Clinical trial NCT04304534
Conditions: Acute Myocardial Infarction
Sponsor: Bayer
Start date: 2020-06-17; Completion date: 2022-02-21
Enrollment: 1601 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 on top of a dual antiplatelet therapy (acetylsalicylic acid +/- clopidogrel) in patients following a recent heart attack (myocardial infarction) that happens when a blood vessel in the heart suddenly becomes blocked. 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.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: BAY2433334 intervention 2: BAY2433334 matching placebo
Intervention descriptions: intervention 1: Tablet, taken orally once a day. intervention 2: Tablet, taken orally once a day.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study protocol 
Official Title: 
Multicenter, randomized, placebo controlled, double-blind, parallel 
group, dose-finding Phase 2 study to evaluate the efficacy and safety 
of BAY 2433334 in patients following an acute myocardial 
infarction 
NCT Number: 
NCT04304534 
Document Date: 
22-Oct-2019 
 


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Clinical Study Protocol
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Title Page
Protocol Title: 
Multicenter, randomized, placebo controlled, double-blind, parallel group, dose-finding Phase 
2 study to evaluate the efficacy and safety of BAY 2433334 in patients following an acute 
myocardial infarction
Protocol Number:
20603
Amendment Number:
not applicable
Compound Number:
BAY 2433334
Study Phase:
Phase 2b
Short Title:
Phase 2 Program of AntiCoagulation via Inhibition of FXIa by 
the oral Compound BAY 2433334 – Acute Myocardial
Infarction study
Acronym:
PACIFIC-AMI
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: 145673
EudraCT: 2019-003244-79
Approval Date: 
22 OCT 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.


CONFIDENTIAL 
Sponsor Signatory 
 
 
 
Clinical Study Protocol 
No. BAY 2433334 / 20603 
Version 1.0 
Date 
Page: 2 of78 
Medical Monitor (Study Medical Expert) name and contact information can be found in the 
Trial Master File (TMF). 
PPD
PPD
PPD
PPD


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Table of Contents
Title Page................................................................................................................................... 1
Sponsor Signatory .................................................................................................................... 2
Table of Tables ......................................................................................................................... 6
Table of Figures........................................................................................................................ 6
1.
Protocol Summary ............................................................................................................ 7
1.1
Synopsis........................................................................................................................... 7
1.2
Schema........................................................................................................................... 10
1.3
Schedule of Activities (SoA) ......................................................................................... 11
2.
Introduction..................................................................................................................... 13
2.1
Study Rationale.............................................................................................................. 14
2.2
Background.................................................................................................................... 14
2.2.1
Disease Background ................................................................................................... 14
2.2.2
Treatment Guidelines ................................................................................................. 15
2.2.3
FXIa Inhibitor: Mode of Action ................................................................................. 15
2.2.4
BAY 2433334............................................................................................................. 16
2.2.4.1
Preclinical / Toxicology Data.................................................................................. 16
2.2.4.2
Clinical Data............................................................................................................ 16
2.3
Benefit/Risk Assessment ............................................................................................... 18
3.
Objectives and Endpoints............................................................................................... 20
4.
Study Design .................................................................................................................... 22
4.1
Overall Design ............................................................................................................... 22
4.2
Scientific Rationale for Study Design ........................................................................... 23
4.3
Justification for Dose..................................................................................................... 24
4.4
End of Study Definition................................................................................................. 25
5.
Study Population............................................................................................................. 25
5.1
Inclusion Criteria ........................................................................................................... 25
5.2
Exclusion Criteria .......................................................................................................... 26
5.3
Lifestyle Considerations ................................................................................................ 27
5.4
Screen Failures............................................................................................................... 27
6.
Study Intervention .......................................................................................................... 28
6.1
Study Intervention(s) Administered............................................................................... 28
6.2
Preparation/Handling/Storage/Accountability............................................................... 29
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 30
6.3.1
Unblinding.................................................................................................................. 30
6.4
Study Intervention Compliance ..................................................................................... 31
6.5
Prior and Concomitant Therapy..................................................................................... 31
6.5.1
Concomitant Antiplatelet Therapy ............................................................................. 32
6.5.2
Guidance for Management of Participants who have Bleeding During the Study..... 32
6.5.3
Guidance for management of participants who have  non-cardiac surgery or non-
cardiac percutaneous/endoscopic procedures............................................................. 33
6.5.4
Guidance for management of participants who experience a suspected ischemic 
stroke  during the study .............................................................................................. 33


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6.5.5
Guidance for management of participants who experience a suspected new, acute 
recurrent cardiac ischemic event during the study ..................................................... 34
6.5.6
Guidance for management of participants who undergo elective coronary 
angiography, PCI, or CABG during the study ........................................................... 34
6.6
Dose Modification ......................................................................................................... 34
6.7
Intervention after the End of the Study.......................................................................... 35
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 35
7.1
Discontinuation of Study Intervention........................................................................... 35
7.1.1
Temporary Discontinuation........................................................................................ 37
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 37
7.3
Lost to Follow Up.......................................................................................................... 37
8.
Study Assessments and Procedures............................................................................... 38
8.1
Efficacy Assessments .................................................................................................... 38
8.1.1
Primary Efficacy Endpoint......................................................................................... 38
8.1.1.1
Cardiovascular Death .............................................................................................. 39
8.1.1.2
Myocardial Infarction.............................................................................................. 39
8.1.1.3
Stroke ...................................................................................................................... 39
8.1.1.4
Stent Thrombosis..................................................................................................... 40
8.1.2
Secondary Efficacy Endpoint..................................................................................... 40
8.2
Safety Assessments........................................................................................................ 40
8.2.1
Primary and Secondary Safety Endpoints .................................................................. 40
8.2.1.1
BARC Bleeding Definition..................................................................................... 41
8.2.2
Exploratory Safety Endpoints..................................................................................... 42
8.2.2.1
TIMI Bleeding Definition ....................................................................................... 42
8.2.2.2
ISTH Major Bleeding.............................................................................................. 43
8.2.2.3
ISTH Clinically Relevant Non-Major Bleeding...................................................... 43
8.2.3
Physical Examinations................................................................................................ 43
8.2.4
Vital Signs .................................................................................................................. 43
8.2.5
Electrocardiograms..................................................................................................... 44
8.2.6
Clinical Safety Laboratory Assessments .................................................................... 44
8.3
Adverse Events and Serious Adverse Events ................................................................ 44
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 45
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 45
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 45
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 45
8.3.5
Pregnancy ................................................................................................................... 46
8.3.6
Disease-Related Events .............................................................................................. 46
8.3.7
Adverse events of special interest .............................................................................. 47
8.4
Treatment of Overdose .................................................................................................. 47
8.5
Pharmacokinetics........................................................................................................... 47
8.6
Pharmacodynamics ........................................................................................................ 48
8.7
Genetics ......................................................................................................................... 49
8.8
Biomarkers..................................................................................................................... 49
8.9
Immunogenicity Assessment ......................................................................................... 50
8.10
Health Economics/Medical Resource Utilization and Health Economics..................... 50
9.
Statistical Considerations ............................................................................................... 50
9.1
Statistical Hypotheses.................................................................................................... 50


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9.2
Sample Size Determination ........................................................................................... 50
9.3
Populations for Analyses ............................................................................................... 50
9.4
Statistical Analyses........................................................................................................ 51
9.4.1
Gerenal considerations ............................................................................................... 51
9.4.2
Primary endpoints....................................................................................................... 52
9.4.3
Secondary endpoints................................................................................................... 52
9.4.4
Tertiary/exploratory endpoints ................................................................................... 53
9.4.5
Other Safety Analyses ................................................................................................ 53
9.4.6
Other Analyses ........................................................................................................... 53
9.5
Interim Analyses............................................................................................................ 53
9.6
Independent Data Monitoring Committee (IDMC)....................................................... 54
10. Supporting Documentation and Operational Considerations .................................... 55
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 55
10.1.1
Regulatory and Ethical Considerations ...................................................................... 55
10.1.2
Financial Disclosure ................................................................................................... 55
10.1.3
Informed Consent Process.......................................................................................... 55
10.1.4
Data Protection ........................................................................................................... 56
10.1.5
Committees Structure ................................................................................................. 56
10.1.5.1
Executive Committee.............................................................................................. 56
10.1.5.2
Steering Committee (SC) ........................................................................................ 56
10.1.5.3
Independent Data Monitoring Committee (IDMC) ................................................ 57
10.1.5.4
Clinical Events Committee (CEC) .......................................................................... 57
10.1.6
Dissemination of Clinical Study Data ........................................................................ 57
10.1.7
Data Quality Assurance.............................................................................................. 58
10.1.7.1
Data Recording........................................................................................................ 58
10.1.7.2
Monitoring............................................................................................................... 59
10.1.7.3
Data processing ....................................................................................................... 60
10.1.7.4
Missing data ............................................................................................................ 60
10.1.7.5
Audit and inspection................................................................................................ 60
10.1.7.6
Archiving................................................................................................................. 61
10.1.8
Source Documents...................................................................................................... 61
10.1.9
Study and Site Start and  Closure............................................................................... 61
10.1.10 Publication Policy....................................................................................................... 62
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 62
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 64
10.3.1
Definition of AE......................................................................................................... 64
10.3.2
Definition of SAE....................................................................................................... 65
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 66
10.3.4
Reporting of SAEs...................................................................................................... 68
10.3.5
Outcome Event Reporting Process Overview ............................................................ 69
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 69
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments................. 71
10.6
Appendix 6: Calculating the Child-Pugh score ............................................................. 72
10.7
Appendix 7: Calculating glomerular filtration rate........................................................ 72
10.8
Appendix 8: Outcome Events: Data Collection............................................................. 73
10.9
Appendix 9: Abbreviations............................................................................................ 74
11. References ........................................................................................................................ 78


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Table of Tables
Table 1–1 PK, PD and Biomarker Sampling ........................................................................... 13
Table 3–1 Objectives and Endpoints........................................................................................ 21
Table 4–1 BAY 2433334: dose selection................................................................................. 24
Table 6–1 Study interventions.................................................................................................. 29
Table 10–1: Protocol-Required Safety Laboratory Assessments............................................. 63
Table 10–2 Liver function monitoring ..................................................................................... 71
Table 10–3 Grading of severity of liver disease....................................................................... 72
Table 10–4 Child-Pugh score ................................................................................................... 72
Table of Figures
Figure 1–1 Study design overview........................................................................................... 10
Figure 2–1  Contact activation ................................................................................................. 15


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1.
Protocol Summary
1.1
Synopsis
Protocol Title:           Multicenter, randomized, placebo controlled, double-blind, parallel 
group, dose-finding Phase 2 study to evaluate the efficacy and safety of 
BAY 2433334 in patients following an acute myocardial infarction.
Short Title:
PACIFIC-AMI - Phase 2 Program of AntiCoagulation via Inhibition 
of FXIa by the oral Compound BAY 2433334 – Acute Myocardial
Infarction study
Rationale:
This study will explore a dose range of BAY 2433334 in order to 
determine the dose that is efficacious and safe and that can be used in a 
Phase 3 study in the same indication. Rivaroxaban in addition to single 
or dual antiplatelet therapy (acetylsalicylic acid +/- clopidogrel) is the 
only non-Vitamin K oral anticoagulants (NOAC) approved for 
secondary prevention of acute coronary syndrome (ACS) in Europe. In 
addition, the COMPASS study has also shown the benefit of this 
combination (rivaroxaban in addition to acetylsalicylic acid) in patients 
with stable coronary artery disease (CAD)/peripheral artery disease 
(PAD). The clinical use of antiplatelet therapies together with an 
anticoagulant in acute coronary syndrome is limited due to concerns 
about bleeding risk. The inhibition of FXIa on top of antiplatelet 
therapy is expected to not lead to a relevant increase in bleeding and 
especially major bleeding, while maintaining the efficacy benefit 
shown for the combination of antiplatelet therapies and rivaroxaban.
Objectives and Endpoints:


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Objectives
Endpoints
Primary

to evaluate whether the oral FXIa 
inhibitor BAY 2433334 compared to 
placebo leads to a lower incidence of 
cardiovascular (CV) death, MI, stroke 
and stent thrombosis in participants with
an acute myocardial infarction and who 
are treated with dual antiplatelet therapy
Primary Efficacy Endpoint

the composite of CV death, MI, stroke
and stent thrombosis 
Secondary Efficacy Endpoints

all cause mortality

CV death

MI

stroke

stent thrombosis

to evaluate whether the incidence of 
bleeding is similar for BAY 2433334 
compared to placebo in participants 
with an acute myocardial infarction and 
who are treated with dual antiplatelet 
therapy
Primary Safety Endpoint

Bleeding Academic Research 
Consortium (BARC) definition type 2, 3 
and 5 
Secondary Safety Endpoints

all bleeding

BARC bleeding definition type 3, 5

BARC bleeding definition type 1, 2, 3, 5
The primary efficacy estimand is the hazard ratio of the composite of CV death, MI, stroke  
and stent thrombosis comparing BAY 2433334 (20 and 50 mg pooled) with placebo in adult 
participants with an AMI treated with DAPT while alive and regardless of treatment 
discontinuation.
The secondary efficacy estimands are defined following the same approach for the 
individual secondary endpoints as done for the primary efficacy estimand.
The primary safety estimand is the hazard ratio of BARC type 2, 3 and 5 bleeding 
comparing pooled BAY 2433334 with placebo in adult participants with an AMI treated 
with DAPT and who have taken at least one dose of study medication of BAY 2433334 or 
placebo and while the patient is alive and exposed to study drug
The secondary safety estimands are defined following the same approach for the individual 
secondary endpoints as done for the primary safety estimand.


