Multicenter, Randomized, Placebo-controlled, Double-blind, Parallel Group, Dose-finding Phase 2 Study to Evaluate Efficacy and Safety of BAY2433334 in Patients Following an Acute Non-cardioembolic Ischemic Stroke
Phase: PHASE2
Conditions: Acute Non-cardioembolic Ischemic Stroke
Sponsor: Bayer

 
Document Type: 
Study protocol 
Official Title: 
Multicenter, randomized, placebo-controlled, double-blind, parallel 
group, dose-finding Phase 2 study to evaluate efficacy and safety of 
BAY 2433334 in patients following an acute noncardioembolic 
ischemic stroke 
NCT Number: 
NCT04304508 
Document Date: 
24-Oct-2019 
 

CONFIDENTIAL
Clinical Study Protocol
No. BAY 2433334 / 19766
Version 1.0
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Title Page
Protocol Title: 
Multicenter, randomized, placebo-controlled, double-blind, parallel group, dose-finding Phase 
2 study to evaluate efficacy and safety of BAY 2433334 in patients following an acute non-
cardioembolic ischemic stroke 
Protocol Number:
19766
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 – non-cardioembolic
STROKE study
Acronym:
PACIFIC-STROKE
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: 145672
EudraCT: 2019-003431-33
Approval Date: 
24 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 / 19766 
Version 1.0 
Date 
Page: 2 of 86 
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 Contents...................................................................................................................... 3
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 ..................................................................................................................... 14
2.1
Study Rationale.............................................................................................................. 15
2.2
Background.................................................................................................................... 15
2.2.1
Disease Background ................................................................................................... 15
2.2.2
Treatment Guidelines.................................................................................................. 16
2.2.3
FXIa Inhibition: Mode of Action................................................................................ 17
2.2.4
BAY2433334.............................................................................................................. 17
2.2.4.1
Preclinical / Toxicology Data.................................................................................. 17
2.2.4.2
Clinical Data............................................................................................................ 18
2.3
Benefit/Risk Assessment ............................................................................................... 19
3.
Objectives and Endpoints............................................................................................... 22
4.
Study Design .................................................................................................................... 24
4.1
Overall Design ............................................................................................................... 24
4.1.1
Study Design: Part A and Part B ................................................................................ 25
4.1.2
MRI Procedures.......................................................................................................... 25
4.2
Scientific Rationale for Study Design............................................................................ 26
4.3
Justification for Dose ..................................................................................................... 27
4.4
End of Study Definition................................................................................................. 28
5.
Study Population ............................................................................................................. 28
5.1
Inclusion Criteria ........................................................................................................... 28
5.2
Exclusion Criteria .......................................................................................................... 29
5.3
Lifestyle Considerations ................................................................................................ 31
5.4
Screen Failures............................................................................................................... 31
6.
Study Intervention........................................................................................................... 31
6.1
Study Interventions Administered ................................................................................. 31
6.2
Preparation / Handling / Storage / Accountability......................................................... 32
6.3
Measures to Minimize Bias: Randomization and Blinding ........................................... 33
6.3.1
Unblinding.................................................................................................................. 33
6.4
Study Intervention Compliance ..................................................................................... 34
6.5
Prior and Concomitant Therapy..................................................................................... 34
6.5.1
Concomitant Antiplatelet Therapy ............................................................................. 35
6.5.2
Guidance for Management of Participants who Have Bleeding During the Study.... 35
6.5.3
Guidance for Management of Participants who Have Surgery or 
Percutaneous/Endoscopic Procedures ........................................................................ 35

