Clinical trial NCT04218266
Conditions: Atrial Fibrillation (AF)
Sponsor: Bayer
Start date: 2020-01-30; Completion date: 2021-10-08
Enrollment: 755 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to try to find the best dose of the new drug BAY 2433334 to give to participants and to look at how well BAY 2433334 works in patients with irregular heartbeat (atrial fibrillation) that can lead to blood clots, stroke and other heart-related complications. In addition researchers want to compare the safety of the study drug to apixaban, a non-vitamin K oral anticoagulant (NOAC) in patients with atrial fibrillation. This study is also done to learn how the drug in this study moves into, through and out of the body. BAY 2433334, works by blocking a step of the blood clotting process in our body and thins the blood and is a so called oral FXIa inhibitor.

Apixaban, works by reducing the production of blood clotting factors in our body and thins the blood and is a so called non-vitamin K oral anticoagulant (NOAC). Thinning the blood can prevent you from blood clots which can cause a stroke.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: Apixaban 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 less than 60 kg, or serum creatinine level of 1.5 mg per dL or more.
Interventions: intervention 1: BAY2433334 intervention 2: Apixaban intervention 3: BAY2433334 matching placebo intervention 4: Apixaban matching placebo
Intervention descriptions: intervention 1: Tablet, taken orally once a day. intervention 2: Capsule, taken orally twice a day. intervention 3: Tablet, taken orally once a day. intervention 4: Capsule, taken orally twice a day.

Protocol documents:
Prot_002.pdf: 
 
Document Type: 
Study protocol 
Official Title: 
Multicenter, randomized, active comparator-controlled, double-
blind, double-dummy, parallel group, dose-finding Phase 2 study to 
compare the safety of the oral FXIa inhibitor BAY 2433334 to 
apixaban in patients with atrial fibrillation 
NCT Number: 
NCT04218266 
Document Date: 
25-Sep-2019 
 


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Title Page
Protocol Title: 
Multicenter, randomized, active comparator-controlled, double-blind, double-dummy, parallel 
group, dose-finding Phase 2 study to compare the safety of the oral FXIa inhibitor 
BAY 2433334 to apixaban in patients with atrial fibrillation 
Protocol Number:
19765
Amendment Number:
not applicable
Compound Number:
BAY 2433334 / INN
Study Phase:
Phase 2b
Short Title:
Phase 2 Program of AntiCoagulation via Inhibition of FXIa by 
the oral Compound BAY 2433334 – Atrial Fibrillation study
Acronym:
PACIFIC-AF
Sponsor Name and 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, USA
Regulatory Agency Identifier Number(s):
IND: 141805
EudraCT: 2019-002365-35
Approval Date: 
25 SEP 2019
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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Sponsor Signatory 
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Medical Monitor (Study Medical Expert) name and contact information can be found in the 
Trial Master File (TMF) 
PPD
PPD


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Table of Contents
Title Page................................................................................................................................... 1
Sponsor Signatory .................................................................................................................... 2
Table of Contents ..................................................................................................................... 3
Table of Tables ......................................................................................................................... 6
Table of Figures........................................................................................................................ 6
1.
Protocol Summary ............................................................................................................ 7
1.1
Synopsis........................................................................................................................... 7
1.2
Schema............................................................................................................................. 9
1.3
Schedule of Activities (SoA) ......................................................................................... 10
2.
Introduction..................................................................................................................... 12
2.1
Study Rationale.............................................................................................................. 13
2.2
Background.................................................................................................................... 13
Disease background.................................................................................................... 13
2.2.1
Treatment Guidelines ................................................................................................. 13
2.2.2
FXIa Inhibition: Mode of Action................................................................................ 13
2.2.3
BAY 2433334............................................................................................................. 14
2.2.4
2.2.4.1
Preclinical / Toxicology Data.................................................................................. 14
2.2.4.2
Clinical Data............................................................................................................ 14
2.3
Benefit / Risk Assessment.............................................................................................. 16
3.
Objectives and Endpoints............................................................................................... 19
4.
Study Design .................................................................................................................... 20
4.1
Overall Design ............................................................................................................... 20
4.2
Scientific Rationale for Study Design ........................................................................... 20
4.3
Justification for Dose..................................................................................................... 21
4.4
End of Study Definition................................................................................................. 22
5.
Study Population............................................................................................................. 22
5.1
Inclusion Criteria ........................................................................................................... 22
5.2
Exclusion Criteria .......................................................................................................... 23
5.3
Lifestyle Considerations ................................................................................................ 24
5.4
Screen Failures............................................................................................................... 24
6.
Study Intervention .......................................................................................................... 25
6.1
Study Interventions Administered ................................................................................. 25
Switching to study intervention and back to open-label anticoagulant...................... 26
6.1.1
6.2
Preparation / Handling / Storage / Accountability.......................................................... 27
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 27
Unblinding.................................................................................................................. 28
6.3.1
6.4
Study Intervention Compliance ..................................................................................... 28
6.5
Concomitant Therapy .................................................................................................... 28
Guidance for Management of Participants who Have Bleeding During the Study.... 29
6.5.1
Guidance for Management of Participants who Have Surgery or 
6.5.2
Percutaneous / Endoscopic Procedures....................................................................... 30
Guidance for Management of Participants who Experience Ischemic Stroke 
6.5.3
During the Study......................................................................................................... 31


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Guidance for Management of Participants who Experience new Myocardial 
6.5.4
Infarction During the Study........................................................................................ 31
6.6
Dose Modification ......................................................................................................... 32
6.7
Intervention after the End of the Study.......................................................................... 32
7.
Discontinuation of Study Intervention and Participant 
Discontinuation / Withdrawal ........................................................................................ 32
7.1
Discontinuation of Study Intervention........................................................................... 32
Temporary Discontinuation........................................................................................ 34
7.1.1
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 34
7.3
Lost to Follow Up.......................................................................................................... 35
8.
Study Assessments and Procedures............................................................................... 35
8.1
Efficacy Assessments .................................................................................................... 36
Exploratory Efficacy Endpoint................................................................................... 36
8.1.1
8.1.1.1
Stroke ...................................................................................................................... 36
8.1.1.2
Systemic Embolism................................................................................................. 36
8.1.1.3
Myocardial Infarction.............................................................................................. 36
8.1.1.4
Cardiovascular Death .............................................................................................. 37
8.2
Safety Assessments........................................................................................................ 37
Primary Safety Endpoint ............................................................................................ 37
8.2.1
8.2.1.1
ISTH Major Bleeding.............................................................................................. 37
8.2.1.2
ISTH Clinically Relevant Non-Major Bleeding...................................................... 37
Secondary Safety Endpoints....................................................................................... 38
8.2.2
8.2.2.1
ISTH Minor Bleeding.............................................................................................. 38
Exploratory Safety Endpoints..................................................................................... 38
8.2.3
8.2.3.1
TIMI Bleeding Definitions...................................................................................... 38
8.2.3.2
BARC Bleeding Definition..................................................................................... 39
Physical Examinations................................................................................................ 40
8.2.4
Vital Signs .................................................................................................................. 40
8.2.5
Electrocardiograms..................................................................................................... 40
8.2.6
Clinical Safety Laboratory Assessments .................................................................... 40
8.2.7
8.3
Adverse Events and Serious Adverse Events ................................................................ 40
Time Period and Frequency for Collecting AE and SAE Information....................... 41
8.3.1
Method of Detecting AEs and SAEs.......................................................................... 41
8.3.2
Follow-up of AEs and SAEs ...................................................................................... 41
8.3.3
Regulatory Reporting Requirements for SAEs .......................................................... 41
8.3.4
Pregnancy ................................................................................................................... 42
8.3.5
Disease-Related Events .............................................................................................. 42
8.3.6
Adverse Events of Special Interest............................................................................. 43
8.3.7
8.4
Treatment of Overdose .................................................................................................. 43
8.5
Pharmacokinetics........................................................................................................... 43
8.6
Pharmacodynamics ........................................................................................................ 44
8.7
Genetics ......................................................................................................................... 45
8.8
Biomarkers..................................................................................................................... 45
8.9
Immunogenicity Assessment ......................................................................................... 46
8.10
Health Economics / Medical Resource Utilization and Health Economics................... 46
9.
Statistical Considerations ............................................................................................... 46
9.1
Statistical Hypotheses.................................................................................................... 46
9.2
Sample Size Determination ........................................................................................... 46


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9.3
Populations for Analyses ............................................................................................... 47
9.4
Statistical Analyses........................................................................................................ 47
General considerations ............................................................................................... 47
9.4.1
Primary endpoints....................................................................................................... 47
9.4.2
Secondary endpoints................................................................................................... 48
9.4.3
Tertiary / exploratory endpoints.................................................................................. 48
9.4.4
Other safety Analyses................................................................................................. 48
9.4.5
Other Analyses ........................................................................................................... 49
9.4.6
9.5
Interim Analyses............................................................................................................ 49
9.6
Independent Data Monitoring Committee (IDMC)....................................................... 50
10. Supporting Documentation and Operational Considerations .................................... 50
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 50
Regulatory and Ethical Considerations ...................................................................... 50
10.1.1
Financial Disclosure ................................................................................................... 51
10.1.2
Informed Consent Process.......................................................................................... 51
10.1.3
Data Protection ........................................................................................................... 51
10.1.4
Committees Structure ................................................................................................. 52
10.1.5
10.1.5.1
Executive Committee.............................................................................................. 52
10.1.5.2
Steering Committee (SC) ........................................................................................ 52
10.1.5.3
IDMC ...................................................................................................................... 52
10.1.5.4
Clinical Events Committee (CEC) .......................................................................... 52
Dissemination of Clinical Study Data ........................................................................ 53
10.1.6
Data Quality Assurance.............................................................................................. 53
10.1.7
10.1.7.1
Data Recording........................................................................................................ 54
10.1.7.2
Monitoring............................................................................................................... 55
10.1.7.3
Data processing ....................................................................................................... 55
10.1.7.4
Missing data ............................................................................................................ 55
10.1.7.5
Audit and inspection................................................................................................ 55
10.1.7.6
Archiving................................................................................................................. 56
Source Documents...................................................................................................... 56
10.1.8
Study and Site Start and Closure................................................................................ 56
10.1.9
Publication Policy....................................................................................................... 57
10.1.10
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 57
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 59
Definition of AE......................................................................................................... 59
10.3.1
Definition of SAE....................................................................................................... 60
10.3.2
Recording and Follow-Up of AE and / or SAE .......................................................... 61
10.3.3
Reporting of SAEs...................................................................................................... 63
10.3.4
Outcome Event Reporting Process Overview ............................................................ 63
10.3.5
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 64
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments................. 65
10.6
Appendix 6: Calculating the Child-Pugh score ............................................................. 66
10.7
Appendix 7: Calculating glomerular filtration rate........................................................ 67
10.8
Appendix 8: Calculating CHA2DS2-VASc score .......................................................... 68
10.9
Appendix 9: Outcome Events: Data Collection............................................................. 68
10.10 Appendix 10: Abbreviations.......................................................................................... 68
11. References ........................................................................................................................ 72


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Table of Tables
Table 1–1: PK, PD and Biomarker sampling........................................................................... 12
Table 3–1: Objectives and Endpoints....................................................................................... 19
Table 4–1: BAY 2433334: dose selection................................................................................ 22
Table 6–1: Study Interventions ................................................................................................ 26
Table 9–1: 90% Confidence Intervals for the ratio of incidence and the corresponding length 
for different scenarios at week 12 ......................................................................... 46
Table 10–1: Protocol-Required Safety Laboratory Assessments............................................. 58
Table 10–2: Liver function monitoring.................................................................................... 66
Table 10–3: Grading of severity of liver disease ..................................................................... 67
Table 10–4: Child-Pugh score.................................................................................................. 67
Table 10–5: CHA2DS2-VASc score......................................................................................... 68
Table of Figures
Figure 1–1: Study design overview............................................................................................ 9
Figure 2–1: Contact activation................................................................................................. 14


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1.
Protocol Summary
1.1
Synopsis
Protocol Title:
Multicenter, randomized, active comparator-controlled, double-blind, 
double-dummy, parallel group, dose-finding Phase 2 study to compare 
the safety of the oral FXIa inhibitor BAY 2433334 to apixaban in 
patients with atrial fibrillation
Short Title:
PACIFIC-AF - Phase 2 Program of AntiCoagulation via Inhibition of 
FXIa by the oral Compound BAY 2433334 – Atrial Fibrillation study
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). Despite 
better benefit-risk profile for NOACs when compared to VKAs, 
patients receiving NOACs continue to have a significant risk for 
developing strokes, systemic embolism and CV death. In addition, there 
is still a significant risk for major bleeding. The inhibition of FXIa is 
expected to not lead to a relevant increase in bleeding and especially 
major bleeding, while maintaining the efficacy benefit of NOACs.
Objectives and Endpoints:
Objectives
Endpoints
Primary

to evaluate that the oral FXIa inhibitor 
BAY 2433334 when compared to 
apixaban leads to a lower incidence of 
bleeding in participants with AF 
Primary Safety Endpoint

composite of International Society on 
Thrombosis and Hemostasis (ISTH) major 
and clinically relevant non-major bleeding
Secondary Safety Endpoints

all bleeding

ISTH major bleeding

ISTH clinically relevant non-major 
bleeding

ISTH minor bleeding
The primary safety estimand is the ratio of the proportions of the composite of ISTH major 
and clinically relevant non-major bleeding within 3 months comparing pooled doses of BAY 
2433334 and comparator drug apixaban in adult participants with AF who have taken at least 
one dose of study medication of BAY 2433334 or comparator drug apixaban, while the 
participant is alive and exposed to study intervention.
The secondary safety estimands are defined following the same approach for the individual 
secondary endpoints, as done for the primary safety estimand.
Overall Design:
This is a multicenter, randomized, active comparator-controlled, double-blind, double-
dummy, parallel-group dose-finding study. 
The study population includes participants with AF documented by ECG evidence with:

CHA2DS2-VASc score ≥ 2 if male or
CHA2DS2-VASc score ≥ 3 if female


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
Indication for treatment with an oral anticoagulant in:

any participant currently not treated with an oral anticoagulant
(e.g. treatment naïve) or alternatively,

participant on a NOAC in case of at least one bleeding risk feature (history of a 
prior bleed within the last 12 months requiring medical attention and / or 
moderate renal dysfunction with eGFR 30-50 ml/min and / or current clinically 
indicated antiplatelet therapy with acetylsalicylic acid [ASA] ≤ 100 mg).
Participants will be screened and randomized within 14 days of screening. 
Stratification will be based on whether participants received a NOAC before study start or 
were not treated with any oral anticoagulant.
If all information is available, participants can be randomized on the day of screening.
Disclosure Statement: This is a parallel group treatment study with 3 arms that is participant
and investigator blinded.
Intervention Model: Parallel
Primary Purpose: Treatment
Number of Arms: 3 arms (2 investigational drug arms and 1 comparator arm)
Number of Participants:
Approximately 800 participants will be screened to achieve 750 evaluable participants for an 
estimated total of 250 evaluable participants per intervention group. More details are available 
in Section 9.2 Sample Size Determination.
Intervention Groups and Duration:
BAY 2433334 is the sponsor’s study drug under investigation. Apixaban is the drug used as 
comparator. The following intervention groups are included in the study:

BAY 2433334 50 mg 

BAY 2433334 20 mg 

Apixaban 5 mg or 2.5 mg, according to label
Study interventions duration and dose regimen are tabulated as follows:
Study Period
Duration
Dose and Frequency
Route of
administration
Screening
2 weeks
Oral
Intervention
12 weeks
BAY 2433334a 50 mg OD 
BAY 2433334a 20 mg OD
Apixabanb 5 mg or 2.5 mg BID
Safety follow-up
2 weeks
Total planned 
number of participants
Total planned study duration (per participant)
750
Between 14 and 16 weeks
Abbreviations: BID = bis in die (twice a day), OD = once a day
a participants receiving BAY 2433334 will also receive the apixaban matching placebo 
b participants receiving apixaban will also receive the BAY 2433334 matching placebo
Data Monitoring Committee:
Yes


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1.2
Schema
Figure 1–1: Study design overview
Abbreviations: BID = bis in die (twice a day), EOT = End of Treatment, N = total number of participants, 
NOAC = Non-Vitamin K oral anticoagulant, OD = once a day, RND = randomization, W = week.
Note: Participants receiving BAY 2433334 will also receive the apixaban matching placebo. 
Participants receiving apixaban will also receive the BAY 2433334 matching placebo.
During the safety follow-up, further therapy (e.g. NOAC) is at discretion of the investigator.


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1.3
Schedule of Activities (SoA)
Study periods 
(Duration)
Screening
(SCR)
(up to 2 weeks 
before RND)
Intervention period
(12 weeks, from BL until EOT visit / ET visit a)
Safety 
Follow-up (SFU)
(14 days after
EOT or ET a)
Visit number
1
2
3
4
5
6
6a
7
Visit type
site
site

site

site
site

Week [W]
Study day and allowed deviations
SCR
-14 1
RND / W0
1
W2
15±4
W4
29±4
W8
57±4
EOT / W12
85±4
ET / Any time
ET+7
W14 / ET+2Ws
99+7 / (ET+14)+7 a
Administrative procedures
Signed informed consent
X
Pharmacogenetic consent
X
Dispense study contact card
X
Inclusion and exclusion criteria
X
X b
Demographics and biometrics
X
Medical history
X
X b
Prior c and concomitant medication
X
X b
X
X
X
X
X
X
Clinical procedures / assessments
12-lead ECG d
X
X b
X
X
Vital signs (BP and HR)
X
X b
X
X
X
Outcome events e
============================continuously===============================
Adverse events 
============================continuously===============================
IxRS
Visit registration / randomization via IxRS
X
X
Laboratory assessments
Safety blood sample 
   X b, f
X f
X
X
X
Pharmacokinetic sampling  g
X
X
X
Pharmacodynamic sampling g
X
X
X
X
Pharmacogenetic sample g
X
Biomarker sample g
X
X
X
Study drug h administration
Study drug h dispensation  
X i
 Study drug h intake at the site g
X
X
no intake
Study drug h collection and accountability
X
X


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Abbreviations: BP = blood pressure, BL = baseline, CRF = case report form, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, EOT = end of treatment, 
ET = early termination, HR = heart rate, IxRS = Interactive Voice/Web Response System, PD = pharmacodynamic(s), PK = pharmacokinetic(s), RND = randomization, 
SCR = screening, SFU = safety follow-up, SoA = Schedule of Activities, W = week
a early termination visit is only applicable to participants who prematurely discontinue intake of study drug; such participants should undergo the ET visit as soon as possible 
after permanent discontinuation of study drug. A safety follow up visit will occur 2 weeks (+ 7 days window) after the day of the premature discontinuation of study drug
(Section 7.1)
b in case screening and randomization are performed on the same day, this procedure does not need to be repeated; CAVE: refer to footnote c
c in case a participant pretreated with NOAC (or treated with another non-oral anticoagulant) has already taken the anticoagulant on the planned day of randomization, 
randomization should be postponed by one day (Section 6.1.1)
d ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals should be used
e outcome events including all bleeding, death, MI and stroke as well as events indicative of a potential outcome (Section 10.1.5.4) need to be reported on dedicated forms in 
the eCRF on an ongoing basis, even if the participant is permanently discontinued from study treatment
f  creatinine and eGFR values, as well as current AST and ALT values, must be available at randomization; if they are not available from screening central lab, the respective 
values should be determined in local laboratories prior to randomization
g refer to Table 1–1
h “Study drug” refers to “study intervention”, as defined in Section 6.1.
i at each contact the participants should be instructed regarding study drug compliance.