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Overall Design:
Study 20603 is a multicenter, randomized, placebo controlled, double-blind, parallel group, 
dose-finding study. 
The study population includes participants following an AMI with a plan for treatment with 
DAPT (acetylsalicylic acid + P2Y12 inhibitor) after discharge from hospital. 
Participants will be screened and have to be randomized within 5 days of hospitalization for 
the index AMI event.
Stratification will be based on the intended P2Y12 inhibitor use (ticagrelor/prasugrel versus 
clopidogrel) after hospital discharge. 
Participants should have the initial coronary angiography and revascularization procedures, 
either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG),
as treatment for the index AMI event performed before randomization. However, a planned,
staged PCI procedure can be performed after randomization. 
If all information is available, participants can be randomized on the day of screening.
Disclosure Statement: This is a parallel-group study with 4 arms that is participant and 
investigator blinded
Intervention Model: Parallel
Primary Purpose: Treatment
Number of Arms: 4 arms (3 investigational drug arms and 1 placebo arm)
Number of Participants:
Approximately 1650 participants will be screened to achieve 1600 randomly assigned to study 
intervention for an estimated total of 400 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 intervention under investigation. Placebo is used as 
comparator. Study intervention duration and dose regimen are tabulated as follows:
Study Period
Duration
*
Dose and Frequency
Route of
administration
Screening
≤5 days
Oral
Intervention
26-52 weeks*
BAY 2433334 10 mg once daily
BAY 2433334 20 mg once daily
BAY 2433334 50 mg once daily
Placebo once daily
Safety follow-up
2 weeks


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Total planned 
number of patients
Total planned study duration
1600
Between 28 and 54 weeks
*The Study Treatment End Date will be 26 weeks after randomization of the last enrolled 
participant in the study. Participants active on treatment at the time the last participant is 
randomized in the study, the maximum treatment duration beyond this date will be no longer 
than an additional 26 weeks. Thus, participants will have a total treatment duration of a 
minimum 26 weeks to a maximum of 52 weeks.
Data Monitoring Committee: Yes
1.2
Schema
Figure 1–1 Study design overview
EOT= End of Treatment, OD=Once Daily, RND=Randomization, N = total number of participants, W = week


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1.3
Schedule of Activities (SoA)
Study periods /
(Duration)
Screening
(SCR)*
Intervention period
(26-52 weeks, from RND until End of Treatment visit [EOT])
Early 
terminat
ion
(ET)
Safety    
Follow-up
(SFU)
(14 days after 
EOT or ET)
Visit number
1
2
3
4f
5
6
7
8
9
10
11
12
12a
13
Visit type
site
Site

site

site

site

site

site
site
(site)
Week [W]
Study day and allowed 
deviations
SCR
-5 1
RND / W0
1
W2
15±4
W4
29±4
W8
57±
4
W13
92±4
W20
141±
4
W26
183±
4
W32
225±
4
W39
274±4
W46
323±
4
W52/EOT
365±4 
Any 
time
ET+7
EOT or 
ETc+2 weeks
379+7
Administrative procedures
Signed informed consent
X
Pharmacogenetic consent
X
Dispense study contact card
X
Inclusion and exclusion criteria
X
Xa
Demographics and biometrics
X
Medical history
X
Prior and Concomitant 
medication
X
X a
Xi
X
Xi
X
Xi
X
Xi
X
X
X
X
X
Clinical procedures / assessments
12-lead ECG d
X
X a
X
X
X
Vital signs (BP and HR)
X
X a
X
X
X
X
X
X
Adverse events
============================ Continuously=========================================
Outcome eventsh
============================ Continuously=========================================
IxRS
Randomization / Visit 
registration via IxRS
X
X
X
X
X
X
X
Laboratory assessments
Safety blood sample
X e
X a,e
X
X
X
X
X
X
Pharmacokinetic sampleg
X
X
X
Pharmacodynamic samplingg
X
X
X
X


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Study periods /
(Duration)
Screening
(SCR)*
Intervention period
(26-52 weeks, from RND until End of Treatment visit [EOT])
Early 
terminat
ion
(ET)
Safety    
Follow-up
(SFU)
(14 days after 
EOT or ET)
Visit number
1
2
3
4h
5
6
7
8
9
10
11
12
12a
13
Visit type
site
Site

site

site

site

site

site
site
(site)
Week [W]
Study day and allowed 
deviations
SCR
-5 1
RND / W0
1
W2
15±4
W4
29±4
W8
57±4
W13
92±4
W20
141±4
W26
183±4
W32
225±4 W39
274±4
W46
323±4
W52/EoT c
365±4 
Any time
ET+7
EoT or 
ETc+2 weeks
379+7
Pharmacogenetic sampleg
X
Biomarker samplingg
X
X
X
Study drugj administration
Study drugj  dispensation
X b
X
X
X
Study drugj intake at the siteg
X
X
X
no intake
Study drugj
collection and accountability
X
X
X
X
X
Abbreviations: BP = blood pressure, CRF = case report form, ECG = electrocardiogram, EoT = end of treatment, ET = early termination, HR  = 
 heart rate, IxRS = Interactive Voice/Web Response System, MI = myocardial infarction PD = pharmacodynamic(s), PK = pharmacokinetic(s), 
RND= randomization, SCR = screening, SFU  =  safety follow -up, SoA = Schedule of Activities, TIA = transient ischemic attack
** Screening and randomization must occur during hospitalization and latest within 5 days of hospital admission. Intake of the first dose of study 
drug will start as soon as possible and on the same day as randomization (day 1).
a if screening and randomization are performed on the same day, this procedure does not need to be repeated.
b at each contact, participants should be reminded regarding study drug compliance.
c Participants will perform their safety follow-up phone call 2 weeks after the EoT visit or the ET visit whichever occurs earlier. (i.e. in case of Early 
Termination 2 weeks after last study drug intake).
d ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals should be used.
e Creatinine and eGFR results as well as AST and ALT values measured in the local laboratory for screening. Current laboratory results available 
for the index hospitalization for the myocardial infarction can be used. Full safety labs done at randomization (Central Lab).
f The visit can be performed at a later time point if participant on inpatient rehabilitation facility and this visit cannot be arranged.
g  Refer to Table 1–1: PK, PD and Biomarker sampling
h  Outcome events including all bleeding, death, MI, stroke and stent thrombosis as well as events indicative of a potential outcome (see 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 
the study treatment.
i at visits 3, 5, 7, 9 and 11: any new concomitant medication and AEs or outcome events will be captured during the telephone calls.
j “Study drug” refers to “study intervention’ as defined in Section 6.1.


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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 
(Visit 4a)
Week 4 or later
(Visit 4
or subsequent 
visit)
Week 26 
(Visit 8)/ETd
Predose 
Day 1
Predose
0.5-1.5h 
postdose
2-4hb
postdose
4-12hb,c
postdose
Predose
PKe
x
x
x
x
x
PDe
x
x
x
x
x
x
Biomarker
s Plasma 
x
x
Biomarker
s 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 before V4 to remind participants is recommended.
b  The minimum time between the 2-4 h post-dose and the 4-12 h post-dose samples, if collected the 
same day, should be at least 1 hour.
c  The late sample 4-12 hr post-dose sample can be taken at week 4 (visit 4) or at a later-on visit (e.g.
Visit 6). The exact time of when the study drug was administered must be recorded as well as PK 
and PD post-dose sample collection time.
d At Visit 8 (week 26) participants should take their study drug at the site, in order to collect pre-dose 
samples for PK/PD and biomarkers. However, in case Visit 8 is also the EOT visit as well as in case 
of ET visit, no study drug will be administered.
e If study drug is temporily stopped, PK/PD blood samples should only be obtained if study drug has
been restarted and sustained for  at least 4 days, see Section 7.1.1
The exact times of PK, PD and biomarker sampling need 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 the previous 
day).
2.
Introduction
BAY 2433334 is a direct, potent inhibitor of activated coagulation factor XI (FXIa) being 
developed for three 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).


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Study 20603 will be a  Phase 2 study with a 6 to 12 months treatment duration and will test 
BAY 2433334 against placebo in patients following an AMI who are treated with dual 
antiplatelet therapy. 
The current clinical development of BAY 2433334 includes two additional Phase 2 studies in 
patients with AF (study 19765, 3 months treatment duration, apixaban as comparator) and in 
patients with non-cardioembolic ischemic stroke (study 19766, 6-12 months treatment 
duration, on top of primarily single antiplatelet therapy, placebo as comparator). 
Each individual study will have its own 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 Phase 2 studies to help further characterize safety and efficacy.
2.1
Study Rationale
This Phase 2 study will explore a dose range of BAY 2433334 in order to determine the dose 
that is efficacious and safe and that can be used in a Phase 3 trial in the same indication.
The benefit of the concept of adding anticoagulation to antiplatelet treatments has been 
proven by rivaroxaban for ACS in the ATLAS TIMI 51 trial (rivaroxaban in addition to single 
or dual antiplatelet therapy consisting of acetylsalicylic acid [ASA] +/- clopidogrel), and for
patients with stable CAD/PAD in the COMPASS trial (rivaroxaban in addition to ASA).
However, its clinical use in ACS is limited, as patients and healthcare providers are concerned 
about the bleeding risk for triple therapy including 2 antiplatelet therapies (ASA + P2Y12
inhibitors) and an anticoagulant. 
The use of BAY 2433334, as an oral FXIa inhibitor, could address this concern, as it is 
expected not to lead to a relevant increase in bleeding and especially major bleeding, while 
maintaining the efficacy benefit of a combination of antiplatelet therapies and an 
anticoagulant. This is based on the available preclinical data, data from patients with inherited 
FXI deficiency and first clinical data from two Phase 2 proof-of-concept studies in patients 
undergoing total knee replacement (please see Section 2.3).
BAY 2433334 as an inhibitor of FXIa is therefore an attractive candidate to evaluate as a 
potential add-on to dual antiplatelet therapy in patients after an acute myocardial infarction.
2.2
Background
2.2.1
Disease Background
CV disease is the most common cause of mortality worldwide, and the majority of CV 
mortality is attributable to coronary heart disease (CHD). The incidence and prevalence rates 
of CHD remain high throughout the developed world. In the United States (US), the 
American Heart Association (AHA) reported that the prevalence of CHD in adults ≥20 years 
of age is 7.0%. Acute myocardial infarction is a subcategory of CHD and typically leads to an 
acute onset of chest pain or discomfort. The majority of myocardial infarctions arise from an 
acute rupture of an atherosclerotic plaque that leads to a complete blockage of the blood flow 
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According to a current report of the American Heart Association, the prevalence of MI is 
3.1% of US adults (7.9 Million US Americans), and the annual incidence rate of MI in the US 
is 935,000. Within one year after MI, 19% of men and 26% of women aged 45 years and 
older will die. 
2.2.2
Treatment Guidelines
Following an acute myocardial infarction, patients remain in a persistent hypercoagulable  
state and are at risk for adverse thromboembolic events. European Society of Cardiology 
(ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines (Valgimigli et 
al. 2018) recommend that in patients with ACS, regardless of initial treatment strategy,  
DAPT with a P2Y12 inhibitor combined with ASA is recommended  for 12 months unless 
there are contraindications such as excessive risk for bleeding.
Similar guidelines are available from the ACC/AHA. The AHA guidelines (AHA/ACC 2014)
also recommend 12 months of DAPT for patients without significant bleeding risks.  Both 
guidelines suggest that the duration of DAPT be adjusted to the individual patient’s risk of 
recurrent ACS vs. risk of bleeding.
2.2.3
FXIa Inhibitor: Mode of Action
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 
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


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Source: adapted from (Chen et al. 2014)
2.2.4
BAY 2433334
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, showed 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 combined without an associated 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. 
Safety
The single dose escalation study (study 19372) with BAY 2433334 is clinically complete. 
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 three 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 
 (mean, compared to baseline) after single dosing and 
 (mean) at 
steady state was seen. 
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
In the 50 mg OD dose step of the MD study 19665 a prolongation of aPTT of 
 
(mean, compared to baseline) after single dosing and 
 (mean) at steady state 
was seen. 