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6.5.4
Guidance for Management of Participants who Experience Recurrent Ischemic 
Stroke.......................................................................................................................... 36
6.5.5
Guidance for Management of Participants who Experience new Myocardial 
Infarction During the Study........................................................................................ 36
6.6
Dose Modification ......................................................................................................... 37
6.7
Intervention after the End of the Study.......................................................................... 37
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 37
7.1
Discontinuation of Study Intervention........................................................................... 37
7.1.1
Temporary Discontinuation........................................................................................ 39
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 39
7.3
Lost to Follow Up .......................................................................................................... 39
8.
Study Assessments and Procedures............................................................................... 40
8.1
Efficacy Assessments..................................................................................................... 40
8.1.1
Primary efficacy endpoint........................................................................................... 40
8.1.1.1
Stroke....................................................................................................................... 41
8.1.2
Secondary efficacy endpoints..................................................................................... 41
8.1.2.1
Systemic Embolism................................................................................................. 42
8.1.2.2
Myocardial Infarction.............................................................................................. 42
8.1.2.3
Cardiovascular Death .............................................................................................. 42
8.2
Safety Assessments........................................................................................................ 42
8.2.1
Primary safety endpoint.............................................................................................. 42
8.2.1.1
ISTH Major Bleeding.............................................................................................. 42
8.2.1.2
ISTH Clinically Relevant Non-Major Bleeding...................................................... 43
8.2.2
Secondary safety endpoints ........................................................................................ 43
8.2.2.1
ISTH Minor bleeding .............................................................................................. 43
8.2.3
Exploratory safety endpoint........................................................................................ 43
8.2.3.1
TIMI Bleeding Definitions...................................................................................... 43
8.2.3.2
BARC Bleeding Definition ..................................................................................... 44
8.2.4
Physical Examinations................................................................................................ 45
8.2.5
Vital Signs .................................................................................................................. 45
8.2.6
Electrocardiograms..................................................................................................... 45
8.2.7
Clinical Safety Laboratory Assessments .................................................................... 45
8.3
Adverse Events and Serious Adverse Events ................................................................ 46
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 46
8.3.2
Method of Detecting AEs and SAEs .......................................................................... 47
8.3.3
Follow-up of AEs and SAEs....................................................................................... 47
8.3.4
Regulatory Reporting Requirements for SAEs........................................................... 47
8.3.5
Pregnancy ................................................................................................................... 47
8.3.6
Disease-Related Events .............................................................................................. 47
8.3.7
Adverse Event of Special Interest............................................................................... 48
8.4
Treatment of Overdose................................................................................................... 48
8.5
Pharmacokinetics ........................................................................................................... 49
8.6
Pharmacodynamics ........................................................................................................ 49
8.7
Genetics.......................................................................................................................... 50
8.8
Biomarkers..................................................................................................................... 50
8.9
Immunogenicity Assessments........................................................................................ 51
8.10
Health Economics / Medical Resource Utilization and Health Economics................... 51