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PK, PD and Biomarkers sampling
An overview of the PK, PD and Biomarkers sampling is shown in Table 1–1.
Table 1–1: PK, PD and Biomarker sampling
Day 1
(Visit 2)
Week 4 a
(Visit 4)
Week 12 b
(Visit 6) / or ET
Pre-dose 
Day 1
Pre-dose
0.5-1.5 h 
post-dose
2-4 h c
post-dose
4-12 h c
post-dose
Prior to dose d
of open-label 
anticoagulant
PK e
X
X
X
X
X
PD e
X
X
X
X
X
X
Biomarkers 
Plasma 
X
X
Biomarkers 
Serum 
X
X
Genetics
X
Abbreviations: ET = Early termination, PD = pharmacodynamic(s), PK = Pharmacokinetic(s)
a at visit 4: in order to collect pre-dose samples for PK and PD, participants should take their study drug at the site
only after blood sampling. The investigator must record the time when the study drug is taken at the site. A 
phone call to remind the participants is recommended
b at visit 6: no study drug intake should take place on the day of this visit anymore. The last intake of study drug is 
occurring on the previous day. A phone call to remind the participants is recommended
c the minimum time between the 2-4 h and the 4-12 h samples should be at least 1 hour
d sampling should occur prior to the intake of an open-label anticoagulant that is supposed to be started instead of 
the blinded study drug after the end of the study drug treatment (refer to Section 6.1.1)
e if study drugs will be temporarily stopped, PK / PD blood samples should only be obtained if the study drugs
have been restarted and sustained for at least 4 days, see Section 7.1.1
The exact time of PK, PD and biomarker sampling needs to be recorded, as well as the time of the most 
recent / associated study drug intake (i.e. on the PK / PD sampling day, as well as on the day before that).
2.
Introduction
BAY 2433334 is a direct, potent inhibitor of activated coagulation factor XI (FXIa) planned 
to be developed for 3 main indications:
1.
Prevention of stroke and systemic embolism in patients with AF (cardioembolic stroke 
prevention) 
2.
Secondary stroke prevention in patients after an ischemic stroke (large artery, lacunar 
stroke, or embolic stroke of undetermined source [ESUS]) (non-cardioembolic stroke 
prevention)
3.
Prevention of major adverse cardiac events (CV death, MI, stroke) in patients after an
acute myocardial infarction (AMI)
Study 19765 will be a 3-month treatment duration Phase 2 study and will test BAY 2433334 
against apixaban (NOAC), a FXa inhibitor, in participants with AF.
The current clinical development of BAY 2433334 (FXIa inhibitor) includes two additional 
Phase 2 studies in participants with non-cardioembolic ischemic stroke (study 19766) and in
participants with AMI (study 20603). These two studies are planned to have a treatment 
duration of 6 to 12 months, testing BAY 2433334 against placebo on top of antiplatelet 
therapy.


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Each individual study will have its own study objectives. However, in order to reach and draw 
conclusions concerning safety in general, and especially bleeding, the program is designed to 
pool the data across the three studies to help further characterize safety and efficacy.
2.1
Study Rationale
This Phase 2 study will explore two doses of BAY 2433334 in order to determine a lower risk 
for bleeding when compared to apixaban (a NOAC) as well as the dose that is safe and can be 
used in a Phase 3 study in the same indication.
Current treatment guidelines recommend the use of long-term oral anticoagulant therapy such 
as VKAs, or NOACs.
Despite a better benefit-risk profile for NOACs when compared to VKAs, patients receiving 
NOACs continue to have a significant risk for developing strokes, systemic embolism and CV 
death. In addition, even though NOACs lead to less intracranial hemorrhage compared to 
VKAs, there is still a significant risk for major and clinically relevant non-major bleeding.
BAY 2433334, as an oral FXIa inhibitor, is expected to show a benefit in reducing the risk for 
stroke in patients with AF in Phase 3. At the same time BAY 2433334 is expected to have a 
low bleeding risk. This is based on the available preclinical data, data from patients with 
inherited FXI deficiency and first clinical data from 2 Phase 2 proof-of-concept studies in 
participants undergoing total knee replacement (please see Section 2.3).
BAY 2433334 is therefore an attractive candidate to evaluate as a potential replacement for 
NOAC therapy in patients with AF.
2.2
Background
Disease background
2.2.1
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. 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 17% among those over 80 years of age. As a consequence of the ageing population, the 
prevalence of AF is predicted to rise.
Patients who have AF are known to have an increased risk of stroke due to a predisposition to 
the development of atrial thrombi. Full anticoagulation with vitamin K antagonists was the 
recommended therapy until the introduction of NOACs. 
Treatment Guidelines 
2.2.2
Current guidelines AHA / ACC / HRS 2014 (January et al. 2014), as well as the focused 
update AHA / ACC / HRS 2019 (January et al. 2019), ESC 2016 (Kirchhof et al. 2016), and 
CHEST 2018 (Lip et al. 2018) 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.
FXIa Inhibition: Mode of Action 
2.2.3
BAY 2433334 is a 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 


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positive feedback loop through activation by thrombin. 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 pathway. 
FXIa inhibition by BAY 2433334 may offer the opportunity to prevent thrombosis without 
interference with primary hemostasis and to thereby set a paradigm shift compared to 
Vitamin K antagonists and Non-Vitamin K oral anticoagulants (NOACs). 
Figure 2–1: Contact activation
Source: adapted from (Chen et al. 2014)
BAY 2433334
2.2.4
2.2.4.1
Preclinical / Toxicology Data
Preclinical data using FXI-deficient mice or studies using pharmacological inhibition of FXIa 
in different animal models, for example a FeCl-induced thrombosis model, have shown a 
benefit in reduced thrombus formation. The data indicate that higher efficacy might be 
possible to achieve when compared to 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 BAY 2433334 was given on top of dual antiplatelet therapy.
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). 
2.2.4.2
Clinical Data
So far, 156 healthy male subjects have received treatment with BAY 2433334 in doses 
ranging from 5 mg to 150 mg after single dosing and up to 100 mg once daily in multiple 
dose settings. 


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Safety
The single dose escalation study (study 19372) with BAY 2433334 is clinically completed. 
Single doses of 5 mg to 150 mg have been investigated, as well as a food effect study part 
with 25 mg. No clinically relevant signs or symptoms of bleeding were observed.
The multiple dose escalation study (study 19665) has also been clinically completed and 
evaluation is still ongoing. Therefore, the results are preliminary. It consisted of 3 parts: part 
A, wherein 25 mg, 50 mg and 100 mg BAY 2433334 were given once daily over 9 
consecutive days; part B, where 25 mg were given twice daily; and part C, where a 
midazolam interaction was investigated with 25 mg and 75 mg BAY 2433334.
Overall, BAY 2433334 was safe and well tolerated. More details on safety can be found in the 
Investigator’s Brochure.
Pharmacodynamics 
The following pharmacodynamic parameters were investigated in both the FiM study (study 
19372) and MDE study (study 19665): aPTT, FXI activity (AXIA assay), and FXI 
concentration. Bleeding time was investigated after single dose administration only (study 
19372).
A dose dependent prolongation of aPTT was observed after single dosing with a close direct 
correlation between aPTT and plasma concentration:

In the 25 mg OD dose step of the multiple dose (MD) study 19665 a prolongation of 
aPTT of ~50% (mean, compared to baseline) after single dosing and ~65% (mean) at 
steady state was seen. 

In the 50 mg OD dose step of the MD study 19665 a prolongation of aPTT of ~75% 
(mean, compared to baseline) after single dosing and ~105% (mean) at steady state 
was seen. 

In the 100 mg OD dose step of the MD study 19665 a prolongation of aPTT of ~85% 
(mean, compared to baseline) after single dosing and ~120% (mean) at steady state 
was seen. 
FXI activity (AXIA assay) is inhibited by a mean of ~85% after 25 mg single dose (SD) and a 
mean of ~95% (25 mg OD) at steady state. After 50 mg and 100 mg SD and MD, activated 
FXI activity is inhibited by a mean of > 95% both after first dose and at steady state. The 
duration of the inhibition of FXI activity (AXIA assay) is dose dependent. Complete 
inhibition was reported for 12 hours for 50 mg at steady state and this is prolonged up to 24 
hours for 100 mg at steady state.
Pharmacodynamic parameters aPTT and FXI activity correlated well with observed plasma 
concentrations of BAY 2433334.
No relevant changes of FXI concentration or PT were observed in either study. 
No clinically relevant changes in bleeding time were observed after single dose application. 
Pharmacokinetics
The key pharmacokinetics features of BAY 2433334 based on current available data and 
when administered as IR tablets can be summarized as follows. 

BAY 2433334 is absorbed with a median time to reach maximum plasma concentration 
(tmax) of 2 to 4 hours (fasted state).


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
There is no hint for any deviation from dose-proportionality found for doses between 
5 mg and 150 mg.

Relative bioavailability of BAY 2433334 administered as IR tablet amounted to 
approximately 89.5% with regard to AUC and of 86.0% with regard to Cmax, compared as 
oral solution

A high-fat, high-calorie meal has minor effect on the AUC of 25 mg BAY 2433334 
(decrease of 12.4%) and results in a reduced absorption rate (31.4% decrease in maximum 
plasma concentration [Cmax] and 2.5 h prolongation in tmax).

The variability was low to moderate for AUC and Cmax (%geoCV approx. 15 to 30%).

The degree of accumulation of BAY 2433334 is low regarding Cmax,md or AUCτ,md after 
once daily multiple dosing with RACmax between 1.4 and 1.6 and RAAUC between 1.5 and 
1.7.

Pharmacokinetics were linear over time. 

The metabolite M-10 (BAY 2826102, formed by amide hydrolysis of the central amide 
and subsequent N-acetylation) is expected to be a main compound in human plasma with a 
metabolic ratio to parent drug of approx. 24 to 37%. This metabolite is not 
pharmacologically active.

Terminal half-life is 14.5 to 16.0 hours supporting once daily dosing.

Low apparent oral plasma clearance (CL/F) of about 3.19-4.27 L/h was observed in 
geometric mean (corresponding to a blood clearance/F of 4.54-6.07 L/h).

Based on preliminary evaluation of the 50 mg dose step in the multiple dose escalation 
study (study 19665) renal elimination was low (15%).  

Based on the preliminary ethnic evaluation up to the 50 mg dose step of single and 
multiple dose in Caucasians (study 19665) and Japanese (study 19667), there is no large 
difference in PK between races though geometric mean of AUC and Cmax in Japanese 
were slightly higher than in Caucasians. 

Based on preliminary evaluation the strong CYP3A4 inhibitor itraconazole increased 
BAY 2433334 exposure by 100% (2-fold) while maximum plasma concentrations were 
not changed (study 19664). Terminal half-life was prolonged from 16 to 29 hours.
More details can be found in the Investigator’s Brochure.
2.3
Benefit / Risk Assessment
The FXIa inhibitor BAY 2433334 is an oral anticoagulant that is planned to be developed for 
patients with AF, acute myocardial infarction as well as non-cardioembolic ischemic stroke. 
This Phase 2 study will be the first study investigating BAY 2433334 in patients with AF. 
Once daily doses of 20 mg and 50 mg will be tested in the study.
BAY 2433334 as an FXIa inhibitor is expected to have a lower risk for clinically significant 
bleeding when compared to other oral anticoagulants (VKAs and NOACs), while leading to
an efficacy benefit.
The expected clinical profile of BAY 2433334 is based on preclinical data as well as clinical 
data from FXI-deficient individuals and other FXI-targeting compounds. The separation of 
bleeding and efficacy might be explained by the fact that inhibition of FXIa affects the 


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intrinsic and propagation pathways, but keeps the extrinsic pathway unaffected, which is 
activated in case of vessel injury. 
At this stage of development there is no clinical evidence available yet to confirm the efficacy 
benefit of BAY 2433334. However, the data supporting that this compound is expected to 
lead to prevention of thrombosis events in the intended indications are the following: 

FXI-deficient knockout mice are protected from thrombosis. In addition, in various 
thrombosis models in rabbits, BAY 2433334 demonstrated reduced thrombus weight, 
and this was seen when given with or without antiplatelets. While therapeutic doses of 
NOACs lead to a 20-30% reduction in thrombus formation in the same animal models, 
BAY 2433334 was able to reduce the thrombus formation by up to ~ 90%.

In people 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. 

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.

A first proof of concept targeting FXI as anticoagulant has been shown by an FXI 
Antisense Oligonucleotide. Reducing FXI levels in patients undergoing total knee 
arthroplasty (TKA) led to an improved prevention of postoperative venous 
thromboembolism (VTE), when compared to enoxaparin. Based on modeling 
approaches, the inhibition levels of FXIa activity in the study can be achieved with the 
20 mg and 50 mg doses of BAY 2433334 (see also the Investigator’s Brochure).

Phase 1 studies in healthy volunteers are not able to assess efficacy. However, after 
multiple dosing the highest planned dose of 50 mg to be tested in Phase 2 lead to 
inhibition of FXI activity by a mean of > 95% and complete inhibition during 12 hours
of the day. This was combined with a mean prolongation of aPTT of ~105%. 
At this stage of development, the safety profile has not been established. The following 
information related to safety, as well as potential risks for participants, is available:
1. Bleeding is the main safety concern related to antithrombotic therapies. For an
inhibitor of FXIa a lower bleeding risk is expected. Data supporting this are listed 
below: 

FXI-deficient knockout mice do not show a bleeding phenotype. In addition, in the 
thrombosis animal models no increase in bleeding time (gum and ear) was 
reported. Importantly, no further increase in bleeding time was seen when BAY
2433334 was given on top of dual antiplatelet. In addition, in the toxicology 
studies no relevant bleeding was reported for up to 37-fold the expected human
exposure of the planned 50 mg multiple dose in participants.

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.


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
In the completed and ongoing Phase 1 studies conducted with BAY 2433334, no 
relevant bleeding events were reported so far.
A risk for bleeding cannot be excluded in participants with AF included in the Phase 2 
study. Therefore, bleeding will be closely monitored in the study and will be 
adjudicated by an independent clinical event 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 liver. Based on this, participants with a > 2.5 ALT or AST increase will be 
excluded from the study and liver findings during the study will be monitored and are 
defined as AE of special interest in the study. 
3. Single doses of BAY 2433334 up to 150 mg and multiple doses up to 100 mg once 
daily for 9 days have been safe and well tolerated. This included general safety, 
laboratory, vital signs and ECGs. The doses were 2 and 3-fold higher than planned in 
this Phase 2 study.
4. Based on preliminary evaluation the strong CYP3A4 inhibitor itraconazole increased 
BAY 2433334 exposure by 100% (2-fold) while maximum plasma concentrations 
were not changed (study 19664). Terminal half-life was prolonged from 16 to 29
hours. Therefore, strong CYP3A4 inhibitors and inducers should not be taken 
concomitantly with BAY 2433334 in this study until further information is available.
Participants assigned to BAY 2433334 will not receive standard of care. In order to address 
the potential risk for stroke in case of undertreatment, the study design follows the 
recommendation from the European Guideline and limits the treatment duration to 3 months. 
During this period the general risk for stroke should be < 1%. In addition, the study 
investigates only the 2 higher doses of 20 mg and 50 mg and not the lower dose of 10 mg, 
which will be tested only in the 2 placebo-controlled studies in participants after an acute 
myocardial infarction or non-cardioembolic ischemic stroke. 20 mg and 50 mg as the selected 
doses will provide significant FXIa inhibition over the 24-hour period > 60% at trough and 
mean > 75%. Based on preclinical data these inhibition levels should lead to an even higher 
anticoagulant effect than reached with available anticoagulants.
In order to ensure the safety of the participants during the study conduct an independent data 
monitoring committee (IDMC) will monitor the safety of all participants enrolled in all 3 
Phase 2 studies with a focus on bleeding and general safety. In addition, a focus of the IDMC 
review will be on any stroke occurring during the study.
Several Factor XI (FXI) and activated Factor XI (FXIa) inhibitor assets are currently in 
development as antithrombotics, including antisense oligonucleotides (ASOs), antibodies and 
small molecules (SMOLs).
In summary, in this Phase 2 study participants with AF will receive for the first time 
BAY 2433334. The main objective of the study is to explore that BAY 2433334 will lead to 
less bleeding when compared to a NOAC (apixaban). An additional objective is to guide dose 
selection for Phase 3. Currently, available preclinical and clinical data from the ongoing 
studies regarding the key risks do not indicate an unfavorable risk profile for BAY 2433334. 
The overall risk is anticipated to be acceptable in the context of the drug benefit. More 
detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of BAY 2433334 may be found in the Investigator’s Brochure.


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3.
Objectives and Endpoints
Objectives and endpoints (primary, secondary and exploratory) of the study are reported 
below, in Table 3–1. Please refer to Section 9.4 for further details.
Table 3–1: Objectives and Endpoints
Objectives
Endpoints
Primary

to evaluate that the oral FXIa inhibitor 
BAY 2433334 when compared to 
apixaban leads to a lower incidence of 
bleeding in participants with AF 
Primary Safety Endpoints

composite of ISTH major and clinically 
relevant non-major bleeding 
Secondary Safety Endpoints

all bleeding

ISTH major bleeding

ISTH clinically relevant non-major 
bleeding

ISTH minor bleeding
Exploratory Safety Endpoints

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

BARC bleeding definition type 2, 3, 5

BARC bleeding definition type 3, 5 

BARC bleeding definition type 1, 2, 3, 5
Exploratory

to explore the efficacy of BAY 2433334 
compared to apixaban in reducing the 
risk for cardiovascular events (CV 
death, MI, stroke, systemic embolism) 
in participants with atrial fibrillation

to explore additional pharmacokinetic 
and pharmacodynamic parameters, 
biomarkers and genetics

to further investigate the study 
intervention (i.e. mode-of-action-related 
effects and/or safety) and to further 
investigate pathomechanisms deemed 
relevant to cardiovascular diseases and 
associated health problems
Exploratory Efficacy Endpoint

composite as well as individual 
components of CV death, MI, ischemic 
stroke, systemic embolism

all-cause mortality
Other Exploratory Endpoints

FXIa inhibition, aPTT, D-Dimer

Pharmacokinetics

Various biomarkers (e.g. diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers)
Abbreviations: AF = atrial fibrillation, aPTT = activated partial thromboplastin time, BARC = Bleeding Academic 
Research Consortium, CV = cardiovascular, ISTH = International Society on Thrombosis and Hemostasis, 
MI = myocardial infarction, TIMI = thrombolysis in myocardial infarction
The primary safety estimand is the ratio of the proportions of the composite of ISTH major 
and clinically relevant non-major bleeding within 3 months comparing pooled doses of BAY 
2433334 and comparator drug apixaban in adult participants with AF who have taken at least 
one dose of study medication of BAY 2433334 or comparator drug apixaban, while the 
participant is alive and exposed to study intervention.
The secondary safety estimands are defined following the same approach for the individual 
secondary endpoints as done for the primary safety estimand. Please also refer to Section 9.4
for further details.