In the 100 mg OD dose step of the MD study 19665 a prolongation of aPTT of 
 
(mean, compared to baseline) after single dosing and 
 (mean) at steady state 
was seen. 
FXI activity (AXIA assay) is inhibited by a mean of ~85% after 25 mg 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).

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 to 
administration as an 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 30%. This metabolite is not 
pharmacologically active.
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
Terminal half-life is 14.0 to 17.4 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 atrial fibrillation, acute myocardial infarction as well as non-cardioembolic 
ischemic stroke. This Phase 2 study will be the first study investigating BAY 2433334 in 
patients after an acute myocardial infarction. Once daily doses of 10 mg, 20 mg and 50 mg 
will be tested in the study.  
BAY 2433334 as a FXIa inhibitor is expected to have a lower risk for clinically significant 
bleeding when compared to other oral anticoagulants (VKAs and NOACs) is not expected to 
increase the risk for clinically significant bleeding, 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 
intrinsic and propagation pathways but keeps the extrinsic pathway unaffected, that 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. 


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
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 a 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
complete of inhibition during 12 hours of the day. This was combined with a mean 
prolongation of aPTT of 
. 
At this stage of development, the safety profile has not been established. The following 
information related to safety as well as potential risks for patients 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:
o
FXI-deficient knockout mice do not show as 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 patients.
o
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.
o
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 patients after an acute myocardial infarction 
included in the Phase 2 study especially as patients will be treated on top of dual 
antiplatelet therapy. 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 
livers. Based on this, patients with a >2.5 ALT or AST increase will be excluded from 
the study and liver findings during the study are defined as AE of special interest in the 
study. 
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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.
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 patients after an acute myocardial infarction will receive for 
the first time BAY 2433334. Study drug will be given  on top of their usual therapy with dual 
antiplatelet therapy. The main objective of the study is to evaluate whether the addition of 
BAY 2433334 will lead to no relevant increase in bleeding when given on top of dual 
antiplatelet therapy and that this is combined with a treatment benefit in terms of reduction of 
CV death, MI, stroke and stent thrombosis.  An additional objective is to guide dose selection 
for Phase 3. Currently, available preclinical and clinical data from the ongoing study 
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.
3.
Objectives and Endpoints
Objectives and endpoints (primary and exploratory) of the study are reported below, in Table 
3–1. Please refer to Section 9.4 for further details.


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Table 3–1 Objectives and Endpoints
Objectives
Endpoints
Primary

to evaluate whether the oral FXIa 
inhibitor BAY 2433334 compared to 
placebo leads to a lower incidence of 
CV death, MI, stroke and stent 
thrombosis in participants with an acute 
myocardial infarction and who are
treated with dual antiplatelet therapy
Primary Efficacy Endpoint

the composite of CV death, MI, stroke 
and stent thrombosis 
Secondary Efficacy Endpoints

all cause mortality

CV death

MI

stroke

stent thrombosis

to evaluate whether the incidence of 
bleeding is similar for BAY 2433334 
compared to placebo in participants 
with an acute myocardial infarction and 
who are treated with dual antiplatelet 
therapy
Primary Safety Endpoint:

Bleeding Academic Research 
Consortium (BARC) classification
definition type 2, 3 and 5   
Secondary Safety Endpoints

all bleeding

BARC bleeding definition type 3, 5

BARC bleeding definition type 1,2,3,5
Exploratory Safety Endpoints

TIMI clinically significant bleeding events 

TIMI major bleeding events

TIMI minor bleeding events

ISTH major and clinical relevant non-
major bleeding

ISTH major bleeding
Exploratory

to explore additional pharmacokinetic 
and pharmacodynamic parameters, 
biomarkers and genetics

to further investigate the study 
intervention and similar drugs (i.e. 
mode-of-action-related effects and / or 
safety) and to further investigate 
pathomechanisms deemed relevant to 
cardiovascular diseases and 
associated health problems
Other Exploratory Endpoints

FXIa inhibition, aPTT

Pharmacokinetics

Various biomarkers and genetics may be 
explored  (e.g. diagnostic, safety, 
pharmcodynamic, monitoring, or 
potentially predictive biomarkers)  
Abbreviations: aPTT = activated partial thromboplastin time, BARC = Bleeding Academic Research 
Consortium, CV = cardiovascular, ISTH = International Society on Thrombosis and Hemostasis, 
MI = myocardial infarction, PD= pharmacodynamic,TIMI = Thrombolysis in myocardial infarction


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The primary efficacy estimand is the hazard ratio of the composite of CV death, MI, stroke 
(ischemic and hemorrhagic) and stent thrombosis comparing BAY 2433334 (20 and 50 mg
pooled) with placebo in adult participants with an AMI treated with DAPT while alive and 
regardless of treatment discontinuation.
The secondary efficacy estimands are defined following the same approach for the individual 
secondary endpoints as done for the primary efficacy estimand.
The primary safety estimand is the hazard ratio of BARC type 2, 3 and 5 bleeding comparing 
pooled BAY 2433334 with placebo in adult participants with an AMI treated with DAPT and 
who have taken at least one dose of study intervention of BAY 2433334 or placebo and while 
the patient is alive and exposed to study drug.
The secondary safety estimands are defined following the same approach for the individual 
secondary endpoints as done for the primary safety estimand.
4.
Study Design
4.1
Overall Design
Study 20603 is a multicenter, randomized, placebo controlled, double-blind, parallel group, 
dose-finding phase 2 study. Figure 1–1 displays the overall study design.
Approximately 1600 participants (400 per arm) from approximately 150 study centers 
worldwide will be randomized 1:1:1:1 to one of the three investigational drug arms (BAY 
2433334) or to the placebo arm, in addition to their SoC dual antiplatelet background therapy
(for details see Section 6.5).
Stratification will be based on the intended P2Y12 inhibitor use (ticagrelor/prasugrel versus 
clopidogrel) after hospital discharge. 
The number of participants with STEMI enrolled in the study will be limited to no more than 
50% of all participants.
The maximum duration of study participation is planned to be approximately 55 weeks, 
consisting of:

Screening Period  (Visit 1 until Visit 2) : ≤ 5 days 
Participants will be screened and have to be randomized during hospitalization for the 
index AMI event and latest within 5 days of hospital admission. Participants should
have the initial coronary angiography and revascularization procedures, either 
percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), 
as treatment for the index AMI event performed before randomization. However, a 
planned, staged PCI procedure can be performed after randomization.  
If all information is available, participants can be randomized on the day of screening.

Treatment Period ( from Visit 2 through Visit 12): Minimum 26 weeks and 52 
weeks maximum 
The duration of the planned double-blind interventional treatment for each participant 
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The planned double-blind treatment phase starts at randomization and ends at week 52 
or the study treatment end date. Participants active on treatment at the time the last 
participant is randomized in the study, the maximum treatment duration beyond this 
date will be no longer than an additional 26 weeks. Thus, participants will have a total 
treatment duration of a minimum 26 weeks to a maximum of 52 weeks.

Safety Follow-up Period ( Visit 13): 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), 
Week 13 (Visit 6), Week 26 (Visit 8), Week 39 (Visit 10) and at Week 52 / EoT ( Visit 12). 
Telephone calls take place at Week 2 (Visit 3), Week 8 (Visit 5), Week 20 (Visit 7), Week 32 
(Visit 9) and at Week 46 (Visit 11), as well as 2 weeks after the end of treatment visit (i.e.
safety follow-up, Visit 13).
For participants who prematurely discontinue from the study drug, an ET visit (Visit 12a) 
should take place as soon as possible as on-site visit. Participants are asked to continue the 
study schedule of visits until completing all the study visits or end of study is declared. 
Telephone calls take place 14 days after ET visit (i.e. Safety follow-up, Visit 13). Further 
details are reported in Section 7.1.
Details of study procedures and their timing are summarized in the SoA (Section 1.3).
4.2
Scientific Rationale for Study Design
This Phase 2 dose finding study in patients after an AMI will test three doses of BAY 
2433334 against placebo. This will allow to test different degrees of FXIa inhibition and 
determine the dose to be tested in Phase 3.
Study 20603 is a multicenter,randomized, placebo controlled, double-blind, parallel group, 
dose-finding Phase 2 study in patients after an AMI. The study will apply the principles of 
randomization, stratification (by intended P2Y12 inhibitor use [ticagrelor/prasugrel versus 
clopidogrel] after hospital discharge) and double-blinding in order to prevent  bias in the 
inclusion of patients 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 
BAY2433334 there are no safety concerns related to the highest dose of 50 mg once daily 
tested in the study. 
The study is placebo controlled and will allow to test whether the addition of BAY 2433334 
on top of the standard therapy with dual antiplatelet therapy leads to a lower incidence of 
major CV events (CV death, stroke, MI and stent thrombosis) and without increasing the 
incidence of bleeding.
CV death, MI, stroke and stent thrombosis are used to assess efficacy in this study and have 
been used as endpoints in earlier studies in patients with an acute coronary syndrome or acute 


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myocardial infarction. Bleeding will be primarily assessed using the BARC bleeding 
definition. 
Participants will be treated on top of dual or later single antiplatelet therapy as prescribed by 
their treating physician. The choice of P2Y12 inhibitor therapy (ticagrelor, clopidogrel or 
prasugrel) and duration of treatment with DAPT after hospital discharge for the index AMI, 
will be left to the discretion of the treating physician and should follow local standard of care 
guidelines. Thus, the study background therapy will reflect how patients are normally treated 
and also allows to assess the combination of the study drug with different P2Y12 inhibitors 
(clopidogrel, ticagrelor, prasugrel) rather than requiring the same for all participants.
4.3
Justification for Dose
The study will test the once daily dose of 10 mg (low dose), 20 mg (mid dose) and 50 mg 
(high dose) 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 once daily for 
9 days were tested in the Phase I 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 
 at trough and 
 at peak. 

The mid dose of 20 mg was selected as the second dose to reflect a linear dose 
response related to FXIa inhibition. This dose leads to a mean FXIa activity of 23%

10 mg was selected as the low dose, as lower doses lead to no or only minimal 
increases in aPTT. For the 10 mg dose, the expected mean FXIa activity is 45% and 
aPTT is increased to 
 at trough and 
 at peak. 
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
20 mg
40
11
23
10 mg
67
27
45
Abbreviations: aPTT = activated partial thromboplastin time, OD = once a day
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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 during hospitalization for the index AMI event and 
latest within 5 days of hospital admission with  the plan to receive DAPT after hospital 
discharge for the index AMI. The number of participants with STEMI enrolled in the study 
will be limited to no more than 50% of all participants.
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. Participants must be 45 years of age or older, at the time of signing the informed consent
Type of Participant and Disease Characteristics
2. Acute myocardial infarction1 (excluding MI associated with PCI or CABG 
revascularization procedures) with:
a.
clinical symptoms of acute myocardial infarction  AND
b. elevated biomarkers of myocardial necrosis (creatine kinase-muscle and brain 
isoenzyme [CK-MB] or cardiac troponins) AND
c.
at least one of the following risk factors need to be fulfilled:
i. Age ≥ 65 years
ii. Prior MI (before the index AMI event)
iii. Prior peripheral arterial disease
iv. Diabetes Mellitus
v. Prior coronary artery bypass grafting (CABG)
AND
                                                
1 Differentiation  will be made between ST elevation myocardial infarction (STEMI) and non-ST elevation 
myocardial infarction (NSTEMI). For diagnosis of STEMI the following criteria will need to be fulfilled:
Elevation of ST-segment more than 0.1 millivolt (mV) in 2 or more contiguous ECG leads, or new bundle 
branch block, or ST-segment depression 0.1 mV or greater in 2 of the precordial leads V1-V4 with evidence 
suggestive of true posterior infarction


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d. initial angiography and revascularization procedures, either PCI or CABG, as 
treatment for the index event performed before randomization. (Note: a planned,
staged PCI procedure can be performed after randomization)
3. Plan for dual antiplatelet therapy (ASA + P2Y12 inhibitor) after hospital discharge for the 
index AMI
4. Randomization during hospitalization for the index AMI event and latest within 5 days of 
hospital admission 
Informed Consent
5. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. Written informed consent has to be signed before any study-
specific procedure. 
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Hemodynamically significant ventricular arrhythmias or cardiogenic shock at time of 
randomization
2. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg) at randomization
3. Active bleeding; known bleeding disorder, history of major bleeding (intracranial, 
retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 
6 months of randomization
4. Prior ischemic stroke within last 30 days of index event  
5. 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 or 
 AST > 2.5 x the upper limit of normal, measured as part of the hospitalization for the 
index event and before randomization
6. 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 
as part of the hospitalization for the index event and measured before randomization  
7. Major surgery during last 30 days or planned major surgery or intervention within 
study period
8.
Known allergy, intolerance or hypersensitivity to either of the study interventions 
(active substance or excipients)
Prior/Concomitant Therapy


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9. Planned use or requirement of full dose and long term anticoagulation therapy during 
study conduct2
10. Anticipated need for chronic (more than 4 weeks) therapy with NSAIDs 
11. 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):

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
12. Known current alcohol and/or illicit drug abuse that may interfere with the participants 
safety and/or compliance at the discretion of the investigator
13. 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
14. 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)
15. Previous (within 30 days or 5 half-lives of the investigational drug, whichever is 
longer) or concomitant participation in another clinical study with investigational 
medicinal product(s) or device(s). Registries and observational studies are allowed.
16. 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 
a life-expectancy < 6 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 
                                                
2 Not  applicable to DVT prophylaxis with LMWH or unfractionated heparin for short periods of time.  


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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) must 
not be rescreened.
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 Intervention(s) Administered
The following study interventions will be administered in the study:

BAY 2433334: sponsor’s study drug under investigation

Placebo to BAY 2433334
BAY 2433334 is supplied in various strengths as film-coated, immediate-release tablets  with 
identical appearance. 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 (Table 6–1).
The study intervenions (tablets) are not to be broken, halved or crushed, and should be 
swallowed whole with a glass of water in the morning. Participants will have to take two 
tablets from two different bottles (one tablet from each bottle) for one dose. Study drug 
(tablets) can be taken irrespective of food intake.
Matching placebos for BAY 2433334 are supplied in the same way. 
Missed study intervention dose
The planned double-blind treatment phase starts at randomization and ends at week 52 or the 
study treatment end date (i.e. 26 weeks after the last participant of the study has been 
randomized), whichever is earlier, or when study drug is permanently discontinued. Study 
drug will start as soon as possible after randomization (day 1), and is expected to continue 
through the end of the planned treatment period as described above.
If a dose of study intervention is missed, the participant should take a dose immediately on 
the same day. The dose should not be doubled to make up for a missed dose. 


