 25-50 ml/min/1.73 m2 (yes/no) label has been 
updated to “moderate to severe renal dysfunction” for demography and other 
baseline characteristics. 
o HAS-BLED score has been updated to modified HAS-BLED score to include 
medical history of anemia for Bleeding, Score 1 in addition to prior major 
bleeding 
o Analyses for change from baseline for Vital Signs deleted as Vital Signs are 
collected only for Visits 1 and 2 (optionally) 
o “Anemia” subgroup: unit for hemoglobin updated from mg/dL to g/dL 
o Section 4.4.2: On-study CRNM bleeding and minor bleeding events, number 
of subjects with more than one bleeding event added to exploratory safety 
endpoints 
o Added section on classification of regions 
o Specific analyses on COVID-19 deleted due to the change of COVID-19 
pandemic. 
o Added clarifications  on definition of CHA2DS2-VASc Score 
o Added rule for Imputation of concomitant medication start dates 
o Removed subgroup cardiac surgery 
o Added primary efficacy outcomes after treatment discontinuation 
o Deleted analyses based on PK; PD and biomarker as they are now done under 
separate cover 
o Add aFAS and aSAF due to request of Japanese MHLW 
o Changes after decision of study stop: 
▪ Additional analyses up until decision of study stop 
▪ Deletion of pre-planned analyses due to study stop, especially all 
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8. 
References 
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