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4.
Study Design
4.1
Overall Design
Study 19765 is a multicenter, randomized, active-comparator controlled, double-blind, 
double-dummy, parallel group, dose-finding Phase 2 study. The overall study design is 
depicted in Figure 1–1.
Approximately 750 participants ≥ 45 years of age, from approximately 115 study centers 
worldwide will be randomized to 1 of the 3 arms (250 participants per arm): 2 investigational 
drug arms (BAY 2433334) and 1 active comparator arm (apixaban), in addition to their 
potential background therapy (for details see Section 6.5). Stratification will be based on 
whether participants received a NOAC before study start or were not treated with any oral 
anticoagulant.
The planned study duration will be 14-16 weeks, consisting of:

Screening period (visit 1 until visit 2): 2 weeks (participants will be screened and 
have to be randomized within 2 weeks of screening. If all information is available, a 
participant can be randomized on the day of screening (visits 1 and 2 are combined).

Treatment period (from visit 2 through visit 6 [EOT] or visit 6a [ET]): 12 weeks

Safety follow-up (visit 7 [SFU]): 14 days (+ 7 days) after EOT or ET.
Study visits will take place as visits at the study sites and telephone calls. Visits at the study 
sites take place at screening and randomization (visit 1 and visit 2), at week 4 (visit 4) and 
week 12 (i.e. EOT, visit 6). 
Telephone calls will take place at week 2 (visit 3), week 8 (visit 5), as well as 2 weeks after 
the EOT visit for participants who will take study intervention until the planned EOT (i.e. 
SFU, visit 7).
For participants who prematurely discontinue from study intervention, an early termination 
(ET) visit (visit 6a) will take place as soon as possible as visit at the study sites. Telephone 
calls take place 14 days after the ET visit (i.e. SFU, visit 7). Further details are reported in 
Section 7.1.
Details of study procedures and their timing are summarized in the SoA.
4.2
Scientific Rationale for Study Design
The Phase 2 study in stroke prevention in AF will be a dose ranging study with the objective 
to identify the dose to be tested in Phase 3. The study aims at showing that the oral FXIa 
inhibitor BAY 2433334 when compared to apixaban (a NOAC, FXa inhibitor, 2.5 mg / 5 mg 
doses according to label) leads to a lower incidence of ISTH major and clinically relevant 
non-major bleeding. The Phase 2 study will not allow for an assessment of efficacy versus 
apixaban due to the limited number of efficacy events within a 3 months treatment period 
(< 0.5% at 3 months). The study is designed in line with the current European Guideline on 
clinical investigation of medicinal products for prevention of stroke and systemic embolic 
events in participants with non-valvular atrial fibrillation (EMA 2014).
Study 19765 is a multicenter, randomized, active comparator-controlled, double-blind, 
double-dummy, parallel group, dose-finding Phase 2 study in 750 participants (250 
participants per arm) with atrial fibrillation. The study will apply the principles of 


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randomization and double-blinding in order to prevent bias in the inclusion of participants or 
reporting of safety or efficacy events.
In addition, the study will follow a parallel group design in order to prevent bias in the data 
due to e.g. different sites in different countries enrolling at different timepoints into the study 
or in case of any seasonally related differences. There does not appear to be a requirement for 
a dose escalation approach, because based on the available preclinical and clinical data for 
BAY 2433334 there are no safety concerns related to the highest dose of 50 mg once daily 
tested in the study. 
The study will include any participant who is not treated with on oral anticoagulant at study 
entry and includes e.g. participants newly diagnosed with AF and who are treatment-naïve. In
addition, participants on a NOAC can be enrolled, but only if they have ≥ 1 additional 
bleeding risk feature, because participants on a NOAC are expected to have a significantly 
lower risk for bleeding when compared to untreated participants, as they were already 
exposed to an anticoagulant before. Participants on Vitamin K antagonists (VKA) are 
excluded from the study, as the switch from VKA to study drug may lead to bleeding events 
related to this switch and not to the assigned treatment.
4.3
Justification for Dose
The study will test the once daily doses of 20 mg (mid dose) and 50 mg (high dose) of BAY 
2433334. 
The selection of the high dose in this study was not limited by the safety and tolerability data 
from toxicology studies, nor from the results of the human Phase 1 studies conducted in 
healthy volunteers.  Single doses up to 150 mg or multiple doses up to 100 mg for 9 days 
were tested in the Phase 1 studies. Due to these favorable results, the dose selection for the 
Phase 2 studies was primarily based on pharmacodynamic assays (preclinical and Phase 1 
studies) including aPTT and FXIa activity. 
Modeling approaches of the available Phase 1 data were used to predict the doses for Phase 2 
studies with the goal to select doses that cover a broad range of inhibition of FXIa and lead to 
different degrees of increases in aPTT (Table 4–1).

The high dose of 50 mg was chosen to reach significant inhibition of FXIa and to 
achieve maximum efficacy. However, this dose should not lead to a complete 
inhibition of FXIa during the majority of the day. The selected 50 mg dose is expected 
to lead to a mean FXIa activity of 7 % with FXIa activity < 10% during 14 hours of 
the day. aPTT is predicted to increase to 1.4 at trough and 1.9 at peak. 

The mid dose of 20 mg was selected as the second dose to reflect a dose linear 
response related to FXIa inhibition. This dose leads to a mean FXIa activity of 23%

The low dose of 10 mg was not selected for this study, where BAY 2433334 is 
compared against standard of care, the NOAC apixaban. The rationale for this is to 
prevent participants from possible underdosing. This dose will be tested only in the 
placebo-controlled studies in participants after an acute myocardial infarction (study 
20603) or non-cardioembolic ischemic stroke (study 19766). For 10 mg the expected 
mean FXIa activity is 45% and aPTT is increased to 1.1 at trough and 1.3 at peak.


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Table 4–1: BAY 2433334: dose selection
Humans, multiple dose, 
modelled
OD dosing
Predicted FXIa activity 
Predicted aPTT increase
Trough %
Peak %
Mean %
Trough %
Peak %
50 mg
13
3
7
1.4
1.9
20 mg
40
11
23
1.2
1.5
Abbreviations: aPTT = activated partial thromboplastin time, OD = once a day
4.4
End of Study Definition
A participant is considered to have completed the study if he / she has completed all phases of 
the study including the last scheduled study visit.
The end of the study is defined as the date of the last visit of the last participant in the study 
globally.
5.
Study Population
The study will enroll adult participants with non-valvular AF at moderate to high risk for 
future thromboembolic events and who therefore qualify for anticoagulant therapy.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Male and female participants are eligible to be included in the study only if all of the 
following criteria apply:
Age
1.
Participant must be 45 years of age or older at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2.
Participant with AF documented by ECG evidence* with

CHA2DS2-VASc score ≥ 2 if male or
CHA2DS2-VASc score ≥ 3 if female

Indication for treatment with an oral anticoagulant in 
any participant currently not treated with an oral anticoagulant 
(e.g. treatment naïve) or alternatively,
participant on a NOAC in case of at least one bleeding risk feature 
(history of a prior bleed within the last 12 months requiring medical 
attention and / or moderate renal dysfunction with eGFR 30-50 ml/min 
and / or current clinically indicated antiplatelet therapy with ASA 
≤100 mg)
                                                
* AF should be either documented on the baseline 12-lead ECG, or otherwise within the last 12 months on a 
  previous 12-lead ECG or 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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Informed Consent
3.
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. Written informed consent has to be signed 
before any study procedure.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Mechanical heart valve prosthesis 
2.
Any degree of rheumatic mitral stenosis or moderate-to-severe, non-rheumatic mitral 
stenosis
3.
Atrial fibrillation due to a reversible cause, participants in sinus rhythm after 
successful ablation, or plan for cardioversion or ablation during study conduct
4.
Stroke within the last 30 days of screening
5.
Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg) at randomization 
6.
Active bleeding; known bleeding disorder
7.
Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, 
cirrhosis) or hepatic insufficiency classified as Child-Pugh B or C (see Section 10.6), 
or ALT/AST > 2.5 x the upper limit of normal, measured between screening and
randomization
8.
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, calculated by 
Modification of Diet in Renal Disease (MDRD) formula (see Section 10.7),
determined between screening and randomization
9.
Major surgery during the last 30 days or planned major surgery or intervention 
within study period (e.g. carotid endarterectomy, coronary artery bypass grafting)
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 labeling for 
apixaban.
Prior / Concomitant Therapy
12. Requirement for chronic anticoagulation (for a different indication than AF e.g. 
mechanical heart valve or cardiac thrombus) or antiplatelet therapy (up to 100 mg 
ASA is allowed). Anticipated need for chronic (more than 4 weeks) therapy with 
NSAIDs
13. Treated with a Vitamin K antagonist in the 30 days prior to screening
14. Concomitant use of any of the following therapies within 14 days (or at least five 
half-lives of the active substance whatever is longer) before randomization and first 
study intervention administration (see Section 6.5):


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
Strong inhibitors of cytochrome P450 isoenzyme 3A4 (CYP3A4) e.g. human 
immunodeficiency virus protease inhibitors, systemically used azole-antimycotic 
agents, clarithromycin or telithromycin

Strong inducers of CYP3A4, e.g. phenytoin, carbamazepine, phenobarbital, 
rifampicin or St. John’s wort.
Other exclusions
15. 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 
16. Women of childbearing potential (women are considered of childbearing potential if 
they are not surgically sterile or postmenopausal, defined as amenorrhea for 
> 12 months). Male participants not willing to use condoms when sexually active 
with a woman of childbearing potential
17. Close affiliation with the investigational site or sponsor; 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. 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
19. Any condition or therapy, which would make the participant unsuitable for the study 
(e.g. non-compliance, dysphagia with inability to swallow study intervention) or 
otherwise vulnerable (e.g. participant in custody by order of an authority or a court)
or life expectancy < 3 months.
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.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. 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 not 
be rescreened. 


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Interventions Administered
The following study interventions will be administered in the study:

BAY 2433334: sponsor’s study drug under investigation

Placebo to BAY 2433334

Apixaban: marketed product used as comparator 

Placebo to apixaban
BAY 2433334 is supplied in various strengths as film-coated, immediate-release tablets with 
identical appearance. BAY 2433334 is taken orally once a day in the morning, preferably 
around the same time each day. The immediate-release tablets will be provided as pink, oval, 
film-coated tablets containing either 5 mg, 15 mg or 25 mg of BAY 2433334 (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 gelatin hard capsules with identical 
appearance. 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 less 
than 60 kg, or serum creatinine level of 1.5 mg per dL or more. Participants have to receive 
the dose of apixaban according to the label and the respective dosage of apixaban for the 
entire duration of the study will be determined based on the values current at the 
randomization visit.
The study interventions (tablets and capsules) are not to be broken, halved or crushed, and 
should be swallowed whole with a glass of water. Both study interventions can be taken 
irrespective of food intake.
Matching placebos for both BAY 2433334 and apixaban are supplied in the same way.
For apixaban / placebo one capsule in the morning and one capsule in the evening are to be 
taken, and in addition for BAY 2433334 / placebo two tablets from two different bottles (one 
tablet from each bottle) are to be taken in the morning only.
Missed study intervention dose
The planned double-blind treatment phase starts at randomization and ends at or when study 
intervention is permanently discontinued. Study intervention intake will start as soon as 
possible after randomization (day 1) and is expected to continue through the end of the 
planned treatment.
If a dose of BAY 2433334 is missed, the participant should take a dose immediately on the 
same day.
If a dose of apixaban is missed, the dose should be taken as soon as possible on the same day 
and a twice daily administration should be resumed. The dose should not be doubled to make 
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Table 6–1: Study Interventions
Arm name
BAY 2433334
high dose
BAY 2433334
medium dose
Apixaban
Intervention 
Name
BAY 2433334
Placebo 
to 
apixaban
BAY 2433334
Placebo 
to 
apixaban
Apixaban
Placebo to 
BAY 
2433334
Type
drug
placebo
drug
placebo
drug
placebo
Dose 
formulation
tablet
capsule
tablet
capsule
capsule
tablet
Unit dose 
strengths
25 mg
NA
5 mg and 
15 mg
NA
2.5 mg or 
5 mg
NA
Dosage 
Level(s)
50 mg
NA
20 mg
NA
2.5 mg or 
5 mg
NA
Frequency
Once a day in 
the morning
Twice a 
day
Once a day in 
the morning
Twice a 
day
Twice a 
day
Once a 
day in the 
morning
Route of 
Administration
oral
oral
oral
oral
oral
oral
Use
experimental
placebo
experimental
placebo
active 
comparator
placebo
IMP/AxMP
IMP
IMP
IMP
IMP
IMP
IMP
Packaging and 
Labeling
HDPE bottles 
with 
desiccant 
capsule
blisters
HDPE bottles 
with 
desiccant 
capsule
blisters
blisters
HDPE 
bottles with 
desiccant 
capsule
Abbreviations: AxMP = auxiliary medicinal product, HDPE = high-density polyethylene, IMP = investigational 
medical product, NA = not applicable
All study interventions will be labelled according to the requirements of local regulations.
For all administered study interventions, a system of numbering in accordance with all 
requirements of Good Manufacturing Practice (GMP) will be used, ensuring that each dose of 
study intervention can be traced back to the respective bulk batch of the ingredients.
A complete record of batch numbers and expiry dates of all administered study interventions 
as well as the labels will be maintained in the sponsor’s study file.
Switching to study intervention and back to open-label anticoagulant
6.1.1
As per inclusion criterion, when being enrolled, study participants may be treated with a 
NOAC or not treated with any oral anticoagulant. Hence participants treated with any VKA
are not eligible.
After the participant is determined to be eligible for the study during the screening period, he 
or she should be instructed to discontinue any treatment with NOAC or any other non-oral 
anticoagulant, to allow that the last intake of the open-label NOAC (or non-oral 
anticoagulant) will occur on the day prior to randomization. Hence, a participant should not
take 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 his open-label NOAC (or other non-oral 
anticoagulant) on the planned day of randomization, randomization should be postponed by a 
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 


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recommended procedure is to start with an open-label anticoagulant on the next day following 
the last day of intake of the blinded study inter (i.e. on the day of the end of treatment visit, as 
no study intervention intake should take place on the day of this visit anymore).
6.2
Preparation / Handling / Storage / 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 appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the Investigator Site File. 
6.3
Measures to Minimize Bias: Randomization and Blinding
All participants will be centrally assigned to randomized study intervention using an 
Interactive Web Response System (IWRS). To accomplish random assignments, computer-
generated randomization lists specified by the sponsor’s responsible statistician will be 
prepared by Randomization Management at the study sponsor. The randomization lists are 
provided to an IWRS vendor. Before the study is initiated, the log in information & directions 
for the IWRS will be provided to each site.
The randomization will be stratified based on whether participants received a NOAC before 
study start or were not treated with any oral anticoagulant.
Study intervention will be dispensed at the study visit 2, as summarized in SoA. 
Returned study intervention should not be re-dispensed to the participants.
Participants will be randomly assigned in a [1:1:1] ratio to receive study intervention. 
Investigators will remain blinded to each participant’s assigned study intervention throughout 
the course of the study.
Tablets containing 5 mg, 15 mg or 25 mg of BAY 2433334 and matching placebo are 
identical in appearance and packed in bottles labeled with a unique number which will be pre-
printed on each bottle. Capsules containing apixaban and corresponding placebo are identical 
in appearance and packed in blisters labeled with a unique number which will be pre-printed 
on each blister. In order to achieve the double blind, double dummy design, participants will 
be provided with bottles and blisters either with active drugs (BAY 2433334 or apixaban), or 
placebo depending on the randomization outcome.


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Unblinding
6.3.1
The IWRS 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 make every 
effort 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 must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable.
BAY 2433334 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. aPTT determinations obtained as part of the study protocol will not be 
reported to investigators during the study in order to maintain the blinding.
6.4
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit by direct 
questioning. At EOT (ET) visit, compliance will be assessed by counting returned 
tablets / capsules. Deviation(s) from the prescribed dosage regimen should be recorded in the 
eCRF.
To monitor compliance, the investigator will be required to document drug dispensing and 
return for each participant. Overall compliance with study intervention intake should be 
between 80% and 120% of the scheduled dose at the end of treatment with study intervention. 
The date of dispensing the study intervention to the participant will be documented. Study 
intervention will be dispensed according to the schedule provided in the SoA (Section 1.3). 
Participants should be instructed to bring all unused study intervention and empty packages at 
the EOT or ET visit for accountability purposes. 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 explanation must be documented in the source records.
6.5
Concomitant Therapy
Any relevant medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and / or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency


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The Medical Monitor (sponsor’s Study Medical Expert) should be contacted if there are any 
questions regarding concomitant or prior 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.
ASA, at doses of ≤ 100 grams/day, is permitted for use any time during the study. Higher 
doses of ASA and / or P2Y12 inhibitors in combination with the study interventions are only 
allowed in the exceptional case of an acute myocardial infarction and / or after PCI that occurs 
during the study. Such treatment may be administered as per discretion of the investigator, 
after thorough assessment of the risk / benefit ratio of such a potential triple therapy approach.
The concomitant use of NSAID therapy during the study is strongly discouraged since this 
has been shown to increase the risk of 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 weeks. Should analgesics be needed, use of 
paracetamol / acetaminophen is recommended.
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 first study intervention
administration, until at least 48 hours after last study intervention administration:

Strong inhibitors of cytochrome P450 isoenzyme 3A4 (CYP3A4) e.g. human 
immunodeficiency virus protease inhibitors (ritonavir, indinavir, nelfinavir, atazanavir, 
or saquinavir), systemically used azole antimycotic agents (ketoconazole, itraconazole, 
voriconazole, or posaconazole), clarithromycin, telithromycin

Strong inducers of CYP3A4, e.g. phenytoin, carbamazepine, phenobarbital, 
rifampicin, or St. John’s wort
A separate complete list with prohibited medications will be provided to the investigator.
Guidance for Management of Participants who Have Bleeding During
6.5.1
the Study
If a participant has serious bleeding during the study treatment period that requires 
hospitalization, the following routine measures should be considered:

Temporarily or permanently discontinue the randomized study medication. The 
decision to discontinue study intervention, temporarily or permanently, will be at the 
discretion of the treating physician and must be documented.

Temporarily discontinue anti-platelet therapies (i.e. ASA) until the bleeding event is 
sufficiently controlled, based upon the discretion of the treating physician.

Investigate other causes of serious bleeding such as coagulopathies, 
thrombocytopenia, kidney / liver dysfunction, or other concomitant medications. 

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, such as tranexamic acid or ε-amino 
caproic acid (Tomaselli et al. 2017). 


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If bleeding cannot be controlled by the above measures, consider urgent surgical or non-
surgical procedures to stop the bleeding (emergency surgery, arterial embolization, 
endoscopic cauterization, etc.) and unblinding of the randomized treatment assignment.  
For those participants treated with BAY 2433334, administration of the following
procoagulants should also be considered (according to the dosages advised in the package 
insert):

Recombinant FVIIa (NovoSeven) or factor eight inhibitor bypass activity (FEIBA), 
based on vitro data showing that it can fully reverse the prolongation of aPTT and 
ROTEM CT induced by BAY 2433334.

FXI concentrate (FXI)
For those participants treated with apixaban, the following agents may be administered:

The antidote to apixaban, Andexanet alfa, which is a recombinant modified human 
factor Xa protein (labelled in the US as ANDEXXA and in the EU as Ondexxya), and 
may be used in case of life-threatening or uncontrolled bleeding (Steffel et al. 2018).
However, its availability may be limited.