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Table 6–1 Study interventions
Arm name
BAY 2433334 
high dose 
BAY 2433334 
medium dose
BAY 2433334 
low dose
Placebo
Intervention 
Name
BAY 2433334
BAY 2433334
BAY 2433334
Placebo
Type
Drug
Drug
Drug
Placebo
Dose 
formulation
tablet
tablet
tablet
Tablet
Unit dose 
strengths
25 mg
5 mg and 15 mg
5 mg
N/A
Dosage 
Level(s)
50 mg
20 mg
10 mg
N/A
Frequency
Once a day in 
the morning
Once a day in 
the morning
Once a day in 
the morning
Once a day in 
the morning
Route of 
Administration
oral
Oral
oral
Oral
Use
experimental
experimental
experimental
Placebo
IMP/AxMP
IMP
IMP
IMP
IMP
Packaging and 
Labeling
HDPE bottles 
with desiccant 
capsule
HDPE bottles 
with desiccant 
capsule
HDPE bottles 
with desiccant 
capsule
HDPE bottles 
with desiccant 
capsule
Abbreviation: AxMP = auxiliary medicinal product; IMP= investigational medical product; NA= not 
applicable
All study interventions will be labelled according to the requirements of local regulations.
For administered study interventions, a system of numbering in accordance with all 
requirements of Good Manufacturing Practice (GMP) will be used, ensuring that each dose 
can be traced back to the respective bulk batch of the ingredients.
A complete record of batch numbers and expiry dates of all investigational interventions and 
placebo as well as the labels will be maintained in the sponsor’s study file.
In all cases BAY 2433334 or placebo is administered on top of standard of care, consisting of 
antiplatelet therapy. The choice of antiplatelet therapy will be left to the discretion of the 
treating physician and can include single or dual antiplatelet therapy (see Section 6.5.1).
The choice of background antiplatelet therapy will be documented in the patient records and 
captured in the eCRF.
6.2
Preparation/Handling/Storage/Accountability
All study interventions will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practice (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 


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(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the 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 drug using an InteractiveWeb 
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 the intended P2Y12 inhibitor use 
(ticagrelor/prasugrel versus clopidogrel) after hospital discharge.
Study drug will be dispensed at the study visits summarized in SoA (Section 1.3). 
Returned study intervention should not be re-dispensed to the participants.
Patients will be randomly assigned in a [1:1:1:1] ratio to receive study drug. 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 corresponding placebo are 
identical in appearance (size, color, shape). In order to maintain the blind study drugs will be
packed in bottles labeled with a unique number which will be pre-printed on each bottle. In 
addition, participants will be provided with 2 bottles either with active drug or placebo 
depending on the randomization outcome.
6.3.1
Unblinding
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 patient’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 patient’s treatment assignment unless this 
could delay emergency treatment of the patient. If a patient’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 
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BAY 2433334 is known to prolong the activated partial thromboplastin time (aPTT) in a dose 
depended manner. aPTT is a commonly used functional coagulation test widely used in 
clinical practice in patients using anticoagulants and is as well commonly used during acute 
hospitalizations, and as a pre-procedural screening test. Thus, inadverted 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 an (emergency) situation, where aPTT may help to guide 
treatment decision. aPTT determinations as part of the study will not be reported to 
investigator 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 each dispensing visit (V6, V8 and V10) and at EoT (V12) or ET (V12a) 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 study  treatment. 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 
Visit 6 , 8, 10 and EoT (or ET) visit for accountability purposes. Any discrepancies between 
actual and expected amount of returned study medication must be discussed with the 
participant the time of the visit, and any explanation must be documented in the source 
records.
6.5
Prior and 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
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Special focus needs to be given to  antiplatelet and anticoagulant medications. Any use in the 
week before the index AMI event, prior to screening, as well as  concomitant use from study 
entry until the last scheduled study visit of the participant, needs to be captured on the 
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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 
drug must be temporarily used, it is recommended that the lowest possible dosage for the 
shortest duration possible be 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.
6.5.1
Concomitant Antiplatelet Therapy
In all cases, the investigational BAY 2433334 or placebo is administered on top of standard of 
care treatments for post-MI patients, consisting of dual antiplatelet therapy and later single 
antiplatelet therapy. The choice of P2Y12 inhibitor therapy (ticagrelor, clopidogrel or 
prasugrel) and duration of treatment with DAPT after hospital discharge for the index AMI ,
will be left to the discretion of the treating physician and should follow local standard of care 
guidelines. The use of the antiplatelet background therapy (ASA and P2Y12 inhibitors) will be 
documented on the eCRF .
6.5.2
Guidance for Management of Participants who have Bleeding During 
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 drug, temporarily or permanently, will be at the 
discretion of the treating physician and must be documented.

Temporarily discontinue antiplatelet therapies (aspirin and/or the chosen P2Y12 
inhibitor) 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 procoagulants can 
also be considered, but there are no definite data to support the use of these agents.
6.5.3
Guidance for management of participants who have  non-cardiac 
surgery or non-cardiac percutaneous/endoscopic procedures 
When possible, non-cardiac surgery and non-cardiac 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 drug to mitigate risks of bleeding.  
For urgent or emergent non-cardiac surgery or non-cardiac percutaneous/endoscopic 
procedures, when waiting for 24 hours is not an option to allow for study drug wash out 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 (BÀY 2433334 or 
placebo) and unblinding of treatment assignment may be necessary. In general, the treatment 
recommendations should follow the Guidelines for Severe Perioperative Bleeding 
Management (Kozek-Langenecker SA 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 non-cardiac 
procedures may be guided by published data regarding patients with an inherited FXI 
deficiency. Apart from giving FXI concentrate (FXI) as replacement therapy to cover a 
surgical bleeding event (Ling et al. 2016), there have been reports in the literature about the 
successful use of tranexamic acid or ε-amino caproic acid for the management of these 
patients with a FXI deficiency when undergoing surgery (Duga and Salomon 2013). More 
detailed information may be found in the Investigator’s Brochure.
6.5.4
Guidance for management of participants who experience a suspected 
ischemic stroke during the study
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).
For participants who undergo thrombolysis; study medication should be withheld until at least 
24 hours after thrombolysis.


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Mechanical clot removal (thrombectomy) without thrombolysis may be performed in any
case. 
6.5.5
Guidance for management of participants who experience a suspected 
new, acute recurrent cardiac ischemic event during the study
For participants who experience a suspected new, acute recurrent cardiac ischemic event 
requiring unplanned hospitalization (unstable angina or AMI), standard of care medications 
should be administered according to local practice guidelines and based upon the chosen 
invasive procedure (dual antiplatelet therapy, if not already being used, 
intravenous/subcutaneous anticoagulants, or intravenous antiplatelet therapies such as 
glycoprotein IIb/IIIa inhibitors or cangrelor).  Study intervention does not need to be
discontinued upon hospital presentation for a suspected acute recurrent cardiac ischemic 
event.  Recurrent cardiac ischemic event (AMI) endpoint reporting guidelines and processes 
should be followed for these situations.
For participants who undergo urgent or emergent coronary angiography (with or without 
PCI) as treatment for the new recurrent ischemic event, continuation of blinded study 
intervention and concomitant peri-procedural use of standard parenteral or subcutaneous 
anticoagulants (unfractionated heparin, bivalirudin, low molecular weight heparin) during PCI 
is recommended. 
For participants who are treated with urgent or emergent CABG surgery, study drug should be 
stopped (if possible) 24 hours before the surgery and 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, 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 drug should be restarted no earlier than 24 hours after 
receiving fibrinolytics.
6.5.6
Guidance for management of participants who undergo elective 
coronary angiography, PCI, or CABG during the study 
For participants who undergo elective (scheduled) coronary angiography, with or without 
elective PCI after randomization or in case of a staged PCI procedure for the index AMI event
continuation of blinded study intervention and concomitant peri-procedural use of standard 
parenteral or subcutaneous anticoagulants (unfractionated heparin, bivalirudin, low molecular 
weight heparin) during PCI is recommended. For participants who undergo elective CABG 
surgery , study intervention should be temporarily discontinued for at least 24 hours before 
elective CABG is performed. Study intervention should be restarted no earlier than 24 hours 
after the post-surgical drains (chest tubes) have been removed.
6.6
Dose Modification
This protocol does not allow any alteration from the outlined dosing schedule (Section 4.3).


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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 for each participant (i.e. 26 to 52 weeks).
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 intervention will be required, if 
concomitant treatment with any of the following medications has to be taken for the 
remaining duration of the study conduct:

requirement of full dose and long term anticoagulation therapy during study conduct  
(e.g de novo atrial fibrillation, pulmonary embolism)

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)


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
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 (ie, 
ET visit) and follow-up and for any further evaluations that need to be completed. 
At 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 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, death, bleeding, stent thrombosis).
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 
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)


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7.1.1
Temporary Discontinuation 
In case of a temporary study medication interruption for any reason, study medication will be 
restarted as soon as medically justified in the opinion of the investigator.  There is no defined 
maximum limit for temporary treatment interruption.  
If study interventions were 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.
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 
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
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 the participant’s children, 
caretaker, legal representative, or primary 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 (Section 1.3). 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.
8.1
Efficacy Assessments 
The efficacy assessments include primary and secondary endpoints of the study (see Section 
3).
8.1.1
Primary Efficacy Endpoint
The primary efficacy endpoints of the study include the analysis of a composite of:

CV death

MI

Stroke (ischemic and hemorrhagic)


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
Stent thrombosis
A definition of the primary 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 10.8.
8.1.1.1
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.
8.1.1.2
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

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.
Five types of myocardial infarction can be differentiated:

Type 1 Spontaneous myocardial infarction

Type 2 MI secondary to an ischemic imbalance

Type 3 MI resulting in death when biomarker values are unavailable

Type 4a MI related to percutaneous coronary intervention (PCI) 

Type 4b MI related to stent thrombosis

Type 4c MI related to re-stenosis associated with PCI

Type 5 MI related to coronary artery bypass grafting (CABG)
8.1.1.3
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 nor 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). 


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The term undetermined stroke will apply when sudden focal neurological deficits persist for 
24 hours (or death if occuring before 24 hours) but without neuroimaging or autopsy.
8.1.1.4
Stent Thrombosis
Uniform definitions have been developed and were updated by the Academic Research 
Consortium-2 (ARC-2), incorporating diagnostic certainty as well as timing 
Definition Based on Diagnostic Certainty of Stent Thrombosis (ST) (Garcia-Garcia et al. 
2018):

“Definite” ST: The highest level of certainty. Either angiographic or pathological 
confirmation of stent thrombosis. 