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9.
Statistical Considerations ............................................................................................... 51
9.1
Statistical Hypotheses .................................................................................................... 51
9.2
Sample Size Determination............................................................................................ 51
9.3
Populations for Analyses ............................................................................................... 52
9.4
Statistical Analyses ........................................................................................................ 52
9.4.1
General Considerations............................................................................................... 52
9.4.2
Primary Endpoints ...................................................................................................... 53
9.4.3
Secondary Endpoints .................................................................................................. 55
9.4.4
Tertiary/exploratory Analyses .................................................................................... 56
9.4.5
Other Safety Analyses ................................................................................................ 56
9.4.6
Other Analyses............................................................................................................ 56
9.5
Interim Analyses ............................................................................................................ 56
9.6
Independent Data Monitoring Committee (IDMC) ....................................................... 57
10. Supporting Documentation and Operational Considerations .................................... 58
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 58
10.1.1
Regulatory and Ethical Considerations ...................................................................... 58
10.1.2
Financial Disclosure ................................................................................................... 58
10.1.3
Informed Consent Process.......................................................................................... 58
10.1.4
Data Protection ........................................................................................................... 59
10.1.5
Committees Structure ................................................................................................. 59
10.1.5.1
Executive Committee .............................................................................................. 59
10.1.5.2
Steering Committee (SC) ........................................................................................ 59
10.1.5.3
IDMC....................................................................................................................... 60
10.1.5.4
Clinical Events Committee (CEC) .......................................................................... 60
10.1.6
Dissemination of Clinical Study Data ........................................................................ 60
10.1.7
Data Quality Assurance.............................................................................................. 61
10.1.7.1
Data Recording........................................................................................................ 61
10.1.7.2
Monitoring............................................................................................................... 62
10.1.7.3
Data processing ....................................................................................................... 63
10.1.7.4
Missing data ............................................................................................................ 63
10.1.7.5
Audit and inspection................................................................................................ 63
10.1.7.6
Archiving................................................................................................................. 63
10.1.8
Source Documents...................................................................................................... 64
10.1.9
Study and Site Start and Closure ................................................................................ 64
10.1.10 Publication Policy....................................................................................................... 64
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 65
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................................. 67
10.3.1
Definition of AE ......................................................................................................... 67
10.3.2
Definition of SAE....................................................................................................... 68
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 69
10.3.4
Reporting of SAEs...................................................................................................... 70
10.3.5
Event Reporting Process Overview............................................................................ 71
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 71
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments................. 73
10.6
Appendix 6: Calculating the Child-Pugh Score............................................................. 74
10.7
Appendix 7: Calculating Glomerular Filtration Rate..................................................... 75
10.8
Appendix 8: Outcome Events: Data Collection............................................................. 75

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10.9
Appendix 9: Study MRI procedure................................................................................ 75
10.10 Appendix 10: Modified Ranking Score ......................................................................... 76
10.11 Appendix 11: NIH Stroke Scale .................................................................................... 76
10.12 Appendix 12: Abbreviations.......................................................................................... 81
11. References ........................................................................................................................ 84
Table of Tables
Table 1–1 PK, PD and Biomarker Sampling ........................................................................... 14
Table 3–1 Objectives and Endpoints........................................................................................ 22
Table 4–1 BAY 2433334: doses selection for Phase 2 ............................................................ 28
Table 6–1 Study interventions.................................................................................................. 32
Table 10–1 Protocol-Required Safety Laboratory Assessments.............................................. 66
Table 10–2 Liver function monitoring ..................................................................................... 74
Table 10–3 Grading of severity of liver disease....................................................................... 74
Table 10–4 Child-Pugh score ................................................................................................... 74
Table of Figures
Figure 1–1 Study design overview .......................................................................................... 10
Figure 2–1 Ischemic stroke sub-type classification (TOAST criteria)..................................... 16
Figure 2–2 Contact activation .................................................................................................. 17

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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 efficacy and safety of 
BAY 2433334 in patients following an acute non-cardioembolic 
ischemic stroke
Short Title:
PACIFIC-STROKE - Phase 2 Program of AntiCoagulation via 
Inhibition of FXIa by the oral Compound BAY 2433334 – non-
cardioembolic STROKE study)
Rationale:
This study will assess the dose response 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. Current guidelines recommend 
antiplatelet therapy for patients after a non-cardioembolic ischemic 
stroke / transient ischemic attack (TIA). The addition of a FXIa 
inhibitor on top of antiplatelet therapy is expected to lead to a benefit 
regarding secondary prevention of stroke combined with no or only 
minimal increase in bleeding and especially no increase in major 
bleeding.
Objectives and Endpoints:
Objectives
Endpoints
Primary

to assess the dose response of 3 different 
doses of BAY 2433334 compared to 
placebo in reducing the composite of 
symptomatic ischemic strokes and covert 
brain infarcts detected by magnetic 
resonance imaging (MRI) as well as other 
cerebro- and cardiovascular endpoints in 
participants with an acute non-
cardioembolic ischemic stroke and who are 
treated with antiplatelet therapy.
Primary Efficacy Endpoint

composite of symptomatic ischemic stroke 
and covert brain infarcts detected by MRI 
Secondary Efficacy Endpoint