4-factor Prothrombin complex concentrate (4F-PCC) or Activated prothrombin 
complex concentrate (APCC)
Guidance for Management of Participants who Have Surgery or 
6.5.2
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 (BAY 2433334 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 of bleeding.
Treatment of participants receiving BAY 2433334 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 an FXI deficiency 
when undergoing surgery (Duga and Salomon 2013). More detailed information may be 
found in the Investigator’s Brochure.
Depending on the participant’s risk of 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.


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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 apixaban. Interactions between apixaban and other antithrombotics (except for
aspirin and P2Y12 inhibitors) have not been evaluated.
Guidance for Management of Participants who Experience Ischemic 
6.5.3
Stroke During the Study
For participants who experience an ischemic stroke during the study, a complete diagnostic 
work-up including brain imaging, at least 24-hour cardiac rhythm monitoring, and 
echocardiography is encouraged. 
The treatment assignment may have to be emergently unblinded if necessary, to facilitate 
management decisions (e.g. intravenous thrombolysis or intra-arterial thrombolysis in case of 
mechanical clot removal). 
For participants with acute ischemic stroke who are receiving BAY 2433334, the risk of 
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 intervention (BAY 2433334)
has not been taken in the previous 48 hours, and the aPTT is normal. In this case, the risk of 
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; 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 medication should be withheld until at least 
24 hours after thrombolysis.
Mechanical clot removal (thrombectomy) without thrombolysis may be performed in any 
case.
Guidance for Management of Participants who Experience new 
6.5.4
Myocardial Infarction During the Study
For participants who experience a suspected new, acute cardiac ischemic event requiring 
unplanned hospitalization (unstable angina or acute MI), standard of care medications should 
be administered according to local practice guidelines and based upon the chosen invasive 
procedure (dual anti-platelet therapy, if not already being used, intravenous / subcutaneous 
anticoagulants, or intravenous anti-platelet therapies such as glycoprotein IIb/IIIa inhibitors or 
cangrelor). Study intervention should be temporarily discontinued upon hospital presentation 
for a suspected acute or cardiac ischemic event to mitigate potential bleeding risks. Cardiac 
ischemic event (acute MI) 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, study intervention should be restarted no earlier than 


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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 anti-platelet agent has 
been administered. 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.
The treatment assignment may have to be emergently unblinded to facilitate decisions 
regarding treatment with intravenous fibrinolytics for acute ST-elevation MI. For participants 
who are receiving BAY 2433334 or apixaban, the risk of bleeding related to the concomitant 
use of an intravenous fibrinolytic is unknown and has not been studied.  For participants 
treated with intravenous fibrinolytics, study intervention should be restarted no earlier than 
24 hours after receiving fibrinolytics.
6.6
Dose Modification
This protocol does not allow any alteration from the currently outlined dosing schedule
(Section 4.3).
6.7
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.
Any further therapy at the end of the study is at the discretion of investigator / treating 
physician.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation / Withdrawal 
7.1
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for bleeding and efficacy outcome events 
until the planned regular end of treatment. 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.
An ET visit is only applicable to participants who prematurely discontinue intake of study 
intervention; such participants should undergo the ET visit as 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 of study intervention (+ 7 days 
window). If the ET visit falls into the time window for the safety follow up visit (≥2 weeks
after permanent discontinuation of study intervention), a safety follow up visit will not be 
performed.
In this study, outcome events and vital status data are crucial to the primary analysis and must 
be collected until the end of the study, as participants will still be part of the study even if they
are no longer taking study medication. Therefore, all efforts will be taken to motivate 
participants to comply with all study procedures and to continue to be followed until the end 
of the study.


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Study intervention will not be routinely 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.
Specifically, a permanent discontinuation of study interventions will be required if 
concomitant treatment with any of the following medications has to be taken for the 
remaining duration of the study:

chronic anticoagulation for a different indication than AF (e.g. cardiac thrombus, 
pulmonary embolism) 

chronic antiplatelet therapy (up to 100 mg ASA is allowed as well as ASA and P2Y12
inhibitors in case of a myocardial infarction and / or PCI)

strong CYP3A4 inhibitors as well as strong CYP3A4 inducers.
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined below, or if the 
investigator believes that it is in best interest of the participant (please also refer to Section 
10.5 for the requirements for liver function monitoring).

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%) 
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. 
At the time of permanent discontinuation of the study intervention, the participant is expected 
to continue regular study clinic visits at the investigator’s site as outlined in the protocol.
If this is not possible for any reason, the investigator and participant must discuss and 
determine further follow-up options, as listed below, in descending order of preference: 
1. Participant will be contacted by phone at the regular follow-up intervals
2. 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)
3. Participant will be contacted only once at the planned End of Treatment period 
(planned regular EOT visit for the participant)
After permanent discontinuation of the study intervention, the following will need to be 
collected at the regular study visits and up to the regular end of treatment visit, preferentially 
directly from the participant and as agreed to by the participant during the initial informed 
consent process:

Vital Status

Antiplatelet and anticoagulant medications

Outcome events (MI, stroke, systemic embolism, death, bleeding).
If a participant is unwilling or unable to return for follow-up visits in person or have follow-
up contacts, sites should collect as much follow-up visit information as possible, including 


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contacting the participant or the participant’s representative, family member or treating 
physician by telephone or by mail. If applicable, vital status may be obtained by reviewing the 
participant’s medical or public sources (e.g. social media, health insurance, public [death]
registry), unless this process is not allowed by local regulations.
Withdrawal of Consent
Note: None of the above options is considered a withdrawal of consent. 
A withdrawal of consent should only occur in exceptional cases and means that the participant 
does not agree to any kind of follow-up and specifically refuses any further contact with the 
investigator (see Section 7.2).
Temporary Discontinuation 
7.1.1
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. 
There is no predefined maximum limit for temporary treatment interruption.  
If study interventions will be temporarily stopped, PK / PD blood samples should only be 
obtained if study interventions have been restarted and sustained for at least 4 days.
7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 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 both from the study intervention and 
from 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 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.


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7.3
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly (twice) fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow up.

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 to re-establish contact with a participant in case 
the site has exhausted all means of regaining contact, if the participant will agree to 
this in the ICF.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

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. 

Procedures conducted as part of the participant’s routine clinical management (e.g.
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.


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8.1
Efficacy Assessments 
Exploratory Efficacy Endpoint
8.1.1
No primary or secondary efficacy endpoints are planned to be analyzed in the study. The 
efficacy endpoints are exploratory endpoints, and include the analysis of composite, as well as 
individual components, of:

ischemic stroke 

systemic embolism 

MI

CV death
In addition, all-cause mortality will be analyzed.
A definition of the efficacy outcome events is provided as follows, and further specified in the 
charter of the clinical event committee (CEC). Details on the time periods for collecting 
Outcome Events information are reported in Section 10.9.
8.1.1.1
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 ischemic stroke and hemorrhagic 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 rapid onset (or presence 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.
8.1.1.2
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 thromboembolism of the pulmonary vasculature or venous thrombosis, e.g. 
pulmonary embolism or deep venous thrombosis).
8.1.1.3
Myocardial Infarction
The term acute myocardial infarction (MI) is used when there is evidence of myocardial 
necrosis in a clinical setting consistent with acute myocardial ischemia. According to the MI 
Universal Definition from 2018 (Thygesen et al. 2018) the diagnosis of MI requires the 
combination of:

Presence of acute myocardial injury (changes in cardiac biomarkers) and


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
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
8.1.1.4
Cardiovascular Death
Cardiovascular death includes death due to stroke, myocardial infarction, heart failure or 
cardiogenic shock, sudden death or any other death due to other cardiovascular causes.  In 
addition, death due to non-traumatic hemorrhage will be included.
8.2
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, the Thrombolysis In Myocardial Infarction (TIMI) and the Bleeding 
Academic Research Consortium (BARC) criteria will be collected in the CRF.
Primary Safety Endpoint
8.2.1
The primary safety endpoint includes the analysis of the composite of ISTH major bleeding 
(Section 8.2.1.1) and clinically relevant non-major bleeding (Section 8.2.1.2).
8.2.1.1
ISTH Major Bleeding
An event that meets at least one of the below criteria for a major bleeding event according to 
the definition given by the ISTH:

Fatal bleeding, and/or

Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, 
pericardial, retroperitoneal, intraarticular, or intramuscular with compartment 
syndrome), and/or 

Clinically overt* bleeding associated with a recent decrease in the hemoglobin level of 
≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared to 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
8.2.1.2
ISTH Clinically Relevant Non-Major Bleeding
Clinically relevant non-major bleeding is considered any sign or symptom of hemorrhage that 
does not fit the criteria for the ISTH definition of major bleeding, but does meet at least one of 
the following criteria (Kaatz et al. 2015):

requiring medical intervention by a healthcare professional

leading to hospitalization or increased level of care

prompting a face to face (i.e. not just a telephone or electronic communication) 
evaluation


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Secondary Safety Endpoints
8.2.2
The secondary safety endpoints include the analysis of the following outcome events:

All bleeding

ISTH major bleeding (Section 8.2.1.1)

ISTH clinically relevant non-major bleeding (Section 8.2.1.2)

ISTH minor bleeding (Section 8.2.2.1).
8.2.2.1
ISTH 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 face-to-face evaluation for a physical examination or laboratory 
testing).
Exploratory Safety Endpoints
8.2.3
The exploratory safety endpoints include the analysis of the following outcome events:

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

BARC bleeding definition type 2, 3, 5

BARC bleeding definition type 3, 5 

BARC bleeding definition type 1, 2, 3, 5
8.2.3.1
TIMI Bleeding Definitions
The non-CABG-related TIMI clinically significant bleeding definition encompasses the 
following bleeding types excluding events that are related to a CABG procedure:

TIMI Major Bleeding

Any symptomatic intracranial hemorrhage

Clinically overt signs of hemorrhage (including imaging) associated with a 
drop in hemoglobin of ≥ 5 g/dL (or when the hemoglobin concentration 
was not available, an absolute drop in hematocrit of ≥ 15%).

Fatal bleeding (bleeding that directly results in death within 7 days)

TIMI Minor Bleeding

Any clinically overt sign of hemorrhage (including imaging) that was 
associated with a fall in hemoglobin concentration of 3 to < 5 g/dL (or, 
when hemoglobin concentration was not available, a fall in hematocrit of 
10 to < 15%).

TIMI Bleeding Events Requiring Medical Attention

Any bleeding event that required medical treatment, surgical treatment, or 
laboratory evaluation and did not meet criteria for a major or minor 
bleeding event, as defined above.
In addition to TIMI significant bleeding also TIMI major bleeding and TIMI minor bleeding 
will be analyzed (Chesebro et al. 1987).


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8.2.3.2
BARC Bleeding Definition
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 nonsurgical, 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

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
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Physical Examinations
8.2.4

Height and weight (also referred to as biometrics in the SoA) will be measured and 
recorded at screening (see Section 1.3).
Vital Signs
8.2.5

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.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g. television, cell 
phones).

Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include systolic and diastolic blood pressure, and pulse 
Electrocardiograms
8.2.6

A single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT and QTc intervals. 
Clinical Safety Laboratory Assessments
8.2.7

See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA 
for the timing and frequency. 

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All laboratory tests with values considered clinically 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.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g.
SAE or AE or dose modification), then the results must be recorded in the CRF. 
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.
Events identified as Adverse Events of Special Interest (AESI) for the study are specified in 
Section 8.3.7.
AEs that are outcome events according to the study protocol are further described in Section 
8.3.6 and Section 10.3.5.


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AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study intervention and/or study. AESIs
have to be followed up regardless of causality or relationship to study intervention.
Time Period and Frequency for Collecting AE and SAE Information 
8.3.1
All SAEs will be collected from the start of intervention (first day of study intervention
intake) until the safety follow-up visit, at the time points specified in the SoA (Section 1.3).
All AEs will be collected from the start of intervention until the safety follow-up visit, at the 
time points specified in the SoA (Section 1.3).
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History / Current Medical Conditions 
section of the case report form (CRF), not the AE section.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstances should this exceed 24 hours after the investigator becomes aware of this 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 AE or SAE 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. 
Method of Detecting AEs and SAEs
8.3.2
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.
Care will be taken not to introduce bias when detecting AEs and / or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
Follow-up of AEs and SAEs
8.3.3
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits / contacts. All SAEs and non-serious AEs of special interest 
(as defined in Section 8.3.7), 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 given in Section 10.3. 
Regulatory Reporting Requirements for SAEs
8.3.4

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 
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relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilizing medical devices, investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

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.
Pregnancy
8.3.5

Details of all pregnancies in female partners of male 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 should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Section 
10.4.

Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
Disease-Related Events
8.3.6
During the study there will be incidences where AEs are also potential efficacy or safety 
endpoints.
In compliance with applicable regulations, in the event of a SUSAR related to the blinded 
treatment, the participant’s treatment code will usually be unblinded before reporting to the 
Health Authorities. Notifications of IECs / IRBs and investigators will be done according to 
all applicable regulations (see Section 8.3.4).
The following disease- and treatment-related events are common in participants with AF who 
are being treated with an anticoagulant:
a.
Bleeding
b. Death
c.
Myocardial Infarction
d. Ischemic stroke
e.
Systemic embolism
These events will be recorded on the corresponding CRF page in the participant’s CRF.
These events will also be monitored and adjudicated by a Central Event Committee (CEC) on 
an ongoing basis. 
In addition, these events require reporting to the sponsor according to the standard process of 
expedited reporting of SAEs within 24 hours of the investigator’s awareness of the event, 
along the timelines set for reporting of SAEs and AESIs.
However, due to their expectedness, efficacy endpoints listed above (b-e: death, myocardial 
infarction, ischemic stroke and systemic embolism), including events indicative of those 


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outcome events (e.g. TIA, cardiac chest pain), will not be subject to systematic unblinding 
and expedited SUSAR reporting to Health Authorities. 
Adverse Events of Special Interest
8.3.7
Adverse events of special interest (AESIs) will be AEs related to hepato-biliary dysfunction, 
i.e. relevant increases in the respective liver lab values (ALT > 3 x ULN or AST > 3 x ULN,
with confirmatory re-testing within 5 days of the initial laboratory value elevation) with or 
without symptoms such as e.g. nausea, vomiting, right upper quadrant abdominal pain, 
fatigue, weakness, weight loss and jaundice. Re-testing of lab values can be performed at the 
local lab and needs to be documented in the eCRF.
AESIs have to be reported to the sponsor within 24 hours of the investigator’s awareness, i.e. 
along the timelines set for SAEs (even though they may not be classified as serious), as 
described in Section 8.3.1.
8.4
Treatment of Overdose
For this study, any dose of BAY 2433334 greater than 3 assigned daily dosages (i.e. more 
than 6 tablets) within a 24-hour time period will be considered an overdose.
The sponsor does not recommend specific treatment for an overdose of BAY 2433334, as a 
specific antidote for the study drug 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 6.5.1 should be followed.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study drug 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 in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5
Pharmacokinetics
For the investigation of systemic exposure to BAY 2433334 and its relationship with 
treatment effects, the plasma concentrations of BAY 2433334 and optionally of its metabolite 
M-10 (BAY 2826102) will be determined at different time points using a sparse sampling 
approach in all participating participants. Details about the collection, processing, storage and 
shipment of samples will be provided separately (e.g. in the Laboratory Manual). Study 


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personnel responsible for bioanalytics will be unblinded and will have access to the 
randomization list. Analysis of samples from participants not treated with BAY 2433334 is 
optional. 
Blood samples will be collected at the time points indicated in the SoA (Section 1.3). PK 
samples obtained at additional time points based on the investigator’s discretion will not 
qualify as a protocol deviation and will be used for PK analysis as well. 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 of the PK/PD sampling day, and of the day before that) must be documented.
At Visit 4 a trough sample for the determination of BAY 2433334 plasma concentrations will 
be drawn before intake of study intervention. At this visit, study intervention will be 
administered at the study center by study personnel and the exact time of study intervention
intake on the day before the visit and on the day of the visit and the exact sampling time will 
be recorded in the eCRF. At Visit 6 a plasma sample will be drawn without previous or 
subsequent study intervention intake; the last intake of study intervention is occurring on the 
previous day (as usual in the morning and evening). Furthermore, the sampling should occur 
prior to the intake of an open-label oral anticoagulant (NOAC or another recommended 
anticoagulant as deemed appropriate by the investigator) that is supposed to be started instead 
of the blinded study intervention after the end of study intervention treatment. Ideally, the 
study personnel should contact the participant prior to Visit 4 and Visit 6 to remind them not 
to take the study intervention as usual in the morning at home. At Visit 4 additional post-dose 
samples will be taken like indicated in the SoA (Section 1.3).
The PK data and the relationship of the BAY 2433334 exposure parameters (e.g. Cmax, AUC) 
with treatment effects might be evaluated using population approaches (e.g. non-linear mixed 
effect modeling) including potential influence of relevant participant co-variables. Analysis 
and report 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. 
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 which will 
be included in the CSR for this study.
8.6
Pharmacodynamics
Blood sampling for PD parameters is scheduled for the time points as given in Section 1.3. 
The actual date and time 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 clinical study report (CSR) of this study.
Concentrations of the analyte are calculated according to the method description. Detailed 
method descriptions of all PD methods will be filed with the study report.
The following parameters will be used to assess the PD effects after administration of the 
investigational drug, but will be performed optionally and/or only in a subset of participants:

aPTT will be measured using a coagulation assay via kaolin-trigger


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
Activated Factor XIa activity (AXIA) will be analyzed using a kaolin-trigger and a 
fluorogenic substrate readout. 

D-Dimer will be measured using an immunoturbidometric method

FXI concentration will be measured via ELISA using polyclonal antibodies

Fibrinogen will be measured using a coagulation assay

Factor XII activity will be assessed with an aPTT-based coagulation test using FXII-
deficient plasma. Factor XII concentration will be analyzed using an enzyme-linked 
immunosorbent assay (ELISA).

vWF antigen level and vWF ristocetin cofactor (i.e. vWF functional activity) will be 
analyzed using turbidometric assays.
The study sponsors reserve the right not to conduct all or part of the above-mentioned
analysis.
In addition, blood samples will be taken for exploratory biomarker work (see Section 8.8).
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 in this 
study. See Section 8.8 for details.
8.8
Biomarkers
Exploratory biomarker analyses (scheduled for the time points as given in Section 1.3), that 
might be performed optionally and/or only in a subset of participants are:

NT-proBNP will be measured using an electrochemiluminescence immunoassay 
(ECLIA)

hsCRP will be measured using an immunoturbidometric method

Thrombin-activatable fibrinolysis inhibitor (TAFI) and C1 inhibitor activity will be 
measured using chromogenic substrate assays

TAT and F1.2 will be analyzed using immunoassays
In addition to the biomarkers described above, further biomarkers related to the mode of 
action or the safety of BAY 2433334 and similar drugs 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, PD, 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.