“Probable” ST: Regardless of the time after the index procedure, any myocardial 
infarction that is related to documented acute ischemia in the territory of the implanted 
stent without angiographic confirmation of stent thrombosis and in the absence of any 
other obvious cause
In this trial the categories of  “probable” ST are excluded and only “definite” ST is selected as 
endpoint.
Definition Based on Timing of Stent Thrombosis (ST):

Acute ST*: 0 to 24 hrs after stent implantation

Subacute ST*: >24 hours to 30 days after stent implantation

Late ST: >30 days to 1 year after stent implantation

Very late ST: >1 year after stent implantation
*Acute or subacute can also be summarized under the term early stent thrombosis
(0 to 30 days).
8.1.2
Secondary Efficacy Endpoint
The secondary efficacy endpoints of the study include the individual components of the CV 
death, MI, stroke, stent thrombosis and all cause mortality.
A definition of the efficacy outcome events is provided in Section 8.1.1 and further specified 
in the Clinical Event Committee Charter.
8.2
Safety Assessments 
The safety assessments include 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.  
8.2.1
Primary and Secondary Safety Endpoints
Primary Safety Endpoints


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
Bleeding Academic Research Consortium (BARC) definition type 2, 3 and 5 as 
defined by the (Section 8.2.1.1)
Secondary Safety Endpoints

all bleeding

BARC bleeding definition type 3, 5

BARC bleeding definition type 1, 2, 3, 5
8.2.1.1
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

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
Type 5: fatal bleeding
Type 5a

Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious
Type 5b

Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1g/dL
  hemoglobin)
8.2.2
Exploratory Safety Endpoints
The exploratory safety endpoints include the analysis of the following outcome events:

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

ISTH major and clinical relevant non-major bleeding

ISTH major bleeding
8.2.2.1
TIMI Bleeding Definition
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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8.2.2.2
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
8.2.2.3
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
8.2.3
Physical Examinations

Height and weight (also referred to as biometrics in the SoA) will be measured and 
recorded at screening (see Section 1.3).
8.2.4
Vital Signs

Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones).

Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
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8.2.5
Electrocardiograms

A single12-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. 
8.2.6
Clinical Safety Laboratory Assessments

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 (eg, 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.
AEs 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 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 the study intervention.


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8.3.1
Time Period and Frequency for Collecting AE and SAE Information 
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 AE 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. 
8.3.2
Method of Detecting AEs and SAEs
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. 
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and serious 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 provided in Section 10.3. 
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.


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
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.
8.3.5
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 94 
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.
8.3.6
Disease-Related Events  
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 (see Section 8.3.4) 
related to the blinded treatment, the participant’s treatment code will usually be unblinded 
before reporting to the health authorities. Notifications of ethic committees and investigators 
will be done according to all applicable regulations (see Section 10.3.4).
The following disease- and treatment-related events are common in participants with acute 
myocardial infarction who are being treated with an anticoagulant:
a.
Bleeding
b. Death 
c.
Myocardial Infarction 
d. Ischemic stroke
e.
Stent thrombosis
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.


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However, due to their expectedness, efficacy endpoints listed above (b-e: death, myocardial 
infarction, ischemic stroke, and stent thrombosis), including events indicative of those 
outcome events (e.g. TIA, cardiac, chest pain) will not be subject to systematic unblinding 
and expedited SUSAR reporting to health authorities.
8.3.7
Adverse events of special interest
Adverse events of special interest (AESIs) will be all 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 initial lab value elevation), see 
Section 10.5, 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 CRF.
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 doses (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.
Due to the mechanism of action, an overdose of the study drug could potentially result in 
hemorrhage. In case of bleeding linked to overdose the guidance on bleeding management as 
found in Section 6.5.2 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.).
4.
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 
personnel responsible for bioanalytics will be unblinded and will have access to the 


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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 (ie, both of the PK/PD sampling day, and of the day before that) must be documented.
At Visit 4 and 8, a trough sample for the determination of BAY 2433334 plasma 
concentrations will be drawn before intake of study drug. At this visit, study intervention will 
be administered at the study center by study personnel and the exact time of study drug 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. Ideally, the study personnel should contact the participant prior to the 
respective Visit to remind them not to take the study drug as usual in the morning at home. At 
Visit 4 additional post-dose samples will be taken as 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 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

Activated Factor XIa activity (AXIA) will be analyzed using a kaolin-trigger and a 
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
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 patients 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 of MACE and bleeding events of 
BAY 2433334 and compare it with the incidence of placebo.
No formal hypothesis testing is planned in this study.
9.2
Sample Size Determination 
Approximately 1650 participants will be screened to achieve 1600 randomly assigned to study 
intervention for an estimated total of 400 evaluable participants per intervention group.
With a sample size of 400 participants per treatment arm, an incidence risk for a primary 
safety event of 4.5% at Day 180 for all treatment arms, and a proportion of about 5% of the 
randomized participants not contributing post-randomization information about the 
occurrence of primary bleeding events, it is expected that about 70 participants will have 
experienced a primary safety outcome until Day 180.
With 70 participants with a primary bleeding event and an observed HR of 1.0 for the 
comparison of BAY 2433334 (all doses pooled) to placebo, the upper bound of the 2-sided 
90% CI for the HR will be approximately 1.44. If the true HR is 1.0 the power to observe a 
2-sided 90% CI for the HR below 1.82 is 80%.
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 drug.
Safety Set
All participants randomly assigned to study drug and who take 
at least 1 dose of study drug. 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)


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The primary and secondary safety endpoints will be analyzed using the Safety Set. The 
analysis of the full analysis set will be used as a supportive analysis. Pharmacokinetic and 
pharmacodynamic data will be analyzed using the Pharmacokinetic analyses set.
9.4
Statistical Analyses
9.4.1
Gerenal considerations
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 and the efficacy of 
BAY 2433334.
For the intercurrent event “discontinuation of study treatment” the “treatment policy” strategy 
is chosen for efficacy estimands and the “while on treatment” strategy is chosen for safety 
estimands.
The intercurrent event Death will be handled with the while alive strategy.
Confidence intervals will be two sided 90% - confidence intervals.
Time to event variables will be analyzed using Kaplan-Meier estimates of cumulative risk and 
cumulative hazard functions. 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.  
Efficacy and bleeding outcomes will be analyzed based on time to their first occurrence. The 
incidence risk for outcome events will be estimated separately for the doses of BAY 2433334 
and/or for the pooled doses and/or the 20 and 50 mg doses combined and compared to 
placebo.
The bleeding risk of BAY 2433334 (all doses pooled) as compared to placebo will be 
estimated using the Cox proportional hazards model.
Main Data scope for safety of the trial is the treatment emergent data scope, counting all 
events from first intake of study drug until 2 days after last study drug intake.
The efficacy of BAY 2433334 (20 and 50 mg pooled) as compared to placebo will be 
estimated using the Cox proportional hazards model.
Main Data scope for efficacy of the trial is the ITT data scope, counting all events from 
randomization until end of study
All time-to-event analyses will be stratified by intended P2Y12 inhibitor use 
(ticagrelor/prasugrel versus clopidogrel) if not mentioned different.
All collected events will be analyzed descriptively, using methods like frequency tables and 
others.
The statistical analyses will be performed using SAS; the version used will be specified in the 
statistical analysis plan (SAP).


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9.4.2
Primary endpoints
Efficacy analysis
The primary efficacy estimand is: The hazard ratio of the composite of CV death, MI, stroke 
and stent thrombosis comparing BAY 2433334 (20 and 50 mg pooled) with placebo in adult 
participants with an AMI treated with DAPT while alive and regardless of treatment 
discontinuation.
The primary efficacy estimator will be the hazard ratio from a Cox proportional hazards 
model comparing BAY 2433334 (20 and 50 mg pooled) with placebo. The estimation will be 
performed on the full analysis set and the ITT data scope.
As sensitivity analyses the estimation on the Safety set and the treatment emergent data scope 
will be performed.
In addition, incidence proportions for the primary efficacy endpoint will be reported.
Safety Analyses
The primary safety estimand is: The hazard ratio of BARC type 2, 3 and 5 bleeding 
comparing pooled BAY 2433334 with placebo in adult participants with an AMI treated with
DAPT and who have taken at least one dose of study intervention of BAY 2433334 or 
placebo and while the participant is alive and exposed to study drug.
The primary safety estimator will be the hazard ratio from a Cox proportional hazards model 
comparing BAY 2433334 (all doses pooled) with placebo. The estimation will be performed 
on the safety set and the treatment emergent data scope.
As sensitivity analyses the estimation on the full analysis set and the ITT data scope will be 
performed.
In addition, incidence proportions for the primary safety endpoint will be reported.
9.4.3
Secondary endpoints
Efficacy analysis
The secondary efficacy estimands are: The hazard ratio of <individual endpoint> of 
comparing BAY 2433334 (20 and 50 mg pooled) with placebo in adult participants with an 
AMI treated with DAPT while alive and regardless of treatment discontinuation
For each of the individual enpoints:

All cause mortality

CV death

MI

stroke (ischemic and hemorrhagic) 

stent thrombosis
Safety analysis
The secondary safety estimands are: The hazard ratio of <individual endpoint> comparing 
pooled BAY 2433334 with placebo in adult participants with an AMI treated with DAPT and 


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who have taken at least one dose of study medication of BAY 2433334 or placebo and while 
the patient is alive and exposed to study drug
For each of the individual enpoints:

all bleeding

BARC bleeding definition Type 3, 5

BARC bleeding definition Type 1, 2, 3, 5
9.4.4
Tertiary/exploratory endpoints
Exploratory safety endpoints are:

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

ISTH major and clinical relevant non-major bleeding

ISTH major bleeding
The analyses of these endpoints will be specified in the SAP.
9.4.5
Other Safety Analyses 
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 affairs (MedDRA).
9.4.6
Other Analyses 
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. The population PK analysis will be presented 
separately from the main clinical study report (CSR). 
9.5
Interim Analyses 
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 two other ongoing Phase 2 studies will be reviewed together 
when the pre-defined criteria for the two interim analyses have been reached. The overall 
approach of the 2 interim analyses is regarded as acceptable, as these are exploratory Phase 2 
studies and not pivotal studies.
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 


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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 three
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 19766 only, data 
and especially bleeding data from this study and study19765 will be taken into consideration.  
The second interim analysis will occur when sufficient data are available from all three Phase 
2 studies. This interim analysis may occur, when approximately 80% of all planned 
participants, taken all three 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 two interim analysis may be close together, 
the decision could be taken to just conduct one interim analysis. 
As part of the two 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 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 20603, and of the overall safety data across all three 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.


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10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 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 
regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

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. 


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
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. 
10.1.4
Data Protection

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. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Committees Structure
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 three Phase 2 studies with 
BAY 2433334, as well as two sponsor representatives, will ensure the overarching integrity of 
the three Phase 2 studies with BAY 2433334. 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
of cardiology, is to support the protocol development and the conduct of the study, to advise 


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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
Independent Data Monitoring Committee (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 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)

Stent thrombosis
In addition, events that might be indicative of a potential outcome event will be reported as 
outcome events to ensure that no outcome event is missed. This includes for example TIA and 
hospitalization for cardiac chest pain with increased cardiac enzymes 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.
10.1.6
Dissemination of Clinical Study Data
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 


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in patients for medicines and indications approved in the United States (US) and European 
Union (EU) on or after January 01, 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical studies are positive or negative.
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or 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 (eg, 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 15years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor. 

If the participant withdraw 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).


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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.
10.1.7.2
Monitoring
In accordance with applicable regulations, ICH-GCP, and sponsor’s/CRO’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.


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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, ICH-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/CRO’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 drug 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 ICH-GCP and regulatory requirements, a member of the sponsor’s 
(or a designated CRO’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.
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 


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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.
10.1.8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data 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.
10.1.9
Study and Site Start and Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.


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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.
10.1.10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.


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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 Chemistry1
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)
NOTES:
1 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 Appendix 10.5.
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)
Investigator 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
10.3.1
Definition of AE 
AE Definition

An AE is any untoward medical occurrence in a patient 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 (eg, 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 (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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 


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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive 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.
10.3.3
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information 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 


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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.

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, 


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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 
 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.
10.3.4
Reporting of SAEs
SAE Reporting to the sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
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.
PPD
PPD
PPD


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10.3.5
Outcome Event Reporting Process Overview
If an AE or SAE is a potential outcome event (all bleeding, death, MI, stroke, TIA and stent 
thrombosis [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 10.8).
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 (eg, 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, (eg, 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. 


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
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 
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. 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, after 
obtaining the signed informed consent from both parents, unless local law or specific 
circumstances of the respective case allow otherwise, 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 will be reported for medical 
reasons will be reported as an AE or SAE. 


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
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth
(occurring at >22 weeks gestional 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 but 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, 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 lab 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), testing of 
ferritin levels, iron, iron binding capacity, antinuclear antibody, and smooth muscle 
antibodies. Patient management is at the discretion of the treating physician but the 
investigator  may continue the study drug 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 drug is interrupted until tested values have 
normalized or returned to patient’s baseline. If close liver monitoring is not possible then the 
patient 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 patient baseline levels
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) 


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
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).
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: 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 (ie, 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.

Outcomes 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 

Outcomes 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 AE’s 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.