composite of symptomatic ischemic stroke 
and covert brain infarcts detected by MRI, 
CV death, myocardial infarction and systemic 
embolism

symptomatic ischemic stroke

covert brain infarcts detected by MRI

symptomatic ischemic stroke, CV death, 
myocardial infarction 

symptomatic ischemic and hemorrhagic 
stroke 

disabling stroke (mRS≥4)

all-cause mortality

to evaluate whether the incidence of 
bleeding for BAY 2433334 is similar 
compared to placebo in participants with an 
acute non-cardioembolic ischemic stroke 
and who are treated with antiplatelet 
therapy.
Primary Safety Endpoint

composite of International Society on 
Thrombosis and Hemostasis (ISTH) major 
bleeding and clinically relevant non-major 
(CRNM) bleeding
Secondary Safety Endpoints

all bleeding

ISTH major bleeding

ISTH CRNM bleeding

ISTH minor bleeding

Intracerebral hemorrhage (non-traumatic)

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The primary efficacy estimand is the incidence of symptomatic ischemic stroke or covert 
brain infarcts detected by MRI in 6 months following a non-cardioembolic ischemic stroke in 
adult participants treated with antiplatelet therapy, while alive and regardless of treatment 
discontinuation, for each of the different doses of BAY 2433334 and placebo.
The primary safety estimand is the hazard ratio of the composite of International Society on 
Thrombosis and Hemostasis (ISTH) major bleeding and clinically relevant non-major 
(CRNM) bleeding comparing pooled BAY 2433334 with placebo following a non-
cardioembolic ischemic stroke in adult participants treated with antiplatelet therapy and who 
have taken at least one dose of study medication of BAY 2433334 or placebo and while the 
participant is alive and exposed to study drug.
The secondary efficacy estimand for the following endpoints:

composite of symptomatic ischemic stroke and covert brain infarcts detected by MRI, 
CV death, myocardial infarction and systemic embolism

covert brain infarcts detected by MRI 
is the incidence in 6 months of each of the individual endpoints following a non-
cardioembolic ischemic stroke in adult participants treated with antiplatelet therapy, while 
alive and regardless of treatment discontinuation, for each of the different doses of BAY 
2433334 and placebo.
The secondary efficacy estimand for the following endpoints:

symptomatic ischemic stroke

symptomatic ischemic stroke, CV death, myocardial infarction 

symptomatic ischemic and hemorrhagic stroke

disabling stroke (mRS≥4)

all-cause mortality
is the hazard ratio of each of the individual endpoints following a non-cardioembolic ischemic 
stroke in adult participants treated with antiplatelet therapy, while alive and regardless of 
treatment discontinuation, comparing each of the different doses of BAY 2433334 with 
placebo. Details are described in Section 9.4.3.
The secondary safety estimand is similar to the primary safety estimand for the following 
endpoints:

all bleeding

ISTH major bleeding

ISTH CRNM bleeding

ISTH minor bleeding

Intracerebral hemorrhage (non-traumatic)
Details are described in Section 9.4.3.
Overall Design:
Study 19766 is a multicenter, randomized, placebo controlled, double-blind, parallel group, 
dose-finding study.

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The study population includes participants to be randomized within 48 hours of onset of an 
acute non-cardioembolic ischemic stroke who are planned to be treated with antiplatelet 
therapy at the discretion of the investigator.
The study will consist of 2 parts, Part A (minor strokes) and Part B (minor and moderate 
strokes). The initiation of Part B will be based on an interim analysis.
Stratification will be based on whether participants will receive single or dual antiplatelet 
therapy after the index stroke and randomization.
If all information is available, participants can be randomized on the day of screening.
Disclosure Statement: This is a parallel group treatment 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 1900 patients will be screened to achieve 1800 randomized participants for an 
estimated total of 450 evaluable participants per intervention group. More details are available 
in Section 9.2.
Intervention Groups and Duration:
BAY 2433334 is the sponsor’s study drug 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 
Within 48 hours of the 
onset of symptoms of 
ischemic stroke
BAY 2433334 10 mg once daily
BAY 2433334 20 mg once daily
BAY 2433334 50 mg once daily
Placebo once daily 
Oral
Intervention
26-52 weeks* 
Safety Follow-up
2 weeks
Total planned 
number of 
participants
Total planned study duration
1800
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