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8.9
Immunogenicity Assessment
Not applicable
8.10
Health Economics / Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9.
Statistical Considerations 
9.1
Statistical Hypotheses
The aim of the study is to estimate the incidence risk of bleeding events of BAY 2433334 and 
compare it with the incidence risk of apixaban.
No hypothesis testing is planned in this study.
9.2
Sample Size Determination 
Approximately 800 participants will be screened to achieve 750 evaluable participants for an 
estimated total of 250 evaluable participants per intervention group.
The bleeding risk for the 2 dose groups of BAY 2433334 is assumed to be similar, such that 
pooling of the BAY 2433334 arms will be done for the bleeding comparison. The precision of 
the estimated incidence risks (measured by the length of the confidence interval) depends on 
both the observed incidence risk and the relative risk reduction. For an observed incidence 
risk for the primary bleeding endpoint of 4% at Week 12 in the apixaban control arm and an 
observed relative risk reduction of 50% for both (mid and high) doses of BAY 2433334, 
sample sizes of 250 (apixaban) and 500 (pooled BAY 2433334 arms) participants produce a 
two-sided 90% confidence interval for the ratio of incidence proportions with a length of 0.77 
(0.25- 1.02). In this case the expected number of bleeding events in the apixaban control arm
is 10 and 5 in each of the BAY 2433334 treatment arms. Further calculations for exemplary 
approximate two-sided 90% confidence intervals and their lengths for different observed 
incidence ratios and relative risk reductions are presented in Table 9–1,below.
Table 9–1: 90% Confidence Intervals for the ratio of incidence and the corresponding 
length for different scenarios at week 12
Observed incidence in comparator arm
Observed Relative Risk 
Reduction under 
BAY 2433334 treatment
3%
4%
5%
6.5%
45%
0.25 – 1.22 
(0.97)
0.28 – 1.10 
(0.82)
0.31 – 1.02 
(0.72)
0.32 – 0.95 
(0.63)
50%
0.22 – 1.13 
(0.91)
0.25 – 1.02 
(0.77)
0.27 – 0.95 
(0.68)
0.29 – 0.88 
(0.59)
55%
0.19 – 1.04 
(0.85)
0.22 – 0.93 
(0.71)
0.24 – 0.86 
(0.64)
0.25 – 0.80 
(0.55) 
Given the assumptions of a true incidence rate for apixaban of 4% for the primary safety 
endpoint and a true relative risk reduction of 50% the point estimator will be lower than or 
equal to 0.72 with a probability of 80%, lower than or equal to 0.88 with a probability of 90% 
and lower than or equal to 1 with a probability of 94%.


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9.3
Populations for Analyses 
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Full Analysis Set
All participants randomized to study intervention.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the intervention they actually 
received.
Pharmacokinetic Analysis Set
All BAY 2433334-treated participants with at least 1 valid 
plasma concentration and without protocol deviation, which 
would interfere with the evaluation of the PK data.
Abbreviations: ICF = Informed consent form, PK = pharmacokinetic(s)
The primary and secondary safety endpoints will be analyzed using the Safety Set. The 
analysis of the Full Analysis Set (FAS) will be used as a supportive analysis. Pharmacokinetic 
and pharmacodynamic data will be analyzed using the Pharmacokinetic analyses set.
9.4
Statistical Analyses
General considerations
9.4.1
The statistical analysis plan (SAP) will be developed and finalized before database lock and 
will describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints and estimands.
The aim of this study is to gain knowledge of the safety profile of BAY 2433334.
For the intercurrent events “death” and “discontinuation of study treatment” the “while on 
treatment” respectively “while alive” strategy will be applied, if not mentioned otherwise, i.e. 
only data up to the respective intercurrent event will be considered for the analysis.
Confidence intervals will be two sided 90% - confidence intervals.
The cumulative incidence risk will be estimated for time to event endpoints. The hazard ratios 
and the corresponding confidence intervals will be estimated on separate Cox proportional 
hazard models for each comparison. No comparison of the different doses of BAY 2433334 is 
planned. 
All collected events will be summarized using methods like frequency tables and descriptive 
statistics.
The statistical analyses will be performed using SAS; the version used will be specified in the 
SAP.
Primary endpoints
9.4.2
Safety Analysis
The primary estimand is the ratio of proportion of participants experiencing the composite of 
ISTH major and clinically relevant non-major bleeding within 3 months comparing pooled 
doses of BAY 2433334 and apixaban, the comparator drug, in adult participants with AF who 
have taken at least one dose of study intervention (BAY 2433334 or apixaban), while the 
participant is alive and exposed to study intervention.


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The primary estimator is a confidence interval for the ratio of incidence risks, accounted for 
the participants under risk, of BAY 2433334 (all doses pooled) and the active comparator.
The estimation will be performed on the safety set.
For the “while on treatment” respectively the “while alive” strategy all events from first 
intake of study intervention until 2 days after last study intervention intake will be counted. A 
supplementary estimand will use the “treatment policy” strategy for the intercurrent event 
“discontinuation of study intervention” and change the population to all participants 
randomized to a study intervention. It will be estimated on the ITT data set, and all events 
from randomization through the safety follow-up visit will be counted and displayed for the 
pooled doses of BAY 2433334, as well as for the individual doses.
As supplementary analysis, the primary safety endpoint will be analyzed as time to event 
variable. The comparison will be done for each dose of BAY 2433334 vs. the active 
comparator as well as for the pooled doses of BAY 2433334.
All analyses will be stratified based on whether participants received a NOAC before study 
start or were not treated with any other oral anticoagulant.
Secondary endpoints
9.4.3
Safety Analyses
The secondary safety estimands are the ratios of the proportions of participants experiencing
the individual endpoints within 3 months, comparing pooled doses of BAY 2433334 and 
comparator drug apixaban in adult participants with AF who have taken at least one dose of 
study intervention (BAY 2433334 or apixaban, the comparator drug), while the participant is 
alive and exposed to study intervention for each of the endpoints: 

all bleeding

ISTH major bleeding

ISTH clinically relevant non-major bleeding

ISTH minor bleeding.
The analyses will be similar to those for the primary safety endpoint.
Tertiary / exploratory endpoints
9.4.4
Exploratory endpoints for this study are the composite as well as individual components of 
CV death, MI, ischemic stroke, systemic embolism and all-cause mortality as efficacy 
endpoints; TIMI clinically significant bleeding, TIMI major bleeding, TIMI minor bleeding,
BARC bleeding definition type 2, 3, 5, BARC bleeding definition type 3, 5 and BARC 
bleeding definition type 1, 2, 3, 5 as safety endpoints and FXIa inhibition, aPTT, D-Dimer
and various biomarkers (e.g. diagnostic, safety, pharmacodynamic, monitoring, or potentially 
predictive biomarkers) as other endpoints.
The analyses of these endpoints will be specified in the SAP. 
Other safety Analyses
9.4.5
Adverse Events (AE) will be analyzed by descriptive statistics, such as frequency tables. All 
AEs will be tabulated according to the affected system organ class and preferred term, as 
coded by the Medical Dictionary for Regulatory Activities (MedDRA).


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Other Analyses 
9.4.6
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. The population PK analysis and 
pharmacodynamic analyses will be presented separately from the CSR. 
9.5
Interim Analyses 
No formal interim analysis is planned for this study.
Two non-formal interim analyses are planned to be performed in the Phase 2 program to 
assess the efficacy and safety profile of BAY 2433334 during the Phase 2 study conduct. Data 
from this study as well as the 2 other ongoing Phase 2 studies will be reviewed together when 
the pre-defined criteria for the 2 interim analyses have been reached.
Analyses of the unblinded safety and efficacy data will be performed by a third party, i.e. the 
statistical analysis center (SAC) that supports the IDMC and thus, is independent of the study 
team and the sponsor. A small group of academic leaders (Executive Committee) including 
the heads of the three Steering Committees that have been established for the individual 
studies and sponsor representatives will participate in the review of these data. IDMC 
members will also be included in this review. The data will be kept strictly confidential by 
this group and will not be shared with the study team and the SC. Thus, the study integrity 
will not be impacted and the study conduct will otherwise not be altered by the results of this 
interim analysis.
The interim analysis will include selected and predefined study data primarily as aggregated 
data for this individual study but may also include pooling of some data across all 3 ongoing
Phase 2 studies.
The first interim analysis will be conducted once about 50% of the participants 
(800 participants) with a minor non-cardioembolic ischemic stroke (NIHSS ≤ 7) are enrolled 
in the study 19766, or 3 months MRI data are available for at least 12.5% of participants 
(200 participants). If the review confirms the safety profile of BAY 2433334 and raises no 
concern regarding (intracranial) hemorrhage or hemorrhagic transformation of the ischemic 
stroke, Part B of the study 19766 will be initiated, during which from then on participants 
with more severe cases of stroke (NIHSS ≥ 8 and ≤ 15) can also be included as well as 
participants after thrombolysis or endovascular therapy (mechanical thrombectomy). Even 
though the primary focus for this interim analysis is specific for the decision for the stroke 
study only, data and especially bleeding data from the other 2 studies will be taken into 
consideration.
The second interim analysis will occur, when approximately 80% of all planned participants,
taken all 3 studies together, are randomized. This meeting will aim to assess whether the 
interim data support decision making on dose and design for a potential Phase 3 clinical 
development program while the Phase 2 studies are still ongoing and may allow interaction 
with Health Authorities before final data from the studies are available. 
The timepoints when these two interim analyses occur are difficult to predict and will depend 
e.g. on study start time, number of sites and countries, on the enrollment rate and other factors 
in all three studies. In case the timepoints for the 2 interim analyses may be close together, the 
decision could be taken to just conduct one interim analysis.
As part of the 2 interim analyses the additional objective to potentially change the dose during 
the ongoing Phase 2 studies will be assessed. This will allow flexibility in case of unexpected 


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findings during the review of the data, e.g. stop of the highest dose (in case of an unexpected 
higher bleeding rate in the highest dose or in the combination with antiplatelet therapy) or 
addition of a lower or higher dose or replacement of one dose (in case of a difference in 
pharmacokinetics or PD parameters such as inhibition of FXIa in the patient populations 
compared to healthy volunteers). 
9.6
Independent Data Monitoring Committee (IDMC)
An independent data monitoring committee (IDMC) will be involved in the review of the
safety data for study 19765, and of the overall safety data across all 3 Phase 2 studies with 
BAY 2433334 (Section 10.1.5.3). Detailed information on the roles and responsibilities of the 
IDMC will be described in the IDMC Charter.
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Regulatory and Ethical Considerations
10.1.1

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 Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB / IEC by the investigator 
and to the appropriate regulatory authority by the sponsor. The submitted documents 
should be reviewed and approved by the IRB / IEC and regulatory authority before the 
study is initiated. 

Any amendments to the protocol will require IRB/IEC and regulatory authority 
approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants. Any 
substantial modifications 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.

The investigator will be responsible for the following:

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 21 CFR, ICH guidelines, the IRB / IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
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Financial Disclosure
10.1.2
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.
Informed Consent Process
10.1.3

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) 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 participant or the participant’s legally 
authorized representative.

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. 

Pharmacogenetic samples will be taken during the study. Study participants will be 
asked to sign a separate informed consent for pharmacogenetic research. 
Data Protection
10.1.4

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB / IEC members, and by inspectors from regulatory 
authorities.


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Committees Structure
10.1.5
10.1.5.1
Executive Committee
The Executive Committee, which consists of external experts in the area of neurology and 
cardiology and will include the Steering Committee heads of the 3 Phase 2 studies with BAY 
2433334, as well as 2 sponsor representatives, will ensure the overarching integrity of the 
3 studies. Details of the committee will be specified in the Executive Committee Charter. 
10.1.5.2
Steering Committee (SC)
The main task of the Steering Committee, which is composed of a panel of experts in the field
cardiology and neurology, is to support the protocol development and the conduct of the 
study, to advise the sponsor on clinical, medical, and scientific questions, and to support 
publications. Details of the committee will be specified in the Steering Committee charter.
10.1.5.3
IDMC
Ongoing safety monitoring during the conduct of the study will be performed by an external 
and unblinded IDMC. An independent statistical analysis center (SAC) will be involved in 
processing unblinded safety 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 Bayer. All 
other definitions will be provided in the IDMC charter.
10.1.5.4
Clinical Events Committee (CEC)
Potential pre-specified clinical outcome events will be submitted for adjudication to an 
independent CEC. Adjudication of all bleeding events as well as potential exploratory 
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 contained in the CEC charter. The adjudication will 
also include algorithm approaches:

Bleeding events according to the following classifications:

ISTH (major, clinically relevant non-major and minor)

TIMI (major, minor, requiring medical attention, minimal)

BARC (type 1, 2, 3, 5)

Death (CV death [including death with unknown 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 and with increased cardiac enzymes reported.
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.


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Dissemination of Clinical Study Data
10.1.6
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 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in participants for medicines and indications approved in the United States (US) and European 
Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
Data Quality Assurance
10.1.7

All participant data relating to the study will be recorded on printed or electronic CRF 
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 
electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB / IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

Monitoring details describing strategy (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).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator 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. 


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No records may be transferred to another location or party without written notification 
to the sponsor. 

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.
10.1.7.1
Data Recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Participant data necessary for analysis and reporting will be entered / transmitted into 
a validated database or data system (LSH).
Data required according to this protocol will be recorded by study site personnel via data 
entry into the internet-based EDC software system RAVE, which Bayer has licensed from 
Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions Worldwide 
and Bayer for use in its clinical studies. RAVE allows for the application of software logic to 
set-up data entry screens and data checks to ensure the completeness and accuracy of the data 
entered by the site personnel. Bayer extensively applies the logic to ensure data are complete 
and reflect the clinical data requirements of the study. Data queries resulting from the 
application of the software logic are resolved by the site personnel. The data are stored at a 
secure host facility maintained by Medidata Solutions Worldwide and transferred on a 
periodic basis to Bayer's internal computer system via a secure Virtual Private Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
participants enrolled in this study.
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (participant number; year of birth/age; sex; if applicable 
race / ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit.
These data will be transferred to the respective database.


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10.1.7.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s procedures, monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of participants are being protected

Study is conducted in accordance with the currently approved protocol
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
10.1.7.3
Data processing
Data will be collected as described in Section 10.1.7.1. Clinical data management will be 
performed in accordance with applicable sponsor’s standards and data cleaning procedures. 
This is applicable for data recorded on eCRF as well as for data from other sources (e.g. IxRS, 
laboratory, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, additional data release for analysis is possible, 
to include, for example, the following data: pharmacokinetic data, pharmacodynamic data, 
anti-drug antibody data etc.
10.1.7.4
Missing data
All efforts will be made to collect complete data for all participants randomized in this study. 
Participants will be followed up to the study end and all required data will be collected, 
regardless of participants’ compliance with study intervention use or the visit schedule. 
Data from participants who prematurely terminate the study will be used to the maximum 
extent possible. All missing or partial data will be presented in the participant data listing as 
they are recorded in the eCRF. Data are collected primarily through an EDC system, which 
allows ongoing data entry and monitoring.
10.1.7.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s 
quality assurance unit may arrange to conduct an audit to assess the performance of the study 
at the study site and of the study documents originating there. The investigator/institution will 
be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.


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The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
10.1.7.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Participant (hospital) files will be archived according to local regulations and in accordance 
with the maximum period of time permitted by the hospital, institution or private practice. 
Where the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
site.
Source Documents
10.1.8

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 can be found in the source data 
identification checklist.

The site must implement processes to ensure availability of all required source 
documentation (e.g. participant file, local laboratory report, etc.). A source document 
checklist (not part of this protocol) will be used at the site to identify the source data 
for key data points collected and the monitor will work with the site to complete this.

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.
Study and Site Start and Closure
10.1.9
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies
have been collected and a study-site closure visit has been performed.


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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:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB / IEC or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development.
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.
Publication Policy
10.1.10

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Steering Committee as well as 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 and the Steering Committee 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.
10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10–1 will be performed by the central laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 4.4 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.


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Table 10–1: Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC Indices:
MCV
MCH
%Reticulocytes
White blood cell (WBC) 
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) 
count
Hemoglobin
Hematocrit
Clinical Chemistrya
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase (AP)
Gamma glutamyl transpeptidase (γGT)
Bilirubin, total and direct
Lactate dehydrogenase (LDH)
Creatinine kinase (CK)
Blood urea nitrogen (BUN)
Creatinine
eGFR
Lipase
Amylase
Sodium
Potassium
Calcium
Uric acid
Glucose
Cholesterol (total, HDL, LDL)
Triglycerides
Albumin
Total protein
Thyroid-stimulating hormone (TSH)
Abbreviations: ALT = alanine aminotransferase, AP = alkaline phosphatase, AST = aspartate 
aminotransferase, BUN = blood urea nitrogen, CK = creatinine kinase, eGFR = estimated glomerular 
filtration rate, γGT = gamma glutamyl transpeptidase, HDL = high-density lipoprotein, LDH = lactate 
dehydrogenase, LDL = low-density lipoprotein, MCH = mean corpuscular hemoglobin, MCV = mean 
corpuscular volume, RBC = red blood cell (count), TSH = thyroid-stimulating hormone, WBC = white blood 
cell (count)
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Section 10.5.
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 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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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE 
10.3.1
AE Definition

An AE is any untoward medical occurrence in a participant or 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.

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.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE.


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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

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.
Definition of SAE
10.3.2
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:
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 detained (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 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, 


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and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording and Follow-Up of AE and / or SAE 
10.3.3
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 in the CRF.

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 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 


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utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.

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.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

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.

The investigator will use clinical judgment to determine the relationship.

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.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

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 health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the sponsor with a copy of any post mortem
findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.


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Reporting of SAEs
10.3.4
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 
collection tool (see next section) in order to report the event within 24 hours.

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 off-line 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 off-line, then the site can report this information on a paper SAE form and 
transmit to 

Contacts for SAE reporting can be found in the Investigator Site File.
SAE Reporting to the sponsor via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the sponsor via 

In rare circumstances and in the absence of facsimile equipment, 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 CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Investigator Site File.
Outcome Event Reporting Process Overview
10.3.5
If an AE or SAE is a potential outcome event (all bleeding, death, MI, stroke, TIA and 
systemic embolism [Section 8.3.6]), it must be collected and reported on the dedicated forms 
on an ongoing basis, until the participant has completed the study. Thus, even if a participant 
is no longer taking study medication this would be until the end of the regular, planned end of 
treatment for this participant (i.e. until the participant’s last visit). After completion of safety 
follow-up visit, for participants that prematurely discontinued study intervention, there is no
further requirement for reporting AEs. Only potential outcome events are to be reported (refer 
to Section 8.3.1 and Section 10.9.
PPD
PPD


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
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.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

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. Müllerian agenesis, androgen insensitivity), 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.
Postmenopausal Female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement (> 40 IU/L) 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.
Contraception Guidance

Female participants must be of non-child bearing potential as per Clinical Trial 
Facilitation Group (CTFG) guidelines.

Male participants must agree to use condoms when sexually active with a woman of 
childbearing potential from the time of the first dose to 7 days after the last dose of 
study intervention. This is in line with the CTFG guideline, as BAY 2433334 is non
genotoxic but data related to teratogenicity/fetotoxicity in early pregnancy (Segment 2 


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studies) are not available at this stage of development. In addition, all men must not 
donate sperm during the study.
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 

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 
8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting. 

Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Any participant with an ALT or AST > 3 x ULN must be re-tested as soon as possible, at the 
latest within 48-72 hours of the investigator becoming aware of the result. This re-testing and 
any subsequent testing based on elevated levels should include measurement of ALT, AST, 


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total and direct bilirubin, AP and INR, and will be assessed by local laboratory. There also 
should be inquiry made about symptoms.
Every effort should be made to clarify the etiology of elevated levels and laboratory testing 
may include, but not be limited to, testing for viral hepatitis, cytomegalovirus, Epstein-Barr 
virus, human immunodeficiency virus (once the participant has provided written consent), 
ferritin levels, iron, iron binding capacity, antinuclear antibody, and smooth muscle 
antibodies. Participant management is at the discretion of the treating physician, but the 
investigator may continue the study intervention during retesting.
Liver function test monitoring should be performed as above for all participants with elevated 
ALT or AST >3 ULN even if the study intervention is interrupted until tested values have 
normalized or returned to participant’s baseline. If close liver monitoring is not possible, then 
the participant should discontinue study medication.
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).
The frequency of liver function tests based on re-test values is shown in Table 10–2. 
Table 10–2: Liver function monitoring
ALT, AST level at re-test
Frequency
Further notice
ALT or AST > 3 x ULN
2-3 times a week
Obtain details on liver related symptoms and 
exclude other causes of liver enzyme elevations
ALT or AST ≤ 3 x ULN
Once a week
Until return to normal or participant baseline levels
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase; ULN = upper limit of normal
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%).
10.6
Appendix 6: Calculating the Child-Pugh score
The severity of liver disease (Table 10–3) will determine the Child-Pugh score (Table 10–4).


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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)
10.7
Appendix 7: Calculating glomerular filtration rate
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated glomerular filtration rate
(eGFR), calculated using the Modification of Diet in Renal Disease (MDRD) study 
abbreviated formula.
Isotope dilution mass spectroscopy (IDMS)-traceable MDRD Study Equation:
Conventional units (serum creatinine level is measured in mg/dL)
GFR (mL/min/1.73 m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American)
GFR can be estimated using the calculator provided in the following link: 
http://www.kidney.org/professionals/kdoqi/gfr_calculator.
For further information on assessing renal function using GFR estimates (Levey et al. 2006).


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10.8
Appendix 8: Calculating CHA2DS2-VASc score
Table 10–5: CHA2DS2-VASc score 
Letter
Risk factor
Score
C
Congestive heart failure/LV dysfunction
1
H
Hypertension
1
A2
Age ≥ 75
2
D
Diabetes mellitus
1
S2
Stroke/TIA/thromboembolism
2
V
Vascular diseasea
1
A
Age 65-74
1
Sc
Sex category (i.e. female sex)b
1
Abbreviations: AF = atrial fibrillation, LV = left ventricular, TIA = transient ischemic attack
Congestive heart failure/LV dysfunction means LV ejection fraction ≤ 40%.
Hypertension includes the participants with current antihypertensive medication.
aPrior myocardial infarction, peripheral artery disease, aortic plaque.
Source: adapted from (Lip et al. 2010).
bRecent 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 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).
10.9
Appendix 9: Outcome Events: Data Collection
All outcome events (efficacy and safety) are to be captured and reported from randomization 
until participant’s regular last scheduled study visits (i.e. safety follow-up visit; in case of 
permanent discontinuation of study intervention, the planned regular EOT visit). The eCRF 
will contain specific Outcome Event pages, as well as AEs subpages to capture the outcome 
events occurring throughout the study. The following points need to be considered when 
reporting outcome events.

Outcome events occurring after randomization and before the first intake of the 
study intervention: the outcome event will be considered part of the medical history 
and should be reported in the outcome event eCRF page 

Outcome events occurring after randomization and after first intake of study 
intervention and up to the SFU visit: the outcome event will be considered both AE 
and outcome event and should be reported in both in the AE page and in the AEs 
subpage for outcome events.

Outcome events occurring after SFU visit through the end of the study (for 
participant who discontinue study intervention): the outcome events should be 
collected until completion of participant’s regular scheduled study visits and should be 
reported in the outcome event eCRF page.
10.10
Appendix 10: Abbreviations
AE
Adverse Event
AESI
Adverse event of special interest
ACC
American College of Cardiology


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AF
Atrial fibrillation
AG
Joint stock company, Aktiengesellschaft
AHA
American Heart Association
ALT
Alanine aminotransferase
AMI
Acute myocardial infarction 
AP
Alkaline phosphatase
APCC
Activated prothrombin complex concentrate
aPTT
Activated partial thromboplastin time
ARC
Academic Research Consortium
ASA
Acetylsalicylic acid
ASO
Antisense oligonucleotide
AST
Aspartate aminotransferase
AUC
Area under the curve
AXIA
Activated Factor XIa activity
AxMP
Auxiliary medicinal product
BARC
Bleeding Academic Research Consortium
BID
Twice a day, Bis in die
BL
Baseline
BMS
Bristol-Myers Squibb
BP
Blood pressure
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CEC
Clinical Events Committee
CFR
Code of Federal Regulations
CHEST
American College of Chest Physicians
CIOMS
Council for International Organizations of Medical Sciences
CHMP
Committee for Medicinal Products for Human Use
CK
Creatinine kinase
CL/F
Apparent oral plasma clearance
Cmax
maximum observed concentration reached after administration
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CSR
Clinical study report
CT
Clotting time
CTFG
Clinical Trial Facilitation Group
CV
Cardiovascular
CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
e.g.
For example, exempli gratia
ECG
Electrocardiogram
ECLIA
Electrochemiluminescence Immunoassay
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
End of Treatment
ESC
European Society of Cardiology


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ESUS
Embolic stroke of undetermined source
ET
Early termination
EU
European Union
EudraCT
European Clinical Trials Database
F1.2
F1.2 fragment of prothrombin
FAS
Full Analysis Set
FeCl
Ferric chloride
FEIBA
Factor eight inhibitor bypass activity
FiM
first in man
FFP
Fresh frozen plasma
4F-PCC
4-factor Prothrombin complex concentrate
FSH
Follicle stimulating hormone
γGT
Gamma glutamyl transpeptidase
GCP
Good Clinical Practice
geoCV
Geometric coefficient of variation
GFR
Glomerular filtration rate
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HDL
High-density lipoprotein
HDPE
High-density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HR
Heart rate
HRS
Heart Rhythm Society
HRT
Hormonal replacement therapy
hsCRP
High-sensitivity C-reactive protein
i.e.
That is, id est
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IDMC
Independent data monitoring committee
IDMS
Isotope dilution mass spectroscopy
IEC
Independent Ethics Committee
IMP
Investigational medical product
IND
Investigational New Drug
INN
International non-proprietary name
INR
International normalized ratio
ISTH
International Society on Thrombosis and Hemostasis 
IR
Immediate-release
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Hemostasis
ITT
Intent-to-treat
IV
Intravenous(ly)
IVRS/IWRS, IxRS
Interactive Voice/Web Response System
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LSH
Life Science Data Hub
LV
Left ventricular


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Version 1.0
Page:  71 of 73
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MD
Medical doctor
MD/MDE
Multiple dose/multiple dose escalation
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic resonance imaging
N
Total number of participants
NA
Not applicable
NIHSS
National Institutes of Health Stroke Scale
NJ
New Jersey
NOAC
Non-Vitamin K oral anticoagulant
NSAID
Nonsteroidal anti-inflammatory drug
NT-proBNP
N-terminal pro B-type Natriuretic Peptide
OD
Once a day
P2Y12
Gi-coupled platelet receptor for adenosine diphosphate
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PT
Prothrombin time
QC
Quality control
RAAUC
Accumulation ratio for AUC
RACmax
Accumulation ratio for Cmax
RAVE
Data collection tool
RBC
Red blood cell (count)
RND
Randomization
ROTEM
Rotational thromboelastometry
SAC
Statistical analysis center
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical analysis software
SC
Steering Committee
SCR
Screening
SD
Single dose
SFU
Safety follow-up
SMOL
Small molecule
SoA 
Schedule of activities
SUSAR
Suspected unexpected serious adverse reaction
TAFI
Thrombin-activatable fibrinolysis inhibitor
TAT
Thrombin-antithrombin complex
TIA
Transient ischemic attack
TIMI
Thrombolysis in myocardial infarction
TKA
Total knee arthroplasty
TM
Trademark
tmax
Time to reach maximum drug concentration in plasma
TMF
Trial Master File


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No. BAY 2433334 / 19765
Version 1.0
Page:  72 of 73
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US/USA
United States/United States of America
VKA
Vitamin K antagonist
VTE
Venous thromboembolism
vWF
Von Willebrand Factor
W
Week
WBC
White blood cell (count)
WOCBP
Woman of Childbearing Potential
11.
References
Chen Z, Seiffert D, Hawes B. Inhibition of Factor XI activity as a promising antithrombotic 
strategy. Drug Discov Today. 2014 Sep;19(9):1435-9.
Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, et al. Thrombolysis in 
Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue 
plasminogen activator and intravenous streptokinase. Clinical findings through 
hospital discharge. Circulation. 1987 Jul;76(1):142-54.
Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 
2013 Sep;39(6):621-31.
EMA. EMA/CHMP/341363/2014. 2014.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et al. 2014 
AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: 
executive summary: a report of the American College of Cardiology/American Heart 
Association Task Force on practice guidelines and the Heart Rhythm Society. 
Circulation. 2014 Dec 2;130(23):2071-104.
January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Jr., et al. 2019 
AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the 
Management of Patients With Atrial Fibrillation. Circulation. 2019 Jan 
28:CIR0000000000000665.
Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of A. Definition 
of clinically relevant non-major bleeding in studies of anticoagulants in atrial 
fibrillation and venous thromboembolic disease in non-surgical patients: 
communication from the SSC of the ISTH. J Thromb Haemost. 2015 
Nov;13(11):2119-26.
Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guideline 
for the management of atrial fibrillation developed in collaboration with EACTS. Eur 
Heart J. 2016;37:2893-962.
Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu 
DC, et al. Management of severe perioperative bleeding: guidelines from the European 
Society of Anaesthesiology. Eur J Anaesthesiol. 2013 Jun;30(6):270-382.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med. 2006 Aug 
15;145(4):247-54.
Ling G, Kagdi H, Subel B, Chowdary P, Gomez K. Safety and efficacy of factor XI (FXI) 
concentrate use in patients with FXI deficiency: a single-centre experience of 19 years. 
Haemophilia. 2016 May;22(3):411-8.


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Clinical Study Protocol
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Version 1.0
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Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for 
predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-
based approach: the euro heart survey on atrial fibrillation. Chest. 2010 
Feb;137(2):263-72.
Lip GYH, Banerjee A, Boriani G, Chiang CE, Fargo R, Freedman B, et al. 2018 CHEST 
Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel 
Report. Chest. 2018 Nov;154(5):1121-201.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9.
Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, et al. The 2018 
European Heart Rhythm Association Practical Guide on the use of non-vitamin K 
antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018 Apr 
21;39(16):1330-93.
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth Universal 
Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018 Oct 
30;72(18):2231-64.

SAP_003.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Randomized, active comparator-controlled, double-blind, double-
dummy, parallel group, dose-finding Phase 2 study to compare the 
safety of the oral FXIa inhibitor BAY 2433334 to apixaban, a 
NOAC, in patients with atrial fibrillation 
NCT Number: 
NCT04218266 
Document Date: 
14-Oct-2021 
 


Statistical Analysis Plan
BAY 2433334 / 19765
Page: 1 of 25:
Reference Number: RD-SOP-1119
Supplement Version: 10
Title page
Study Title: Randomized, active comparator-controlled, double-blind, double-dummy, 
parallel group, dose-finding Phase 2 study to compare the safety of the oral FXIa inhibitor
BAY 2433334 to apixaban, a NOAC, in patients with atrial fibrillation
Short Title: Phase 2 Program of AntiCoagulation via Inhibition of FXIa by the oral 
Compound BAY 2433334 – Atrial Fibrillation study
(PACIFIC-AF)
Bayer study drug
BAY 2433334 / INN
Clinical study 
phase:
Phase 2b
Date:
14 OCT 2021
Study No.:
19765
Version:
2.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance 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) are not 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.
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 4
PPD


Statistical Analysis Plan
Protocol No.: BAY 2433334 / 19765
Page: 2 of 25:
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations .................................................................................. 7
4.1
General Principles............................................................................................................ 7
4.2
Handling of Dropouts ...................................................................................................... 8
4.3
Handling of Missing Data................................................................................................ 8
4.4
Interim Analyses and Data Monitoring ........................................................................... 9
4.5
Data Rules........................................................................................................................ 9
4.5.1
Baseline values ............................................................................................................. 9
4.5.2
Data Scopes .................................................................................................................. 9
4.5.3
Time-to-Event variables ............................................................................................. 10
4.5.4
Special cases of censoring.......................................................................................... 10
4.5.5
Classification of investigator reported bleeding......................................................... 11
4.5.6
Blind Review of important deviations and validity findings...................................... 13
5.
Analysis Sets .................................................................................................................... 13
5.1
Assignment of analysis sets ........................................................................................... 13
6.
Statistical Methodology .................................................................................................. 14
6.1
Population characteristics .............................................................................................. 14
6.1.1
Disposition.................................................................................................................. 14
6.1.2
Protocol Deviations .................................................................................................... 14
6.1.3
Demography and baseline characteristics................................................................... 15
6.1.4
Medical history........................................................................................................... 15
6.1.5
Prior and concomitant medication.............................................................................. 15
6.1.6
Subgroup analyses ...................................................................................................... 16
6.2
Efficacy.......................................................................................................................... 16
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 18
6.3.1
Pharmacokinetics........................................................................................................ 18
6.3.2
Pharmacodynamics..................................................................................................... 18
6.4
Safety ............................................................................................................................. 19
6.4.1
Primary Safety............................................................................................................ 19
6.4.2
Subgroup analyses ...................................................................................................... 22
6.4.3
Analyses related to COVID-19 .................................................................................. 22
6.4.4
Vital Signs .................................................................................................................. 23
6.4.5
Laboratory parameter ................................................................................................. 23
6.4.6
Biomarker................................................................................................................... 23
6.4.7
Electrocardiograms..................................................................................................... 24
6.4.8
Adverse events............................................................................................................ 24
6.4.9
Pregnancies................................................................................................................. 25
7.
Document history and changes in the planned statistical analysis............................. 25
8.
References ........................................................................................................................ 25


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Protocol No.: BAY 2433334 / 19765
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Abbreviations
AE
Adverse event
AF
Atrial fibrillation
ALT
Alanine aminotransferase
ASA
Acetylsalicylic acid
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BARC
Bleeding Academic Research Consortium
CABG
Coronary artery bypass graft
CEC
Clinical Events Committee
CI
Confidence interval
CRF
Case report form
csHR
Cause-specific hazard ratio
CV
Cardiovascular
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EOT
End of treatment
ET
Early Termination
F1.2
F1.2 fragment of prothrombin
FAS
Full Analysis Set
FXIa
Activated Factor XI
hsCRP
High-sensitivity C-reactive protein
IDMC
Independent data monitoring committee
ISTH
International Society on Thrombosis and Hemostasis
ITT
Intention-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
NOAC
Non-Vitamin K oral anticoagulant
NT-proBNP
N-terminal pro B-type Natriuretic Peptide
PK
Pharmacokinetic(s)
PT
Preferred term
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SFU
Safety follow up
SOC
System organ class
TAFI
Thrombin-activatable fibrinolysis inhibitor
TAT
Thrombin antithrombin complex
TIA
Transient ischemic attack
TIMI
Thrombolysis in myocardial infarction
VKA
Vitamin K antagonist
1.
Introduction
This Phase 2 study will explore two doses of BAY 2433334 in order to determine a lower risk 
for bleeding when compared to apixaban (a NOAC) as well as the dose that is safe and can be 
used in a Phase 3 study in the same indication.
Current treatment guidelines recommend the use of long-term oral anticoagulant therapy such 
as VKAs, or NOACs.
Despite a better benefit-risk profile for NOACs when compared to VKAs, patients receiving 
NOACs continue to have a significant risk for developing strokes, systemic embolism and CV


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Protocol No.: BAY 2433334 / 19765
Page: 4 of 25:
death. In addition, even though NOACs lead to less intracranial hemorrhage compared to 
VKAs, there is still a significant risk for major and clinically relevant non-major bleeding.
BAY 2433334, as an oral FXIa inhibitor, is expected to show a benefit in reducing the risk for 
stroke in patients with AF in Phase 3. At the same time BAY 2433334 is expected to have a 
low bleeding risk. This is based on the available preclinical data, data from patients with 
inherited FXI deficiency and first clinical data from 2 Phase 2 proof-of-concept studies in 
participants undergoing total knee replacement.
BAY 2433334 is therefore an attractive candidate to evaluate as a potential replacement for 
NOAC therapy in patients with AF.
The SAP is based on the protocol version 1.0 (approved: 25 SEP 2019).
2.
Study Objectives
The primary safety objective of the study is to evaluate if the oral FXIa inhibitor BAY 
2433334 when compared to apixaban leads to a lower incidence of bleeding in participants 
with AF.
The primary safety estimand is the ratio of the proportions of the composite of ISTH major 
and clinically relevant non-major bleeding within 3 months comparing pooled doses of BAY 
2433334 and comparator drug apixaban in adult participants with AF who have taken at least 
one dose of study medication of BAY 2433334 or comparator drug apixaban, while the 
participant is alive and exposed to study intervention.
There are no primary efficacy objectives for this trial.
Exploratory efficacy and safety objectives are:

to explore the efficacy of BAY 2433334 compared to apixaban in reducing the risk for 
cardiovascular events (CV death, MI, stroke, systemic embolism) in participants with 
atrial fibrillation,

to explore additional pharmacokinetic and pharmacodynamic parameters, biomarkers 
and genetics, and

to further investigate the study intervention (i.e. mode-of-action-related effects and/or 
safety) and to further investigate pathomechanisms deemed relevant to cardiovascular 
diseases and associated health problems.
An overview of the objectives and corresponding endpoints is given in Table 2-1.


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Table 2-1 Objectives and Endpoints
Objectives
Endpoints
Primary

to evaluate that the oral FXIa inhibitor 
BAY 2433334 when compared to 
apixaban leads to a lower incidence of 
bleeding in participants with AF 
Primary Safety Endpoints

composite of ISTH major and clinically 
relevant non-major bleeding 
Secondary Safety Endpoints

all bleeding

ISTH major bleeding

ISTH clinically relevant non-major 
bleeding

ISTH minor bleeding
Exploratory Safety Endpoints

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

BARC bleeding definition type 1, 2, 3, 5

BARC bleeding definition type 3, 5 

BARC bleeding definition type 2, 3, 5

BARC bleeding definition type 1
Exploratory 

to explore the efficacy of BAY 2433334 
compared to apixaban in reducing the 
risk for cardiovascular events (CV 
death, MI, stroke, systemic embolism) 
in participants with atrial fibrillation

to explore additional pharmacokinetic 
and pharmacodynamic parameters, 
biomarkers and genetics

to further investigate the study 
intervention (i.e. mode-of-action-related 
effects and/or safety) and to further 
investigate pathomechanisms deemed 
relevant to cardiovascular diseases and 
associated health problems
Exploratory Efficacy Endpoint

composite as well as individual 
components of CV death, MI, ischemic 
stroke, systemic embolism

all-cause mortality
Other Exploratory Endpoints

FXIa inhibition, aPTT, D-Dimer

Pharmacokinetics

Various biomarkers (e.g. diagnostic, 
safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers)
Abbreviations: AF = atrial fibrillation, aPTT = activated partial thromboplastin time, BARC = Bleeding Academic 
Research Consortium, CV = cardiovascular, ISTH = International Society on Thrombosis and Hemostasis, 
MI = myocardial infarction, TIMI = Thrombolysis in myocardial infarction
3.
Study Design
Study 19765 is a multicenter, randomized, active-comparator controlled, double-blind, 
double-dummy, parallel group, dose-finding Phase 2 study.
The study population includes participants of 45 years of age or older with AF documented by 
ECG evidence with:

CHA2DS2-VASc score ≥ 2 if male or

CHA2DS2-VASc score ≥ 3 if female.