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10.9
Appendix 9: Abbreviations
ACC
American College of Cardiology
ACS
Acute coronary syndrome
AE
Adverse Event
AESI
Adverse event of special interest
AF
Atrial fibrillation
AG
Joint stock company, Aktiengesellschaft
AHA
American Heart Association
ALT
Alanine aminotransferase
AMI
Acute myocardial infarction
AP
Alkaline phosphatase
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
BP
Blood pressure
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CAD
Coronary artery disease
CEC
Clinical event committee
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CHD
Coronary heart disease
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
CTFG
Clinical Trial Facilitation Group
CRNM
Clinical relevant non-major
CRO
Contract Research Organization
CV 
Cardiovascular 
CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
DAPT
Dual antiplatelet therapy
e.g.
For example, exempli gratia


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eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
ECG
Electrocardiogram
ECLIA
Electrochemiluminescence Immunoassay
EDC
Electronic data capture
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
End of Treatment
ESC
European Society of Cardiology
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
FiM
first in man
FFP
Fresh frozen plasma
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
Hb
Hemoglobin
HR
Hazard ratio
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 commitee
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
IR
Immediate release


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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
LSF
Liquid service formulation
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
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 daily
P2Y12
Purinergic receptor P2Y, G-protein coupled, 12
PAD
Peripheral artery disease
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic
PK
Pharmacokinetic(s)
QC
Quality control
RAAUC
Accumulation ratio for AUC
RACmax
Accumulation ratio for Cmax
RAVE
Data collection tool
RBC
Red blood cell
RND
Randomization
SAC
Statictical 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


CONFIDENTIAL
Clinical Study Protocol
No. BAY 2433334 / 20603
Version 1.0                                                                      Page:  77 of 78
SOC
System Organ Class
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
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US/USA
United States/United States of America
VKA
Vitamin K antagonist
VTE
Venous thromoembolism
vWF
Von Willebrand Factor
W
Week
WBC
White blood cell
WOCBP
Woman of childrenbearing potential


CONFIDENTIAL
Clinical Study Protocol
No. BAY 2433334 / 20603
Version 1.0                                                                      Page:  78 of 78
11.
References
AHA/ACC. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-
Elevation Acute Coronary Syndromes: Executive Summary. 2014.
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.
Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, Stone GW, Spertus J, et al. 
Standardized End Point Definitions for Coronary Intervention Trials: The Academic 
Research Consortium-2 Consensus Document. Eur Heart J. 2018 Jun 14;39(23):2192-
207.
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.
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.
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.
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.
Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, et al. 2017 
ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on 
Oral Anticoagulants: A Report of the American College of Cardiology Task Force on 
Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017 Dec 19;70(24):3042-
67.
Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused 
update on dual antiplatelet therapy in coronary artery disease developed in 
collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary 
artery disease of the European Society of Cardiology (ESC) and of the European 
Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 
14;39(3):213-60.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Multicenter, randomized, placebo controlled, double-blind, parallel 
group, dose-finding Phase 2 study to evaluate the efficacy and safety 
of BAY 2433334 in patients following an acute myocardial 
infarction 
NCT Number: 
NCT04304534 
Document Date: 
26-Jan-2022 
 


Statistical Analysis Plan
BAY 2433334 / 20603
Page: 1 of 29:
Title page
Study Title: Multicenter, randomized, placebo controlled, double-blind, parallel group, 
dose-finding Phase 2 study to evaluate the efficacy and safety of BAY 2433334 in patients 
following an acute myocardial infarction
Short Title: Phase 2 Program of AntiCoagulation via Inhibition of FXIa by the oral 
Compound BAY 2433334 – Acute Myocardial Infarction 
study
(PACIFIC-AMI)
Bayer study drug
BAY 2433334 / INN
Clinical study 
phase:
Phase 2b
Date:
26 JAN 2022
Study No.:
20603
Version:
1.0
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.
PPD


Statistical Analysis Plan
Protocol No.: BAY 2433334 / 20603
Page: 2 of 29:
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 4
1.
Introduction....................................................................................................................... 6
2.
Study Objectives................................................................................................................ 6
3.
Study Design ...................................................................................................................... 7
4.
General Statistical Considerations .................................................................................. 9
4.1
General Principles............................................................................................................ 9
4.2
Handling of Dropouts .................................................................................................... 10
4.3
Handling of Missing Data.............................................................................................. 10
4.4
Interim Analyses and Data Monitoring ......................................................................... 11
4.5
Data Rules...................................................................................................................... 12
4.5.1
Baseline values ........................................................................................................... 12
4.5.2
Data Scopes ................................................................................................................ 12
4.5.3
Time-to-Event variables ............................................................................................. 12
4.5.4
Special cases of censoring.......................................................................................... 12
4.5.5
Classification of investigator reported bleeding......................................................... 13
4.5.6
Blind Review of important deviations and validity findings...................................... 16
5.
Analysis Sets .................................................................................................................... 16
5.1
Assignment of analysis sets ........................................................................................... 16
6.
Statistical Methodology .................................................................................................. 16
6.1
Population characteristics .............................................................................................. 17
6.1.1
Disposition.................................................................................................................. 17
6.1.2
Protocol Deviations .................................................................................................... 17
6.1.3
Demography and baseline characteristics................................................................... 17
6.1.4
Medical history........................................................................................................... 18
6.1.5
Prior and concomitant medication.............................................................................. 18
6.1.6
Subgroup analyses ...................................................................................................... 19
6.1.7
Region Classification.................................................................................................. 19
6.2
Efficacy.......................................................................................................................... 19
6.2.1
Primary Efficacy......................................................................................................... 19
6.3
Secondary efficacy......................................................................................................... 23
6.3.1
Secondary efficacy estimands .................................................................................... 23
6.3.2
Secondary efficacy analyses....................................................................................... 23
6.3.3
Subgroup analyses ...................................................................................................... 23
6.4
Pharmacokinetics/pharmacodynamics........................................................................... 24
6.4.1
Pharmacokinetics........................................................................................................ 24
6.4.2
Pharmacodynamics..................................................................................................... 24
6.5
Safety ............................................................................................................................. 25
6.5.1
Primary Safety............................................................................................................ 25
6.5.2
Subgroup analyses ...................................................................................................... 26
6.5.3
Vital Signs .................................................................................................................. 26
6.5.4
Laboratory parameter ................................................................................................. 26
6.5.5
Biomarker................................................................................................................... 27


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Protocol No.: BAY 2433334 / 20603
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6.5.6
Adverse events............................................................................................................ 27
6.6
Analyses related to COVID-19...................................................................................... 28
7.
Document history and changes in the planned statistical analysis............................. 28
8.
References ........................................................................................................................ 28


Statistical Analysis Plan
Protocol No.: BAY 2433334 / 20603
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Abbreviations


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Protocol No.: BAY 2433334 / 20603
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AE
Adverse event
AESI
Adverse event of special interest
AF
Atrial fibrillation
ALT
Alanine aminotransferase
AMI
Acute myocardial infarction
aPTT
Activated partial thromboplastin time
ASA
Acetylsalicylic acid
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AXIA
Activated Factor XIa activity
BARC
Bleeding Academic Research Consortium
CABG
Coronary artery bypass graft
CEC
Clinical Events Committee
CRF
Case report form
CRNM
Clinically relevant non-major
csHR
Cause-specific hazard ratio
CSR
Clinical study report
CV
Cardiovascular
CYP4A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
DAPT
Dual antiplatelet therapy
DWI
Diffusion-weighted imaging
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
LOQ
Limit of quantification
LPFV
Last participant first visit
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
mRS
Modified Rankin Score
NIHSS
National Institutes of Health Stroke Scale
NT-proBNP
N-terminal pro B-type Natriuretic Peptide
P2Y12
Chemoreceptor for adenosine diphosphate
PD
Pharmacodynamic(s)
PDS
PD analysis set
PK
Pharmacokinetic(s)
PT
Preferred term
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SOC
System organ class
STEMI
ST-elevation myocardial infarction
TAFI
Thrombin-activatable fibrinolysis inhibitor
TAT
Thrombin antithrombin complex
TIA
Transient ischemic attack
TIMI
Thrombolysis in myocardial infarction
ULN
Upper limit of normal


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Protocol No.: BAY 2433334 / 20603
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1.
Introduction
This Phase 2 study with a 6 to 12 months treatment duration tests BAY 2433334 against 
placebo in patients following an AMI who are treated with dual antiplatelet therapy (DAPT).
The current clinical development of BAY 2433334 includes two additional Phase 2 studies in 
patients with AF (study 19765, 3 months treatment duration, apixaban as comparator) and in 
patients with non-cardioembolic ischemic stroke (study 19766, 6-12 months treatment 
duration, on top of primarily single antiplatelet therapy, placebo as comparator).
Each individual study has its own objectives, and study results will be analyzed and reported 
individually in the respective Clinical Study Reports (CSRs). 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 Phase 2 studies to help further characterize safety 
and efficacy.
The SAP is based on the protocol version 1.0, approved on 22 OCT 2019.
2.
Study Objectives
The primary efficacy objective of the study is to to evaluate whether the oral FXIa inhibitor 
BAY 2433334 compared to placebo leads to a lower incidence of CV death, MI, stroke and 
stent thrombosis in participants with an AMI and who are treated with dual antiplatelet 
therapy.
The primary efficacy estimand is the hazard ratio of the composite of CV death, MI, stroke 
(ischemic and hemorrhagic) and stent thrombosis comparing BAY 2433334 (20 and 50 mg 
pooled) with placebo in adult participants with an AMI treated with DAPT while alive and 
regardless of treatment discontinuation.
The primary and secondary safety objective of the study is to evaluate whether the incidence 
of bleeding is similar for BAY 2433334 (10, 20 and 50 mg pooled) compared to placebo in 
participants with an AMI and who are treated with dual antiplatelet therapy.
The primary safety estimand is the hazard ratio of BARC type 2, 3 and 5 bleeding comparing 
pooled BAY 2433334 with placebo in adult participants with an AMI treated with DAPT and 
who have taken at least one dose of study intervention of BAY 2433334 or placebo and while 
the patient is alive and exposed to study drug.
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 whether the oral FXIa 
inhibitor BAY 2433334 compared to 
placebo leads to a lower incidence of 
CV death, MI, stroke and stent 
thrombosis in participants with an AMI  
and who started treatment with DAPT
Primary Efficacy Endpoint

the composite of CV death, MI, stroke 
and stent thrombosis 
Secondary Efficacy Endpoints

all cause mortality

CV death

MI

Stroke

stent thrombosis

to evaluate whether the incidence of 
bleeding is similar for BAY 2433334 
compared to placebo in participants 
with an AMI and who started treatment
with DAPT

Primary Safety Endpoint:

BARC classification definition type 2, 3 
and 5   
Secondary Safety Endpoints

all bleeding

BARC bleeding definition type 3, 5

BARC bleeding definition type 1,2,3,5
Exploratory Safety Endpoints

TIMI clinically significant bleeding events 

TIMI major bleeding events

TIMI minor bleeding events

ISTH major and clinically relevant non-
major bleeding

ISTH major bleeding
Exploratory

to explore additional pharmacokinetic 
and pharmacodynamic parameters, 
biomarkers and genetics

to further investigate the study 
intervention and similar drugs (i.e.
mode-of-action-related effects and / or 
safety) and to further investigate 
pathomechanisms deemed relevant to 
CV diseases and associated health 
problems
Other Exploratory Endpoints

FXIa inhibition, aPTT

Pharmacokinetics

Various biomarkers and genetics may be 
explored  (e.g. diagnostic, safety, 
pharmacodynamic, monitoring, or 
potentially predictive biomarkers)  
Abbreviations: aPTT = activated partial thromboplastin time, BARC = Bleeding Academic Research 
Consortium, CV = cardiovascular, ISTH = International Society on Thrombosis and Hemostasis, 
AMI = acute myocardial infarction, DAPT = dual antiplatelet therapy, MI = myocardial infarction, 
TIMI = thrombolysis in myocardial infarction
3.
Study Design
Study 20603 is a multicenter, randomized, placebo controlled, double-blind, parallel group, 
dose-finding Phase 2 study. Figure 3–1 displays the overall study design.
Approximately 1600 participants (400 per arm) from approximately 150 study centers 
worldwide will be randomized 1:1:1:1 to one of the three investigational drug arms (BAY 
2433334) or to the placebo arm, in addition to their standard of care dual antiplatelet 
background therapy.