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1.2
Schema
Figure 1–1
Study design overview
Abbreviations:
EOT = End of Treatment; IA = Interim Analysis; MRI = Magnetic Resonance Imaging; 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)a
Intervention period
Safety 
Follow-up (SFU)
(14 days after EOT or 
ET)
(from RND until End of Treatment visit [EOT], 26 to 52 weeks)
Early 
termination 
(ET)b
Visit number
1
2
3
4
g
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
-2 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
Xd
Demographics and 
biometrics
X
Medical history
X
Prior and Concomitant 
medication
X
Xd
Xe
X
Xe
X
Xe
X
Xe
X
Xe
X
X
X
Clinical procedures / assessments
mRSf, NIHSS assessment
X
Xd
Xf
X
X
X
12-lead ECGg
Xc
Xd
X
X
X
Vital signs (BP and HR)
X
Xd
X
X
X
X
X
X
Adverse events
==================================== continuously=======================================
Outcome eventsh
==================================== continuously=======================================
bMRIi [Part A and/or B] 
(study day and 
allowed time window)
A,B
 (-2+3)
Aj 
(±7)
A,B 
(±7)
A,B
 (+7)
IxRS
Randomization / Visit 
registration via IxRS
X
X
X
X
X
X
X
Laboratory assessments
Safety blood sample
Xk
Xd,k
X
X
X
X
X
X

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Abbreviations: BP = blood pressure, CRF = case report form, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, EoT = end of treatment, ET = early 
termination, HR = heart rate, IxRS = Interactive Voice/Web Response System, MRI = magnetic resonance imaging, mRS = modified ranking score, NIHSS = National 
Institute of Health Stroke Scale, PD = pharmacodynamic(s), PK = pharmacokinetic(s), RND = randomization, SCR = screening, SFU = safety follow-up, SoA = Schedule of 
Activities, TIA = transient ischemic attack, W = week
a Screening, randomization and intake of first study drug must occur within 48 hours of symptom onset.
b The visit can be performed at a later time point if participant on inpatient rehabilitation facility and this visit cannot be arranged.
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 In case screening and randomization are performed on the same day, this procedure does not need to be repeated.
e At Visit 3, 5, 7, 9 and 11: any new concomitant medication and AEs or outcome event will be captured during the calls.
f modified Ranking Score (mRS) (Section 10.10) and NIHSS (Section 10.11) should be assessed as follows: 
Index event: at time of screening and time of randomization (NIHSS), day 7 after the event (or at hospital discharge, if this occurs before day 7; NIHSS 
and mRS), at 3, 6 and 12 months visits (mRS). 
For recurrent stroke events: maximum score during hospitalization (NIHSS), day 7 after the event (or at hospital discharge, if this occurs before day 7: 
NIHSS and mRS); visit closest to 3 months after recurrent stroke (mRS).
g ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals should be used.
Study periods
(Duration)
Screening
(SCR)*
Intervention period
Safety 
Follow-up (SFU)
(14 days after EOT or 
ET)
(from RND until End of Treatment visit [EOT], 26 to 52 weeks)
Early 
termination 
(ET)b
Visit number
1
2
3
4
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
-2 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
Pharmacokinetic samplel
X
X
X
Pharmacodynamic samplingl
X
X
X
X
Pharmacogenetic sample
X
Biomarker samplingl
X
X
X
Study drugm administration
Study drugm dispensation
Xn
Xn
Xn
Xn
Study drug m intake at the 
sitel
X
X
X
no intake
Stud drug m collection and 
accountability
X
X
X
X
X