Indication for treatment with an oral anticoagulant in:


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Protocol No.: BAY 2433334 / 19765
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
any participant currently not treated with an oral anticoagulant
(e.g. treatment naïve) or alternatively,

participant on a NOAC in case of at least one bleeding risk feature (history of a 
prior bleed within the last 12 months requiring medical attention and / or 
moderate renal dysfunction with eGFR 30-50 ml/min and / or current clinically 
indicated antiplatelet therapy with acetylsalicylic acid [ASA] ≤ 100 mg).
Stratification will be based on whether participants received a NOAC before study start or 
were not treated with any oral anticoagulant.
The planned study duration will be 14-16 weeks, consisting of:

Screening period (visit 1 until visit 2): 2 weeks (participants will be screened and 
have to be randomized within 2 weeks of screening. If all information is available, a 
participant can be randomized on the day of screening (visits 1 and 2 are combined).

Treatment period (from visit 2 through visit 6 [EOT] or visit 6a [ET]): 12 weeks

Safety follow-up (visit 7 [SFU]): 14 days (+ 7 days) after EOT or ET.
Study visits will take place as visits at the study sites and telephone calls. Visits at the study 
sites take place at screening and randomization (visit 1 and visit 2), at week 4 (visit 4) and 
week 12 (i.e. EOT, visit 6).
Telephone calls will take place at week 2 (visit 3), week 8 (visit 5), as well as 2 weeks after 
the EOT visit for participants who will take study intervention until the planned EOT (i.e. 
SFU, visit 7).
For participants who prematurely discontinue from study intervention, an early termination 
(ET) visit (visit 6a) will take place as soon as possible as visit at the study sites. Telephone 
calls take place 14 days after the ET visit (i.e. SFU, visit 7).
The study design is presented in Figure 3-1: Study design overview.


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Protocol No.: BAY 2433334 / 19765
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Figure 3-1: Study design overview
Note: Participants receiving BAY 2433334 will also receive the apixaban matching placebo.
Participants receiving apixaban will also receive the BAY 2433334 matching placebo.
During the safety follow-up, further therapy (e.g. NOAC) is at discretion of the investigator.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.4
(SAS Institute Inc., Cary, NC, USA).
All variables will be analyzed by descriptive statistical methods. The number of data available 
and missing data, mean, standard deviation, minimum, quartiles, median, and maximum will 
be calculated for metric data. Frequency tables will be generated for categorical data.
Data will be displayed by randomized treatment arm.
Potential 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 
potential exploratory 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 contained in the CEC charter:

Bleeding events according to the following classifications:

ISTH (major, clinically relevant non-major and minor)

TIMI (major, minor, requiring medical attention, minimal)

BARC (type 1, 2, 3, 5)

Death (CV death [including death with unknown cause] or non-CV death)

MI


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Protocol No.: BAY 2433334 / 19765
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
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 and with increased cardiac enzymes reported.
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.
4.2
Handling of Dropouts
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is definitively discontinued, the participant will remain in 
the study to be evaluated for bleeding and efficacy outcome events until the planned regular 
end of treatment. In this study, all efforts must be taken to engage patients to comply with all 
study procedures and to continue to be followed until the end of the study.
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject is randomized to study treatment. A subject is regarded a “screening
failure” if he or she consented to participate in the study but is not subsequently assigned to 
study intervention.
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject's medical records.
A participant will be considered lost to follow-up if he or she repeatedly (twice) fails to return
for scheduled visits and is unable to be contacted by the study site. A participant may 
withdrawal of consent at any time. This should only occur in exceptional cases and means that 
the participant does not agree to any kind of follow-up and specifically refuses any further 
contact with the investigator. All data collected before withdrawal of consent will be used for 
analysis.
The number of subjects who prematurely discontinue the study during the treatment phase or 
during the post-treatment observation phase for any reason, as well as the reasons for 
premature discontinuation of study, will be displayed by treatment arm. Baseline 
characteristics will be displayed by premature discontinuation (yes/no) from study. The 
number of subjects who are considered lost to follow-up during the treatment phase or during 
the post-treatment observation phase will be displayed by treatment arm.
4.3
Handling of Missing Data
All efforts will be made to collect complete data for all participants randomized in this study. 
Participants will be followed up to the safety follow-up visit and all required data will be 
collected.
Data from participants who prematurely discontinue the study will be used to the maximum 
extent possible. Participants that discontinued from study drug will remain in the study to be 
evaluated for bleeding and efficacy outcome events until their planned regular end of 
treatment visit. All missing or partial data will be presented in the participant data listing as 
they are recorded in the eCRF. Data are collected primarily through an EDC system, which 
allows ongoing data entry and monitoring.


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Additional descriptive analyses in the presence of missing data
All dropouts will be carefully evaluated with respect to

baseline characteristics,

potential differences between the treatment groups in the proportion of participants
withdrawals or in the timing of withdrawals, and

the reasons for premature discontinuation of study and/or study treatment, and 
potential dropout patterns will be described.
General rules
When appropriate, the following rules will be implemented so as not to exclude participant
from statistical analyses due to missing or incomplete data:

Incomplete date of outcome
When only partial dates are available, the following rule will be used for the 
derivation of dates for efficacy and safety events as well as for the date of Adverse 
events: Any event will be assumed to happen as early as possible, i.e. the earliest of 
the timeframe known but not earlier than the last date where the participant is known
event free.

Incomplete time of outcome
For events happening at the day of first study drug intake with no timepoint it will be 
assumed that they happen after the first intake of study drug, i.e. the time of study 
drug intake will be used for the time of the outcome.
4.4
Interim Analyses and Data Monitoring
An independent Data Monitoring Committee will review safety data according to the IDMC
charter. No alpha adjustment is required. No formal interim analysis is planned. Two non-
formal interim analyses are planned, and the statistical analysis will be done by an 
independent statistical analysis center. A separate SAP will be prepared for this.
4.5
Data Rules
4.5.1
Baseline values
Baseline values for vital sign measures and laboratory values are planned to be taken at Visit 
2 before administration of study drug. If these values are not available, values taken before 
first administration of study drug will be considered (e.g., values taken on Visit 1). In case of 
more than one available value before first administration of study drug, the non-missing value 
closest to Visit 2 will be taken.
4.5.2
Data Scopes
Treatment emergent data scope
For the treatment emergent data scope all events from first intake of study drug up until 2 
days after the last intake of study treatment will be counted. The time to event for participants
with no event until 2 days after the last intake of study drug (end of data scope) will be 
censored at that day.
For events at the day of randomization will be counted if the time of occurrence is later than 
the time of first study drug intake.


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This data scope will be used to handle intercurrent events according to the “while on 
treatment” strategy.
Intention-to-treat (ITT) data scope
For the intention-to-treat (ITT) data scope all events from randomization up until end of 
treatment visit (Visit 6) (end of data scope) will be counted. The time to event for participants 
with no event up until the end of treatment visit will be censored at that day.
This data scope will be used to handle intercurrent events according to the “treatment policy” 
strategy.
4.5.3
Time-to-Event variables
For the treatment emergent data scope, the time from first intake of study drug to an event is 
of interest. The time to an event (in days) will be derived the following:
Date of Event – Date of first study drug intake + 1.
For time to event variables in the intention-to-treat (ITT) data scope the time from 
randomization to an event is of interest. The time to an event (in days) will be derived the 
following:
Date of Event – Date of randomization + 1.
Survival functions, incidence rates and cumulative hazard calculations will be done only for 
endpoints with at least 3 events in at least one treatment arm. (Cause specific) hazard ratios 
(csHR) will be calculated only if in addition at least 1 event in each of the compared treatment 
arm occur.
If treatment arms are pooled the number of events needed applies on the pooled arm not on 
each treatment arm.
4.5.4
Special cases of censoring
In special cases, the censoring differs from the section before.
If no event is observed, the censoring date will be determined by the following:

In case of death of the participant before visit 6:
o
the date of the death.

In case the participant dies after the end of treatment visit (visit 6) but before the 
safety follow-up (visit 7)
o
the censoring date according to the “treatment policy” strategy is the date of 
visit 6
o
the censoring date according to the “while on treatment” strategy is the earliest 
of 2 days after last study drug intake and the date of death.

In case the participant is lost to follow up before end of data scope
o
the last study contact date, defined as the latest date of any visit date and dates 
of any (outcome) events
o
if the vital status is known alive at any date after the last study contact date: for 
the event death (including CV and non-CV-death): the date of this information.

In case the participant withdraws consent before end of data scope
o
the date of withdrawal of informed consent


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o
if the vital status is known alive at any date after the last study contact date: for 
the event death (including CV and non CV-death): the date of this information.
4.5.5
Classification of investigator reported bleeding
Bleedings will be adjudicated by an independent CEC. To compare the investigator reported 
bleeding with the adjudicated bleeding an investigator reported bleeding classification is 
needed.
4.5.5.1
ISTH Major Bleeding, ISTH Clinically Relevant Non-Major and ISTH
Minor Bleeding
A bleeding will be counted as investigator reported ISTH major bleeding if:
1. The outcome of the bleeding is fatal and/or
2. The bleeding is symptomatic and site is in a critical area or organ, i.e. bleeding site 
is: intracranial, intraocular, intraspinal, pericardial, retroperitoneal, intraarticular, 
or intramuscular with compartment syndrome and/or
3. The bleeding is clinically overt
a.
with a recent decrease in the hemoglobin level of ≥2 g/dl within 48 hours 
of bleeding event, that was related to the bleeding event and/or
b. leading to transfusion of 2 or more unites of packed red blood cells or 
whole blood.
A bleeding will be counted as investigator reported ISTH Clinically Relevant non-major 
bleeding if it is considered any sign or symptom of hemorrhage, but does not fit the ISTH 
definition of major bleeding but does meet at least one of the following criteria:
1. requiring any healthcare professional guided treatment to control the bleeding
2. leading to hospitalization or increased level of care
3. prompting a face to face (i.e. not just a telephone or electronic communication) 
evaluation
A bleeding is considered any sign or symptom of hemorrhage, if the bleeding is overt, i.e.
visible or documented by imaging.
An increased level of care is similar to the requirement 3., i.e. prompting a face to face (i.e. 
not just a telephone or electronic communication) evaluation
An overt bleeding that does not met the criteria for either ISTH major or clinically relevant 
non-major bleeding will be classified as ISTH minor bleeding.
4.5.5.2
TIMI Bleeding Definitions
The non-CABG-related TIMI clinically significant bleeding definition encompasses the 
following bleeding types excluding events that are related to a CABG procedure: TIMI Major 
bleeding, TIMI Minor bleeding and TIMI Bleeding requiring medical attention.
A bleeding will be counted as non-CABG related TIMI Major bleeding if
1. it is not related to a CABG procedure and


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2. is any symptomatic intracranial hemorrhage and/or
3. has clinically overt signs of hemorrhage (including imaging) associated with a 
drop in hemoglobin of ≥5 g/dl (or when hemoglobin concentration is not 
available, an absolute drop in hemocrit of ≥15%) and/or
4. is fatal (bleeding leading to death within 7 days).
A bleeding will be counted as non-CABG related TIMI Minor bleeding if
1. it is not related to a CABG procedure and
2. has clinically overt signs of hemorrhage (including imaging) associated with a fall 
in hemoglobin of 3 to < 5 g/dl (or when hemoglobin concentration is not available, 
a fall in hemocrit of 10 to < 15%.
A bleeding will be counted as non-CABG related TIMI Bleeding event requiring medical 
attention if
1. it is not related to a CABG procedure and
2. requires medical treatment, surgical treatment, or laboratory evaluation and
3. does not meet criteria for major or minor bleeding event.
A bleeding will be counted as non-CABG mininal TIMI Bleeding event if
1. it is an overt bleeding and
2. does not meet criteria for major or minor TIMI Bleedign event or a TIMI Bleeding 
event requiring medical attention.
A bleeding is related to a CABG procedure if the site of bleeding is Cardiovascular system –
CABG related.
In addition to TIMI significant bleeding also TIMI major bleeding and TIMI minor bleeding 
will be analyzed, i.e. adding bleeding events that fulfill all criteria of the respective bleeding 
but that are related to a CABG procedure.
4.5.5.3
BARC Bleeding Definition
In this study the BARC bleeding definitions will be used. For that, different types are defined.
A bleeding will be counted as BARC bleeding Type 1 if it
1. is not actionable and does not cause the participant to seek any unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional.
A bleeding be counted as BARC bleeding Type 2 if it
1. has any overt, actionable sign of hemorrhage and
2. does not fit the criteria for type 3 or 5 and
3. requires non-surgical, medical intervention by healthcare professional and/or
4. leads to hospitalization or increased level of care and/or
5. prompts evaluation.
A bleeding “prompts evaluation” if it leads to diagnostic testing (laboratory or imaging).
BARC bleeding Type 3 subdivides in types 3a, 3b and 3c.


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A bleeding will be counted as BARC bleeding Type 3a if it
1. is an overt bleeding with a hemoglobin drop of 3 to <5 g/dL and/or
2. any transfusion with overt bleeding is related to the bleeding.
A bleeding will be counted as BARC bleeding Type 3b if it
1. is an overt bleeding with a hemoglobin drop of ≥5 g/dL and/or
2. is cardiac tamponade and/or
3. requires surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) 
and/or
4. requires intravenous vasoactive agents.
A bleeding will be counted as BARC bleeding Type 3c if it
1. is intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, includes intraspinal), subcategories confirmed by autopsy or 
imaging or lumbar puncture and/or
2. intraocular bleeding compromising vision
The hemoglobin drop can be corrected for transfusion. 1 U of packed red blood cells or whole 
blood equals 1g/Dl hemoglobin.
BARC bleeding Type 5 are fatal bleedings. They subdivide into Type 5a and Type 5b.
A bleeding will be counted as BARC bleeding Type 5a if it
1. is probable fatal, i.e. no autopsy or imaging confirmation is done but it is clinically 
suspicious.
A bleeding will be counted as BARC bleeding Type 5b if it
1. is definite fatal, i.e. it is overt or autopsy or imaging confirmation has been done.
4.5.6
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 set(s). Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the
review of study data before data base closure and documented in the final list of important 
deviations, validity findings and assignment to analysis set(s).
Full analysis set (FAS)
A subject will be included in the FAS if he/she is randomized to a treatment group.
Safety analysis set (SAF)
A subject will be included in the SAF if he/she is randomized to a treatment group and has 
taken at least one unit of the study medication.


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Pharmacokinetic Analysis Set
A subject will be included in the pharmacokinetic analysis set, if it has received active 
treatment, has at least 1 valid plasma concentration of BAY 2433334 and is without protocol 
deviation, which would interfere with the evaluation of the PK data.
Pharmacodynamic Analysis Set
A subject will be included in the pharmacodynamic analysis set, has at least 1 valid 
pharmacodynamic value and is without protocol deviation, which would interfere with the 
evaluation of the pharmacodynamic data. All PD analyses will be performed on the PD
analysis set (PDS).
6.
Statistical Methodology
The primary analysis population for all analyses will be the SAF. Tables will be shown by 
treatment arm and overall. No adjustment for multiplicity will be performed.
6.1
Population characteristics
6.1.1
Disposition
The following will be tabulated by treatment group and overall:
•
Study sample sizes by region and country
•
Study sample sizes by country and site
•
Participants disposition
•
Number of participants and primary reasons for screening failures
•
Number of participants and primary reasons for premature discontinuation 
of study medication 
•
Number of participants and primary reasons for premature discontinuation 
of study follow up.
Incidences for permanent discontinuation of the double-blinded study drug and of the follow-
up period will be provided by randomized study treatment groups, based on the case report 
form data.
Kaplan-Meier estimates will be used to present
•
time to the date of last double-blind dose of study treatment,
•
time to the date of last follow-up contact,
all calculated as days from randomization, by study treatment group.
Other details regarding visit adherence (e.g., visit completed in person, by telephone, through 
third party) and completion as well as study drug adherence collected via CRFs will be 
summarized using frequency tables by visit and study treatment group.
6.1.2
Protocol Deviations
No per protocol analysis set will be defined in this study. The number of participants with 
major protocol deviations and validity findings according to the CRF will be summarized by 
study treatment group as well as reasons.


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6.1.3
Demography and baseline characteristics
Demographic and baseline data as collected in the CRF will be evaluated descriptively for the 
SAF as well for the FAS, by treatment groups and overall. No statistical tests will be 
performed to compare these characteristics across treatment groups.
Descriptive statistics (such as mean, standard deviation, median, quartiles, minimum and 
maximum) will be provided for continuous variables.
Counts and (appropriate) percentages will be provided for categorical variables.
Besides others the following variables will be displayed:

Sex

Race (White, Black, Asian, other)

Region (North America; Western Europe and Australia; Eastern Europe; Asia)

Age (< 65 years, 65 – 75 years, > 75 years)

BMI: < 25; ≥ 25 to < 30; ≥ 30kg/m2

Weight: <60; 60-90; >90 kg

eGFR: <50; 50-80; >80 mL/min

AF pattern: Paroxysmal, Persistent, Long-standing persistent, Permanent

For patients currently treated with a NOAC the following subgroups will be defined
o
History of a prior bleed within the last 12 months requiring medical attention 
(yes/no)
o
Moderate renal dysfunction with eGFR 30-50 ml/min (yes/no)
o
Current clinically indicated antiplatelet therapy with ASA ≤ 100 mg (yes/no)

Stroke or TIA prior to enrollment (yes/no)

Time from AF diagnosis to randomization:  ≤30 days; 30 days to 3 months; > 3months

Chronic Kidney Disease (yes/no)

Coronary Artery Disease (yes/no)

Hypertension (yes/no) 

Diabetes (yes/no)

Tobacco use: Never; Former; Current 
6.1.4
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 and that are considered relevant 
for the participant’s study eligibility using MedDRA Primary System Organ Class / Preferred
Term. Number and percentages of subjects with AF pattern will be shown separately.
6.1.5
Prior and concomitant medication
Prior and concomitant medication will be evaluated by frequency tables, showing the number 
and percentage of participants with

prior medication, i.e. medications taken before start of study drug, regardless of when 
they ended,


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
concomitant medication, i.e. medications taken within the treatment period

ongoing concomitant medication at start of study drug,

medication started during the treatment period, and

medication started after stop of study medication.
Prior and concomitant medication will be shown by ATC classes and subclasses.
Separate tables will be provided for anticoagulants, antiplatelet therapy used and for CYP3A4 
inhibitors and inducers.
A separate table for concomitant prohibited medication will be shown.
6.1.6
Subgroup analyses
Selected demography and baseline characteristics, medical history and prior and 
concomitant medication tables will be repeated for the following subgroups:

Prior use of NOAC (yes/no)

Risk factors for apixaban dosage (0-1, 2-3)
6.2
Efficacy
Efficacy analyses in this study will be exploratory only.
Exploratory endpoints for this study are:

the composite as well as individual components of CV death, MI, ischemic stroke, 
and systemic embolism,

all-cause mortality.
Events will be counted in the intention-to-treat data scope for the full analysis set.
The number of participants with an efficacy endpoint and percentages will be shown by 
treatment arm.
Taking the time under risk into account, the exposure-adjusted incidence rate will be 
calculated for each treatment arm with an 90% confidence interval.
The incidence rate (IR) will be expressed as “participants with an event per 100 participant
years”. For that the following formula (Unkel, et al. 2019) is used:
 =
#  !"#$%$&!'#( )$#ℎ !' +,+'#
∑#$.+ #/ +,+'# (/" %+'(/"$'1)($' 3!4()/(100 ∗365.25).
The 90% confidence interval for the IR will be computed as
< ∗ =>(0.05; 2+)
2+
;  ∗ =>(0.95; 2+)
2+
 A ,
with =>(C; 2+) the q quantile of a chi square distribution with 2e degrees of freedoms and e 
the number of participants with an event. (Nelson 1982)
In addition, time-to-first-event analyses taking competing events into account will be 
performed. For that Aalen-Johansen estimates for the cause specific cumulative risk will be 
presented.
The competing event for the efficacy events is death or non-CV death for endpoints that 
include CV death. There will be no competing event for all-cause mortality.