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Protocol No.: BAY 2433334 / 20603
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Figure 3–1 Study design overview
EOT= End of Treatment, OD=Once Daily, RND=Randomization, N = total number of participants, W = week
Stratification will be based on the intended P2Y12 inhibitor use (ticagrelor/prasugrel versus 
clopidogrel) after hospital discharge.  
The number of participants with STEMI enrolled in the study will be limited to no more than 
50% of all participants.
The maximum duration of study participation is planned to be approximately 55 weeks,
consisting of:

Screening Period (Visit 1 until Visit 2) : ≤ 5 days 
Participants will be screened and have to be randomized during hospitalization for the 
index AMI event and latest within 5 days of hospital admission. If required as 
treatment for the index event, participants should have the initial coronary 
angiography and revascularization procedures, either percutaneous coronary 
intervention (PCI) or coronary artery bypass grafting (CABG), as treatment for the 
index AMI event performed before randomization. However, a planned, staged PCI 
procedure can be performed after randomization.
If all information is available, participants can be randomized on the day of screening.

Treatment Period (from Visit 2 through Visit 12): Minimum 26 weeks and 
52 weeks maximum 
The duration of the planned double-blind interventional treatment for each participant 
will be 26 to 52 weeks.


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The planned double-blind treatment phase starts at randomization and ends at week 52 
or the study treatment end date. For participants active on treatment at the time the last 
participant is randomized in the study, the maximum treatment duration beyond this 
date will be no longer than an additional 26 weeks. Thus, participants will have a total 
treatment duration of a minimum 26 weeks to a maximum of 52 weeks.

Safety Follow-up Period (Visit 13): 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), 
Week 13 (Visit 6), Week 26 (Visit 8), Week 39 (Visit 10) and at Week 52 / EoT ( Visit 12). 
Telephone calls take place at Week 2 (Visit 3), Week 8 (Visit 5), Week 20 (Visit 7), Week 32 
(Visit 9) and at Week 46 (Visit 11), as well as 2 weeks after the EoT visit (i.e. safety follow-
up, Visit 13).
For participants who prematurely discontinue from the study drug, an ET visit (Visit 12a) 
should take place as soon as possible as on-site visit. Participants are asked to continue the 
study schedule of visits until completing all the study visits or end of study is declared. 
Telephone calls take place 14 days after ET visit (i.e. Safety follow-up, Visit 13).
4.
General Statistical Considerations
4.1
General Principles
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 intervention arm and overall, as applicable.
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 efficacy events will be performed by the CEC group who will review events in a 
blinded fashion and will algorithmically and manually 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

Stroke (ischemic, hemorrhagic, undetermined)

Stent thrombosis
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.


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Data entry procedures and documentation necessary for case adjudication will also be 
described in the CEC charter. Adjudication results will be the basis for the final analysis.
The statistical evaluation will be performed by using the software package SAS release 9.4
(SAS Institute Inc., Cary, NC, USA).
4.2
Handling of Dropouts
In rare 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 participants to comply with 
all study procedures and to continue to be followed until the end of the study.
A participant who prematurely discontinues the study for any reason is defined as a “dropout” 
if the participant is randomized to study intervention. A participant 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 participant'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 has been unable to be contacted by the study site until the end of the 
study.
A participant may withdraw 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 participants who prematurely discontinue the study during the treatment 
period 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 participants who are considered lost to follow-up or withdrew consent during the 
treatment period 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. 
Generally 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 intervention 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 (AEs): 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 intervention intake with no timepoint it 
will be assumed that they happen after the first intake of study intervention, i.e. the 
time of study intervention intake will be used for the time of the outcome.
4.4
Interim Analyses and Data Monitoring
Two non-formal interim analyses were 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 two other ongoing Phase 2 studies were planned to be reviewed 
together when the pre-defined criteria for the two interim analyses were  reached. The overall 
approach of the 2 interim analyses is regarded as acceptable, as these are exploratory Phase 2 
studies and not pivotal studies.
The first of the two interim analyses was conducted once about 50% of the participants of the 
PACIFIC Stroke study 19766 had been randomized to assess the safety of BAY 2433334 to 
include participants with more severe cases of stroke in that study. The second interim 
analysis was planned when approximately 80% of all planned participants, taken all three 
studies together, would have been randomized. This interim analysis was not performed.  
A separate interim SAP was prepared by the SAC.
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 Steering Committee. Thus, the 
study integrity will not be impacted and the study conduct will otherwise not be altered by the 
results of this interim analysis. 


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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 intervention. If these values are not available, values taken 
before first administration of study intervention will be considered (e.g., values taken on visit 
1 or before randomization). In case of more than one available value before first 
administration of study intervention, the 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 intervention until 
2 days after the last intake of study intervention will be counted. The time-to-event for 
participants with no event until 2 days after the last intake of study intervention (end of data 
scope) will be censored at that day.
Events at the day of randomization will be counted if the time of occurrence is later than the 
time of first study intervention intake.
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 ITT data scope all events from randomization up until scheduled end of treatment visit
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 intervention 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 intervention 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 intervention arm. (Cause specific) hazard ratios 
(csHR) will be calculated only if in one arm at least 3 events and in addition at least 1 event in 
each of the compared treatment arm occur.
If intervention arms are pooled the number of events needed applies on the pooled arm not on 
each intervention 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:


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
In case of death of the participant before the scheduled end of treatment visit:
o
the date of the death.

In case the participant dies after the scheduled end of treatment visit but before the 
safety follow-up (visit 13)
o
the censoring date according to the “treatment policy” strategy is the date of 
the end of treatment visit
o
the censoring date according to the “while on treatment” strategy is the earliest 
of 2 days after last study intervention 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
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-CVdeath): 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
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. 
It may include episodes leading to self-discontinuation of medical therapy by the 
patient without consulting a healthcare professional.
A bleeding will be counted as BARC bleeding Type 2 if it
1. has any overt, actionable sign of hemorrhage (e.g. more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) 
and
2. does not fit the criteria for type 3, 4 or 5 and
3. does meet one of the following criteria (1) requires non-surgical, medical 
intervention by healthcare professional and/or (2) leads to hospitalization or 
increased level of care and/or (3) prompts evaluationa.
a A bleeding “prompts evaluation” if it leads to diagnostic testing (laboratory or imaging).
BARC bleeding Type 3 subdivides in types 3a, 3b and 3c.
A bleeding will be counted as BARC bleeding Type 3a if 
1. it is an overt bleeding with a hemoglobin dropb of 3 to <5 g/dL and/or


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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 dropb 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 
1. it is intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal), and/or
2. subcategories confirmed by autopsy or imaging or lumbar puncture and/or
3. intraocular bleeding compromising vision
b The hemoglobin drop can be corrected for transfusion. 1 U of packed red blood cells or 
whole blood equals to 1g/dL hemoglobin.
A bleeding will be counted as BARC bleeding Type 4 (CABG-related) if it is
1. perioperative intracranial bleeding with 48 h and/or requires
2. reoperation after closure of sternotomy for the purpose of controlling bleeding
and/or
3. Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period
and/or
4. Chest tube output ≥2L within a 24-h period
BARC bleeding Type 5 are fatal bleedings. They are subdivided 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.
4.5.5.2
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 event 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
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


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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. has any overt sign of hemorrhage that requires medical or surgical treatment,  
laboratory or imaging evaluation, or prolonged hospitalization and
3. does not meet criteria for major or minor bleeding event.
A bleeding will be counted as non-CABG related TIMI minimal if
1. it is not related to a CABG procedure and
2. is an overt bleeding event that does not meet the criteria above
A bleeding is related to a CABG procedure if the site of bleeding is Cardiovascular system –
CABG related. No specific analysis on CAGB related TIMI bleeding is planned due to the 
expected low number of CABG during study.
4.5.5.3
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 
(ISTH CRNM) bleeding if it is considered any sign or symptom of hemorrhage, 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


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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.
4.5.6
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.
Pharmacokinetic values to be excluded from the statistical analysis will be documented and 
respective flags will be incorporated in the clinical database.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of participants 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 participant will be included in the FAS if he/she is randomized to study 
intervention.

Safety analysis set (SAF)
A participant will be included in the SAF if he/she is randomized to study intervention
and has taken at least one dose of the study intervention.

Pharmacokinetic Analysis Set
A participant will be included in the pharmacokinetic analysis set, if he/she has
received active intervention, has at least 1 valid plasma concentration of 
BAY 2433334 without protocol deviation, which would interfere with the evaluation 
of the PK data.

Pharmacodynamic Analysis Set
A participant will be included in the pharmacodynamic analysis set, if he/she has
received active intervention, has at least 1 valid plasma concentration of 
BAY 2433334 without protocol deviation, which would interfere with the evaluation 
of the PK data, 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 efficacy analyses will be the FAS while for safety 
analyses the SAF will be used.
Confidence intervals will be two-sided 90% confidence intervals.


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For the intercurrent event “discontinuation of study treatment” the “treatment policy” strategy 
is chosen for efficacy estimands and the “while on treatment” strategy is chosen for safety 
estimands.
The intercurrent event Death will be handled with the while alive strategy.
Efficacy and bleeding outcomes will be analyzed based on time to their first occurrence. The 
incidence risk for outcome events will be estimated separately for the individual doses of 
BAY 2433334 and/or for the pooled BAY 2433334 doses and/or the 20 and 50 mg doses 
combined and compared to placebo.
6.1
Population characteristics
6.1.1
Disposition
The following will be tabulated by intervention 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 permanent discontinuation 
of study intervention

Flow of participant through study epochs with number of participants and primary 
reasons for premature permanent discontinuation for each study phase
Incidences for permanent discontinuation of the double-blinded study intervention and of the 
follow-up period will be provided by randomized study intervention groups, based on the 
CRF data.
Kaplan-Meier estimates will be used to present

time to the date of last double-blind dose of study intervention,

time to the date of last contact,
all calculated as days from randomization, by study intervention group.
Other details regarding visit adherence (e.g., visit completed in person, by telephone, through 
third party) and completion as well as study intervention adherence collected via CRFs will be 
summarized using frequency tables by visit and study intervention group.
6.1.2
Protocol Deviations
No per protocol analysis set will be defined in this study. The number of participants with 
important protocol deviations and validity findings according to the CRF will be summarized 
together with the relevant reasons, by study intervention group.
6.1.3
Demography and baseline characteristics
Demographic and baseline data as collected in the CRF will be evaluated descriptively for the 
FAS as well for the SAF, by intervention groups and overall. No statistical tests will be 
performed to compare these characteristics across intervention groups.


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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 or african American, Asian, other)

Region (North America; Western Europe; Eastern Europe; Asia)

Age (< 65, 65 – 75, > 75 years)

Age over 65 years (yes/no)

BMI (< 25, ≥ 25 to < 30, ≥ 30kg/m2)

Weight (<60, 60-90, >90 kg)

eGFR (<60, 60-90, >90 mL/min)

Blood pressure

History of stroke or TIA (yes/no)

Prior MI (yes/no)

Prior CABG (yes/no)

Chronic Kidney Disease (yes/no)

Coronary Artery Disease (yes/no)

Peripheral Artery Disease (yes/no)

Hypertension (yes/no) 

Diabetes Mellitus (yes/no)

Intended P2Y12 inhibitor use (ticagrelor/prasugrel versus clopidogrel) after hospital 
discharge

Type of index MI (STEMI/NSTEMI)

PCI for index event (yes/no)

CABG for index event (yes/no)
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 the first intake of study intervention and that are considered 
relevant for the participant’s study eligibility using MedDRA Primary System Organ Class / 
Preferred Term.
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 intervention, regardless 
of when they ended, and

concomitant medication, i.e. medications taken within the treatment period.
Prior and concomitant medication will be shown by ATC classes and subclasses.


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Separate tables will be provided for anticoagulants, antiplatelet therapy used and for strong 
CYP4A4 inhibitors and inducers. In addition, information of duration of DAPT use (at 
randomization, 1, 3, 6 months, EOT) will be provided.
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 subgroup(s):

intended P2Y12 inhibitor use (ticagrelor/prasugrel versus clopidogrel) after hospital 
discharge
6.1.7
Region Classification
Countries will be grouped into regions in the following way:
Region
Country
Western Europe
AUSTRIA
BELGIUM
GERMANY
ITALY
NETHERLANDS
SPAIN
SWEDEN
SWITZERLAND
UNITED 
KINGDOM
Eastern Europe
CZECH REPUBLIC
HUNGARY
POLAND
Asia
JAPAN
North America
UNITED STATES
6.2
Efficacy
6.2.1
Primary Efficacy
6.2.1.1
Primary Efficacy Estimand
The primary efficacy estimand is: The hazard ratio of the composite of CV death, MI, stroke 
and stent thrombosis comparing BAY 2433334 (20 and 50 mg pooled) with placebo in adult 
participants with an AMI treated with DAPT while alive and regardless of treatment 
discontinuation.
6.2.1.2
Primary Efficacy Analyses
Events will be counted in the intention-to-treat data scope for the FAS.
For time-to-event variables number and percentages of participants with an efficacy endpoint 
will be shown by intervention arm and for pooled BAY 2433334 20 and 50 mg arms.
Incidence rate will be calculated for each intervention arm and the pooled arms with an 90% 
confidence interval.