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h outcome events including all bleeding, death, MI, recurrent stroke and systemic embolism as well as events indicative of a potential outcome (Section 
10.1.5.4) need to be reported on dedicated forms in the eCRF on an ongoing basis, even if the participant is permanently discontinued from study treatment.
i MRI is required before or latest within 72 after randomization.
j For part A only until Part B starts.
k Creatinine, eGFR results, AST and ALT values measured in the local laboratory for screening. Current local laboratory results available for the index 
hospitalization for the stroke can be used. Full safety laboratory assessments to be done at randomization in the central laboratory.
l Refer to Table 1–1 PK, PD and Biomarker sampling.
m “Study drug” refers to “study intervention’ as defined in Section 6.1.
n At each contact, participants should be again instructed regarding study drug compliance.

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PK, PD and Biomarkers Sampling
An overview of the PK, PD and Biomarkers sampling is shown in Table 1–1.
Table 1–1 PK, PD and Biomarker Sampling
Day 1
(Visit 2)
Week 4 
(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
2-4 hb
Postdose
4-12 hb,c
postdose
Predose
PKe
X
x
X
x
x
PDe
x
X
x
X
x
x
Biomarke
rs Plasma 
x
x
Biomarke
rs Serum 
x
x
Genetics
x
Abbreviations: ET = Early termination, PD = pharmacodynamic(s), PK = Pharmacokinetic(s)
a At Visit 4: in order to collect pre-dose samples for PK and PD, participants should take their study 
drug at the site only after blood sampling. The investigator must record the time when the study 
drug is taken at the site. A phone call to remind the participants is recommended.
b 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 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) in order to collect pre-dose samples for PK and PD, participants should take 
their study drug at the site only after blood sampling. The investigator must record the time when 
the study drug is taken at the site. A phone call to remind the participants is recommended.
However, in case Visit 8 is also the EOT visit as well as in case the sample is taken at ET visit, no 
study drug will be administered.
e If study drug is temporarily 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 study drug intake (i.e: on the PK / PD sampling day, as well as the day before that).
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) 
Study 19766 will be a Phase 2 study with a 6 to 12 months treatment duration and will test 
BAY 2433334 against placebo in participants following an acute non-cardioembolic ischemic 
stroke who are planned to be treated with antiplatelet therapy at the discretion of the 
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The current clinical development of BAY 2433334 (FXIa inhibitor) includes two additional 
Phase 2 studies in participants with AF (study 19765) and in participants with AMI (study 
20603). These two studies are planned to have a treatment duration of 3 months and 6 to 12 
months, respectively, testing BAY 2433334 against apixaban (NOAC) and BAY 2433334 
against placebo on top of dual antiplatelet therapy.
Each individual study will have its own objectives. However, in order to reach and draw 
conclusions concerning safety in general, and specially 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 assess the dose response of BAY 2433334 in order to determine the 
dose that is both efficacious and safe and that can be tested in a subsequent Phase 3 trial for
the same indication.
Currently, patients with non-cardioembolic ischemic stroke are treated with antiplatelet 
therapy. No clinical studies have proven the benefit of anticoagulation therapy in patients with 
non-cardioembolic stroke. However, it has been shown that patients with a stroke have 
increased levels of FXI and patients with FXI deficiency have a lower risk for stroke. 
In the planned Phase 2 study, BAY 2433334 will be tested against placebo, added on top of 
antiplatelet therapy. This approach is supported by data from the COMPASS study in patients 
with stable coronary and peripheral artery disease. Patients who received the combination of 
2.5 mg bid rivaroxaban plus ASA had fewer ischemic/uncertain stroke when compared to 
those who received ASA alone (HR 0.58) (Sharma et al. 2019).
Inhibition of FXIa is expected to lead to a benefit versus placebo regarding secondary 
prevention of ischemic stroke as well as to not lead to a relevant increase in bleeding and 
especially major bleeding. This is based on the available preclinical data, data from patients 
with inherited FXI deficiency and first clinical data from 2 Phase 2 proof-of-concept studies 
in patients undergoing total knee replacement (please see Section 2.3). 
The primary endpoint will be symptomatic ischemic stroke and covert brain infarcts. Covert
brain infarcts are also called silent strokes and are identified by MRI. These are seen in 30% 
of the elderly and are 2-4 times more frequent  compared with symptomatic strokes. Covert
brain infarcts occur in regions of the brain that do not lead to typical stroke symptoms (i.e. 
hemiparesis) and hence clinical diagnosis, but they are linked to vascular cognitive 
impairment gait disorders, depression and dementia. In addition, available data indicate that 
covert brain infarcts are similarly reduced as symptomatic strokes by anticoagulation with 
rivaroxaban on top of single antiplatelet agent ASA in patients with a history of CAD or PAD
based on COMPASS study (Sharma M et al. 2019)BAY 2433334 as an inhibitor of FXIa is 
therefore an attractive candidate to evaluate as a potential add-on to antiplatelet therapy in 
patients after an acute non cardioembolic stroke
2.2
Background
2.2.1
Disease Background
Worldwide, 13.7 million people suffered a first ever stroke in 2016 and 5.5 million people 
died of a stroke (Johnson et al. 2019). About 25% of all ischemic strokes are recurrent strokes.  
The ischemic stroke recurrence rate is substantial and remains at 3 to 6% per year despite of 
guideline-recommended preventive therapies.