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The cumulative incidence, i.e. the probability of having a specific event E at or before a 
timepoint t,  (D ≤#, F = 1), will be estimated for time-to-event endpoints by Aalen-
Johansen estimators with the competing event as defined before. For the Aalen-Johansen 
estimator the cumulative hazard calculated by the cause-specific Nelson-Aalen estimator is 
needed. The calculation of the estimators follows Allignol, Beyersmann and Schmoor
(Allignol, Beyersmann and Schmoor 2016).
The cause-specific Nelson-Aalen estimator for an event E at timepoint t is calculated as:
GHI(#) = J # !"#$%$&!'#( )$#ℎ !' +,+'# F !# #K
# !"#$%$&!'#( L'3+" "$(M !# #K
NOPN
.
The Aalen-Johansen estimator takes the difference of the cause-specific Nelson-Aalen 
estimator into account, weighted with the Kaplan-Meier (KM) survival function, i.e. the 
Aalen-Johansen estimator for time t is defined as:
QRI
S (#) = J TH(#KUV)(GHIW#KX −GHIW#KUVX) 
NOPN
.
Gray’s (Gray 1988) test for equivalence of the cumulative incidence functions, stratified by 
prior usage of NOAC, will be performed. To derive the Aalen-Johansen estimators and the 
test statistics with the corresponding confidence intervals, SAS program code corresponding 
to the following will be used:
PROC LIFETEST DATA = <dataset> ALPHA=0.1 ERROR=AALEN;
  STRATA stratumn / GROUP=trtgrpn;
  TIME ttevalue * status(0)/eventcode=1;
RUN;
/*
where
dataset  = name of sub-dataset including all FAS participants randomized to 
           respective BAY2433334 treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = apixaban control group, 1 = BAY2433334 treatment
ttevalue = time to first occurrence of outcome event or competing event
status  = status of the participant at event time (0 = right-censored,
          1 = event of interest, 2 = competing event)
stratumn = variable for NOAC stratification factor (two levels)
*/
Cause-specific HRs will be calculated for the respective event and the competing event. The 
cause-specific hazard ratios and the corresponding confidence intervals will be estimated on 
separate cause-specific hazard models for the comparison of the pooled doses of BAY 
2433334 versus apixaban and for each treatment dose of BAY 2433334 versus apixaban (if 
applicable). No comparison of the different doses of BAY 2433334 is planned.
To derive the cause specific hazard ratios and the corresponding confidence intervals, SAS 
program code corresponding to the following will be used:


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PROC PHREG DATA = <dataset>;
  MODEL ttevalue*status(0)=trtgrpn / RL ALPHA=0.1 EVENTCODE=1 TIES=EFRON;
STRATA stratumn;
RUN;
/*
where
dataset  = name of sub-dataset including all FAS participants randomized to 
           respective BAY2433334 treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
ttevalue = time to first occurrence of outcome event or competing event
status  = status of the participant at event time (0 = right-censored,
          1 = event of interest, 2 = competing event)
stratumn = variable for stratification factor (two levels)
*/
6.3
Pharmacokinetics/pharmacodynamics
The population PK analysis and pharmacodynamic analyses may be presented separately 
from the CSR and will be described in a separate analysis plan.
6.3.1
Pharmacokinetics
BAY 2433334 and BAY 2826102 concentrations will be summarized per sampling interval 
and visit, separated according to actual dose.
The analyses will be focused on descriptive statistics. The following statistics will be 
calculated for each of the sampling intervals: arithmetic mean, standard deviation and 
coefficient of variation (CV), geometric mean, geometric standard deviation (re-transformed 
standard deviation of the logarithms), and CV, minimum, median, maximum value and the
number of measurements.
Means at any time will only be calculated if at least 2/3 of the individual data were measured
and were above the lower limit of quantification (LLOQ). For the calculation of the mean 
value a data point below LLOQ will be substituted by ½ LLOQ.
Plots will be prepared by naïve pooling all individual plasma concentrations (naïve pooling) 
versus actual relative study times (time of sample collection after time of study drug 
administration, time after most recent dose) using both a linear and semi-logarithmic scale, 
and presented by visit and treatment. Samples which are collected outside of the predefined 
windows will nevertheless be valid for PK analysis.
6.3.2
Pharmacodynamics
Plots will be prepared by pooling all individual PD data (naïve pooling) versus actual relative 
study times (time of sample collection after time of study drug administration, time after most 
recent dose) using both a linear and semi-logarithmic scale, and presented by visit and 
treatment, for absolute values, change from baseline and ratio to baseline. Samples which are 
collected outside of the predefined windows will nevertheless be valid for PD analysis.
The following PD/PD correlations will be provided as scatterplots (with observed values, 
changes from baseline and ratios to baseline): 


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
aPTT versus inhibition of FXIa (AXIA) 

D-Dimer versus inhibition of FXIa (AXIA)

D-Dimer versus aPTT
The following PK/PD correlations will be provided as scatterplots (with observed values, 
changes from baseline and ratios to baseline):

aPTT versus plasma concentrations of BAY 2433334.

inhibition of FXIa (AXIA) versus plasma concentrations of BAY 2433334.

D-Dimer versus plasma concentrations of BAY 2433334
The following data rules apply:

Changes from baseline = Actual value - Baseline value

Ratio to Baseline = Actual value / Baseline value
Further data-driven exploratory analyses may be applied.
For the calculation of the mean value a data point below LOQ will be substituted by one half 
of the limit.
6.4
Safety
6.4.1
Primary Safety
6.4.1.1
Primary Safety Estimand
The primary safety estimand is the ratio of the proportions of the composite of ISTH major 
and clinically relevant non-major bleeding within 3 months comparing pooled doses of BAY 
2433334 and comparator drug apixaban in adult participants with AF who have taken at least 
one dose of study medication of BAY 2433334 or comparator drug apixaban, while the 
participant is alive and exposed to study intervention.
6.4.1.2
Primary Safety Analyses
The primary estimator is the ratio of incidence proportions of the primary safety endpoint 
observed in participants who are under treatment with BAY 2433334 (all doses pooled) and 
the active comparator for up to 12 weeks with corresponding 90% confidence interval.
The (crude) incidence proportion of the primary safety endpoint is defined as the number 
participants with an event in 12 weeks while the participant is under exposure of study drug
(counting treatment according to the treatment emergent data scope) divided by the number of 
participants in the treatment arm who took at least one dose of study drug, (the SAF 
population) i.e.
Z
S[ =
# !"#$%$&!'#( )$#ℎ !' +,+'#
# !"#$%$&!'#( #ℎ!# #//M !# \+!(# /'+ 3/(+ /] (#L34 3"L1 Q.
These incidences proportions will be estimated for BAY 2433334 arm (all doses pooled) and 
the apixaban arm. The main estimator for this study is the ratio of the (crude) incidence
proportions


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Protocol No.: BAY 2433334 / 19765
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Z
S = Z
S^[_ >`aaaa`
Z
S[bcdefeg
.  
The corresponding 90% two-sided confidence interval will be calculated using the Farrington-
Manning score for an exact confidence interval. The calculation of the ratio of crude 
incidences and the confidence intervals will be done by using SAS code corresponding to the 
following:
proc freq data=<dataset>;
     tables trtgroup * status / alpha=0.1;
     exact relrisk (method=FMSCORE);
run;
/*
where
dataset  = name of sub-dataset including all SAF participants randomized to 
           respective BAY2433334 treatment group and control group
trtgrpn  = variable coding randomized antithrombotic treatment group
           (0 = apixaban control group, 1 = BAY2433334 treatment
status  = status of the participant at event time (0 = right-censored,
          1 = event of interest)
*/
Taking the time under risk into account, the exposure-adjusted incidence rate will be 
calculated for each treatment arm with an 90% confidence interval.
The exposure-adjusted incidence rate will be expressed a “subjects with an event – per 100 
participant years”. For that the following formula is used:
ehK =
# !"#$%$&!'#( )$#ℎ !' +,+'#
∑ #$.+ L'3+" #"+!#.+'# ($' 3!4()/(100 ∗365.25)
The 90% confidence interval for the exposure-adjusted IR will be computed as
<ehK ∗ =>(0.05; 2+)
2+
; ehK ∗ =>(0.95; 2+)
2+
 A ,
with =>(C; 2+) the q quantile of a chi square distribution with 2e degrees of freedoms and e 
the number of participants with an event. (Nelson 1982)
In addition to the main analysis, time-to-first-event analyses taking competing events into 
account will be performed. For that Aalen-Johansen estimates for the cause specific 
cumulative risk will be presented.
The competing events for the primary safety endpoint are Death (all causes) and premature 
discontinuation.
The cumulative incidence risk, i.e. the probability of having a specific event E at or before a 
timepoint t,  (D ≤#, F = 1), will be estimated for time-to-event endpoints by Aalen-
Johansen estimators with the competing event as defined in section 6.2.
The difference of the Aalen-Johansen estimators at day 85 (week 12) between BAY 2433334 
treatment and Apixaban will be presented with a 90% confidence interval. 
As the Aalen-Johansen estimator is approximately normal distributed (Aalen, Borgan and 
Gjessing 2008), the difference of Aalen-Johansen estimators is approximately normal
distributed. Thus, the two-sided 90% confidence interval is obtained via:


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<(QR
S ^[_(85) −QR
S[bcdefeg(85)) ± kl.mnop>(QR
S^[_(85)) + p>(QR
S^[_(85))   A ,
with QR
Sqrq(85) the Aalen-Johansen estimator for treatment TRT at day 85, kl.mn the 95% 
quantile of the standard normal distribution and p>(QR
Sqrq(85)) the estimated variance of the 
Aalen-Johansen estimator at day 85, estimated with the Aalen method.
All analyses will be done for the pooled doses of BAY 2433334 and for each of the two 
doses.
csHRs will be calculated for the respective event and the competing event. Gray’s test of 
equivalence of the cumulative incidence functions, stratified by prior usage of NOAC, will be 
performed. The cause specific hazard ratios and the corresponding confidence intervals will 
be estimated on separate models for the pooled doses of BAY 2433334 and each comparison 
(if applicable). No comparison of the different doses of BAY 2433334 is planned.
6.4.1.3
Secondary Safety Analyses
The secondary safety estimands are the ratios of the proportions of participants experiencing 
the individual endpoints within 3 months, comparing pooled doses of BAY 2433334 and 
comparator drug apixaban in adult participants with AF who have taken at least one dose of 
study intervention (BAY 2433334 or apixaban, the comparator drug), while the participant is 
alive and exposed to study intervention for each of the endpoints:

all bleeding

ISTH major bleeding

ISTH clinically relevant non-major bleeding

ISTH minor bleeding.
The main analyses will follow the main estimation for the primary safety endpoint. In 
treatment arms with 3 or more events, in addition exposure-adjusted incidence rates and
Aalen-Johansen estimators will be presented.
6.4.1.4
Exploratory Safety Analyses
Exploratory safety endpoints are: 

TIMI clinically significant bleeding,

TIMI major bleeding, 

TIMI minor bleeding,

BARC bleeding definition type 2, 3, 5,

BARC bleeding definition type 3, 5

BARC bleeding definition type 1, 2, 3, 5, and.

BARC bleeding definition type 1.
For these endpoints the analyses follow the the estimations for the other bleeding.
Descriptive tables of crude incidences of investigator-reported bleeding will be shown for all 
bleeding scales (ISTH, TIMI, BARC). A table will compare adjudicated and investigator-
reported bleeding outcomes.


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6.4.2
Subgroup analyses
For the primary endpoint and the endpoint all bleeding, subgroups analyses will be done for 
the following subgroups:

Treated with NOAC at randomization (yes/no)

Atrial fibrillation paroxysmal, persistent/permanent

Weight (<60; 60-90; >90 kg)

Age Group (< 65 years, 65 – 75 years, > 75 years)

eGFR: <50; 50-80; >80 mL/min

Risk factors for apixaban dosage (0-1, 2-3)

Sex

Race: White, Black, Asian, other

Region:  North America; Western Europe; Eastern Europe; Asia (Japan)

Stroke or TIA prior to enrollment (yes/no)

Treated with mild and moderate CYP3A4 inhibitors + inducers at randomization 
(yes/no)

CHA2DS2VASc-Score (2&3 vs. > 3 for male participants, 3&4 vs. >4 for female 
participants)
For these subgroups descriptive tables of crude incidence will be presented. In treatment arms 
with 3 or more events exposure-adjusted incidence rates will be presented.
Comparison between treatment arms is only planned for the following subgroups:

Treated with NOAC at randomization (yes/no)

Stroke or TIA prior to enrollment (yes/no)

Atrial fibrillation paroxysmal, persistent/permanent

Risk factors for apixaban dosage (0-1, 2-3)
6.4.3
Analyses related to COVID-19
Analysis due to COVID-19 pandemic will be described in this section but might affect all 
sections of the analyses.
A description of the number of study participants whose assessments and follow up in the 
study was impacted by the COVID-19 pandemic will be shown. In addition, a listing of all 
study participants affected by the COVID-19 pandemic by unique subject number identifier 
and by investigational site, and a description of how the individual’s participation was altered 
will be created.
For the primary safety estimand the intercurrent event “Treatment discontinuation due to 
COVID-19 related events” will be handled similar to any other premature discontinuation, i.e. 
all events from first intake of study drug up until 2 days after the last intake of study treatment 
will be counted.
Subgroup analyses for incidence tables will include the subgroup “Participants that are 
effected to any site closing due to COVID-19” will include all subjects that are randomized at 
sites that are closed due to COVID-19 before their individual end of treatment visit, resp. last 
study contact date, whatever is earlier. If there are more than one phase of closing in a site no 
distinction between the phases will be done. 


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Demographics, Medical history as well of the tables showing the number of participants with 
an efficacy or safety event will be additionally shown for this subgroup.
Protocotol deviations due to COVID-19 will be shown in the protocol deviations section as a 
separate category.
COVID-19 disease itself will be counted as an adverse event and therefore listed in the 
repective adverse event tables
If the number of patients with a dignosed COVID-19 disease is sufficiently high (i.e. 10 
participants or more), the following sensitivity analyses will be done for the efficacy and 
safety outcomes:
The primary estimand will handle the COVID-19 disease with an “while not having COVID-
19 disease” approach and censor any patients data 14 days before the (first) start of a COVID-
19 disease.
In addition the number of subjects with an event occurring after COVID-19 disease will be 
shown for efficacy and safety events.
6.4.4
Vital Signs
Vital signs (systolic and diastolic blood pressure, heart rate) obtained at Visit 1 (Screening), 
Visit 2 (Randomization (if not on the same day as Visit 1)), Visit 4 as well as during Final 
visit (Visit 6) and Early termination visit (Visit 6a) will be displayed by means of descriptive 
statistics and change from baseline.
6.4.5
Laboratory parameter 
Only centrally analyzed blood samples will be considered for analysis.
Central laboratory parameters (e.g. AST, ALT, eGFR) obtained at Visit 1 (Screening), Visit 2 
(Randomization (if not on the same day as Visit 1)), Visit 4 as well as during Final visit (Visit 
6) and Early termination visit (Visit 6a) will be displayed by means of descriptive statistics 
and change from baseline.
Number of participants with treatment emergent high abnormalities will be shown overall and 
by visit for the following laboratory parameter:

AST or ALT > 3xULN

AST and/or ALT >3xULN and bilirubin > 2xULN

AST or ALT >5xULN

AST or ALT >8x ULN.
6.4.6
Biomarker
Exploratory biomarker analyses, that might be performed optionally and/or only in a subset of 
participants are:

NT-proBNP

hsCRP

Thrombin-activatable fibrinolysis inhibitor (TAFI)

C1 inhibitor activity

TAT, and

F1.2


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The analyses will be performed at Visit 1 before the first dose and at the final Visit or Early 
Termination visit prior to the dose of open-label anticoagulant.
The biomarkers will be by means of descriptive statistics and change from baseline.
6.4.7
Electrocardiograms
A single 12-lead ECG will be performed  at Visit 1 (Screening), Visit 2 (Randomization (if 
not on the same day as Visit 1)) as well as during Final visit (Visit 6) and Early termination 
visit (Visit 6a). QRS, QT and QTc intervals will be displayed by means of descriptive 
statistics and change from baseline.
The number of participants with abnormal electrocardiograms findings will be displayed by 
visit.
6.4.8
Adverse events
The investigator has to record on the respective CRF pages all adverse events occurring in the 
period from start of intervention (first day of study intervention) until the safety follow-up 
visit. The original terms used by investigators to report AEs via the CRFs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA).
For each AE, the number and percentage of participants who experienced at least 1 
occurrence of the given event will be tabulated according to the affected primary system 
organ class (SOC) and preferred term (PT) by randomized treatment arm. A total column will 
be included in all safety summaries.
Frequency tables, showing an overall summary of number of participants with AEs, study 
drug related AEs, SAEs and AESIs will be given, and will include the following information:

maximum intensity for any AE,

AE related deaths,

AE resulting in permanent discontinuation of study drug,

treatment emergent AE.
AEs will be considered treatment-emergent if they begin after the first administration of study 
drug and they do not start after more than 2 days after the last administration. Determination 
of whether or not 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 4.3.
The severity or intensity of an (S)AE should be graded by the investigator with the following 
guidance:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.


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An event is defined as ‘serious’ when it meets at least 1 of the predefined criteria as described 
in the definition of an SAE, not when it is rated as severe.
6.4.9
Pregnancies
Any reported pregnancy occurring in female participants will be displayed. In addition, any 
reported pregnancy occurring in female partners of male participants after start of study 
intervention up until 4 days of the last intake of study drug will be displayed.
7.
Document history and changes in the planned statistical analysis

SAP Version 1.0 completed 10 DEC 2019

SAP Version 2.0: Changes in categorization of age added SAS code and statement on 
multiplicity adjustment, clarification of exploratory efficacy variable; add section for 
COVID-19 related (sensitivity) analyses; update Pharmacokinetics analysis part; 
changes in subgroups; add TIMI minimal bleeding definition, completed on 14  OCT 
2021
8.
References
Aalen, Borgan, and Gjessing. Survival and Event History Analysis. New York: Springer, 
2008.
Allignol, Beyersmann, and Schmoor. "Statistical issues in the analysis of adverse events in 
time-to-event-data." Pharmaceutical Statistics, no. 15 (2016): 297-305.
Gray. "A class of k-sample tests for comparing the cumulative incidence risk of a competing 
risk." The Annals of Statistics 16, no. 3 (1988): 1141-1154.
Nelson. Applied Life Data Analysis. New York: Wiley, 1982.
Unkel, et al. "On estimands and the analysis of adverse events in the presence of varying 
follow-up times within the benefit assesment of therapies." Pharmaceutical Statistics, 
no. 18 (2019): 166-183.