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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  & *+*&"
∑"#-* ". *+*&" (.! $*&'.!#&0)(#& 2 3')/(100 ∗365.25).
The 90% confidence interval for the IR will be computed as
; ∗ <=(0.05; 2*)
2*
;  ∗ <=(0.95; 2*)
2*
 @ ,
with <=(B; 2*) the q quantile of a chi square distribution with 2e degrees of freedoms and e 
the number of participants with an event (Nelson 1982).
In addition, time-to-first-event analyses taking competing events into account will be 
performed. For that Aalen-Johansen estimates for the cause specific cumulative risk will be 
presented.
The competing event for the efficacy events is death or non-CV death for endpoints that 
include CV death. There will be no competing event for all-cause mortality.
The cumulative incidence, i.e. the probability of having a specific event E at or before a 
timepoint t, (C ≤", E = 1), will be estimated for time-to-event endpoints by Aalen-
Johansen estimators with the competing event as defined before. For the Aalen-Johansen 
estimator the cumulative hazard calculated by the cause-specific Nelson-Aalen estimator is 
needed. The calculation of the estimators follows Allignol, Beyersmann and Schmoor 
(Allignol, Beyersmann and Schmoor 2016).
The cause-specific Nelson-Aalen estimator for an event E at timepoint t is calculated as:
FGH(") = I # !"#$#% &"' (#"ℎ  & *+*&" E  " "J
# !"#$#% &"' K&2*! !#'L  " "J
 
MNOM
.
The Aalen-Johansen estimator takes the difference of the cause-specific Nelson-Aalen 
estimator into account, weighted with the Kaplan-Meier survival function, i.e. the Aalen-
Johansen estimator for time t is defined as:
PQH
R (") = I SG("JTU)(FGHV"JW −FGHV"JTUW) 
MNOM
.
To derive the Aalen-Johansen estimators and the corresponding confidence intervals, SAS 
program code corresponding to the following will be used:


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PROC LIFETEST DATA = <dataset> ALPHA=0.1 ERROR=AALEN;
      STRATA TRTGRPN;
      TIME TTEVLAUE * STATUS(1)/failcode=0;
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 = event of interest, 
          1 = right-censored,, 2,3… = competing event(s))
stratumn = variable for stratification factor (two levels)
*/
To estimate the relative change in the instantaneous rate of the occurrence of the 
outcome in participants taking BAY 2433334 versus placebo according to the 
defined estimand, csHRs and their associated confidence intervals will be derived 
from a stratified cause-specific Cox proportional hazards regression model. The results will 
be presented together with estimates of the csHRs for the associated competing 
risks. Corresponding to a (non-formal) superiority testing, a stratified log-rank test will be 
used.
To derive the csHRs, the p-value for the stratified log-rank test and the corresponding 
confidence intervals, SAS program code corresponding to the following will be used:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue*status(1,2,3)=trtgrpn / RL ALPHA=0.1 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 = event of interest, 
          1 = right-censored, 2,3,… = competing event(s))
stratumn = variable for stratification factor
*/
In a supplementary analysis the objective will be explored from a different angle, comparing 
the probability for the primary safety outcome as compared to the hazard rates based on a 
Fine-Gray model and Gray’s (Gray 1988) test for equivalence of the cumulative incidence 
functions, stratified by intended P2Y12 inhibitor use, will be performed.
To derive the cause subdistribution hazard ratios for the Fine-Gray model, the corresponding 
confidence intervals program code corresponding to the following will be used:


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PROC PHREG DATA = <dataset>;
STRATA STRATUMN;
MODEL TTEVALUE*STATUS(1) = TRTGRPN / RL ALPHA = 0.1 eventcode(FG)=0;
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 = event of interest, 
          1 = right-censored, 2,3,… = competing event)
stratumn = variable for stratification factor
*/
For Gray’s test SAS program code corresponding to the following will be used:
PROC LIFETEST DATA = DATASET ERROR=AALEN ;
STRATA STRATUMN / GROUP=TRTGRPN;
TIME TTEVALUE * STATUS(1)/failcode=0;
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 = event of interest, 
          1 = right-censored, 2,3,… = competing event)
stratumn = variable for stratification factor (two levels)
*/
Cause-specific and subdistribution HRs will be calculated for the respective event and the 
competing event(s). These hazard ratios and corresponding confidence intervals will be 
estimated on separate cause-specific hazard models for the comparison of the each of the 
doses of BAY 2433334 versus placebo. No comparison of the different doses of 
BAY 2433334 is planned.
6.2.1.3
Sensitivity analyses for the primary efficacy analysis
The primary efficacy analyses will be repeated for 

the model described above, but without stratification factor

each level of the stratification factor

the estimation on the safety set and the treatment emergent data scope (as described 
for the safety estimand).


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6.3
Secondary efficacy
6.3.1
Secondary efficacy estimands
The secondary efficacy estimands are: The hazard ratio of <individual endpoint> of 
comparing BAY 2433334 (20 and 50 mg pooled) with placebo in adult participants with an 
AMI treated with DAPT while alive and regardless of treatment discontinuation
For each of the individual enpoints:

All cause mortality

CV death

MI

Stroke (ischemic and hemorrhagic) 

Stent thrombosis
6.3.2
Secondary efficacy analyses
The analyses of the secondary efficacy endpoints will be the same as described for the 
primary efficacy analysis.
6.3.3
Subgroup analyses
For the primary and secondary efficacy endpoints subgroups analyses will be done for the 
following subgroups:

Intended P2Y12 inhibitor use (ticagrelor/prasugrel versus clopidogrel) after hospital 
discharge (stratification factor)

Sex

Race (White, Black, Asian, other)

Region (North America, Western Europe and Australia, Eastern Europe, Asia)

Weight (<60; 60-90; >90 kg)

Age Group (< 65 years, 65 – 75 years, > 75 years)

BMI (< 25, ≥ 25 to < 30, ≥ 30kg/m2)

eGFR (< 60; 60-90; >90 mL/min)

History of stroke / TIA (yes/no)

Prior MI (yes/no)

Prior CABG (yes/no)

Chronic Kidney Disease (yes/no)

Coronary Artery Disease (yes/no)

Peripheral Artery Disease (yes/no)

Hypertension (yes/no) 

Diabetes Mellitus (yes/no)

Type of MI (STEMI/NSTEMI)

PCI for index event (yes/no)

CABG for index event (yes/no)


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For these subgroups number and percentages of participants with an efficacy endpoint will be 
presented.
CsHRs will be calculated for each of the subgroups, if enough events in that subpopulation 
exist. Homogeneity of study intervention effect in these subgroups will be assessed by adding 
a covariate for the subgroup variable and the corresponding intervention – subgroup 
interaction to the respective cause specific hazards model. Forest plots will be generated.
Note that, the probability of observing at least one statistically significant but spurious 
interaction is high despite the lack of a biological or pharmacological basis for expecting an 
interaction as the number of subgroup analyses may be large. Thus, any significant 
interactions will be interpreted as “flags” to prompt further investigation.
6.4
Pharmacokinetics/pharmacodynamics
The population PK analysis and pharmacodynamic analyses will be presented separately from 
the CSR and will be described in a separate analysis plan.
6.4.1
Pharmacokinetics
BAY 2433334 concentrations will be summarized per sampling interval and visit, separated 
according to actual dose.
All valid results will be included in the listings and graphical displays of the individual data, 
which are displayed using actual times. Measurements taken outside the predefined time 
window will be flagged by the pharmacokinetic expert to be excluded from the calculation of 
the summary statistics (with respect to planned times) in order to avoid biased results. 
Samples flagged for other reasons, as defined in the respective guidance document for PK 
validity for study #20603, will be excluded from statistics accordingly (see also Section 
4.5.6).
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, geometric mean, geometric standard deviation (re-transformed 
standard deviation of the logarithms), and coefficient of variation, 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 will be 
measured and will be above the limit of quantification (LOQ). For the calculation of the mean 
value a data point below LOQ will be substituted by one half of the limit.
Plots will be prepared by naïve pooling all individual plasma concentrations versus actual 
relative study times (time of sample collection after time of study intervention administration, 
time after most recent dose) using both a linear and semi-logarithmic scale. Samples which 
are collected outside of the predefined windows will nevertheless be valid for PK analysis.
6.4.2
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.
6.5
Safety
6.5.1
Primary Safety
6.5.1.1
Primary Safety Estimand
The primary safety estimand is the hazard ratio of BARC type 2, 3 and 5 bleeding comparing 
pooled BAY 2433334 with placebo in adult participants with an AMI treated with DAPT and 
who have taken at least one dose of study intervention of BAY 2433334 or placebo and while 
the participant is alive and exposed to study drug.
6.5.1.2
Primary Safety Analyses
The primary safety estimator is the hazard ratio from a Cox proportional hazards model 
comparing BAY 2433334 (all doses pooled) with placebo. The estimation will be performed 
on the safety set and the treatment emergent data scope.
These analyses will be replicated for the comparison of each dose of BAY 2433334 and 
placebo.
The time-to-event analyses will follow the analyses for efficacy outcomes.
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:
YZJ =
# !"#$#% &"' (#"ℎ  & *+*&"
∑ "#-* K&2*! "!* "-*&" (#& 2 3')/(100 ∗365.25)
The 90% confidence interval for the exposure-adjusted IR will be computed as
;YZJ ∗ <=(0.05; 2*)
2*
; YZJ ∗ <=(0.95; 2*)
2*
 @ ,
with <=(B; 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)


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The cause specific and subdistribution hazard ratios and the corresponding confidence 
intervals will be estimated on separate models for the comparison of the pooled doses of BAY 
2433334 and placebo and the comparison of each dose of BAY 2433334 and placebo (if 
applicable). No comparison of the different doses of BAY 2433334 is planned.
6.5.1.3
Secondary Safety Analyses
The secondary safety estimand is the hazard ratio of <individual endpoint> comparing pooled 
BAY 2433334 with placebo in adult participants with an AMI treated with DAPT and who 
have taken at least one dose of study medication of BAY 2433334 or placebo and while the 
patient is alive and exposed to study drug
For each of the individual endpoints:

all bleeding

BARC bleeding definition Type 3, 5

BARC bleeding definition Type 1, 2, 3, 5
The main analyses will follow the main estimation for the primary safety endpoint.
6.5.1.4
Tertiary/exploratory Safety Analyses
Exploratory safety endpoints are: 

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

TIMI minimal bleeding

ISTH major and clinically relevant non-major bleeding

ISTH major bleeding
For these endpoints, descriptive tables of crude incidence will be presented. In treatment arms 
with 3 or more events exposure-adjusted incidence rates will be presented. No comparison
between the different treatment arms is planned.
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.
6.5.2
Subgroup analyses
Subgroup analyses for primary and secondary safety events will be done in the same 
subgroups as for efficacy variables. In addition SSRI use will be a subgroup for bleeding 
events.
6.5.3
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, Visit 6, Visit 8, Visit 10,
as well as Visit 12 (end of treatment visit [EOT]) or Visit 12a (early termination [ET]) will be 
displayed by means of descriptive statistics and change from baseline.
6.5.4
Laboratory parameter
Only centrally analyzed blood samples will be considered for analysis.


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Central laboratory parameters (e.g. AST, ALT, eGFR), Visit 2 (Randomization), Visit 4, Visit 
6, Visit 8, Visit 10, as well as Visit 12 (EOT) or Visit 12a (ET) 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

eGFR < 30 mL/min.
6.5.5
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
The analyses will be performed at Visit 1 before the first dose and Visit 8 (Week 26) or Early 
Termination visit.
The biomarkers will be displayed by means of descriptive statistics and change from baseline.
6.5.6
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).
Any AEs starting from the first intake of study intervention until 2 days of the last intake of 
study intervention will be considered treatment-emergent. Any AEs starting after 2 days of 
the last intake of study intervention until the safety follow up visit will be considered post-
treatment AEs. Determination of whether an event is treatment-emergent will be derived after 
the missing or incomplete AE start date is imputed. Imputation rules for missing and 
incomplete AE start data are described in section 4.3.
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 intervention arm. A total column 
will be included in all safety summaries.
Frequency tables, showing an overall summary of number of participants with AEs, study 
intervention-related (TE)AEs, (TE)SAEs and (TE)AESIs will be given, and will include the 
following information:


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
maximum intensity for any (TE)AE,

(TE)AE related deaths,

(TE)AE resulting in permanent discontinuation of study intervention,
Post-treatment AEs will be summarized by frequency tables.
6.6
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 intervention up until 2 days after the last intake of study 
intervention will be counted.
Events that occur in timely relationship to a COVID-19 diagnosis (7 days before diagnosis 
and 30 days after diagnosis) will be shown separately for efficacy (in the full analysis set) and 
safety (for the safety set).
Protocol 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 AE and therefore listed in the respective AE
tables.
If the number of participants with a diagnosed 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 participants 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.
7.
Document history and changes in the planned statistical analysis
Not applicable
8.
References
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.


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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.