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Non-cardioembolic stroke includes lacunar stroke, large artery arteriosclerotic stroke and 
cryptogenic stroke / ESUS, that together account for 75% of all ischemic strokes and are 
currently treated with antiplatelet therapy (e.g. ASA, clopidogrel, ASA + dipyridamole). 
Figure 2–1 Ischemic stroke sub-type classification (TOAST criteria)
Source: adapted from (Adams et al. 1993, Hart et al. 2014); 
TOAST = Trial of ORG 10172 in Acute Stroke Treatment.
2.2.2
Treatment Guidelines
For secondary prevention of stroke in patients with non-cardioembolic stroke, BAY 2433334 
will be given on top of antiplatelet therapy, which represents standard of care according to 
current guidelines (2008 European Stroke Organization guideline (Ringleb et al. 2008), the 
2014 American Heart Association revised guideline for the prevention of stroke (Kernan et al. 
2014), 2018 guidelines for the early management of patients with acute ischemic stroke
(Powers et al. 2018), the 2012 American College of Chest Physicians guideline (Lansberg et 
al. 2012), and the 2014 Canadian Best Practice Recommendations for Stroke Care (Coutts et 
al. 2015). Preferences for standard of care antiplatelet therapy varies by region and by 
country, stroke management guidelines recommend a range of single antiplatelet therapies 
that include acetylsalicylic acid (ASA), clopidogrel, the combination of ASA and 
dipyridamole or ASA and cilostazol. Recent studies (Johnston et al. 2018, Wang et al. 2013)
support the use of dual antiplatelet therapy  with ASA and clopidogrel for 21 days after an 
acute ischemic stroke, and although widely used in Europe and North America, this 
combination has not as yet been consistently advocated in stroke management guidelines
(Johnston et al. 2016, Johnston et al. 2018, Wang et al. 2013).
The use of anticoagulation therapy in patients with non-cardioembolic ischemic stroke is 
currently not recommended. In contrast, in patients with atrial fibrillation (AF) suffering a 
stroke or TIA, anticoagulation is recommended, but initiation of NOACs is typically delayed 

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for 1-3-6-12 days after the stroke or TIA depending on the severity (TIA-minor-moderate-
severe stroke).  
2.2.3
FXIa Inhibition: 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 (Figure 2–2). 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 2–2 Contact activation
Source: adapted from Chen et al. 2014 (Chen et al. 2014).
2.2.4
BAY2433334
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 BAY2433334 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). 

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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 completed. 
Single doses of 5 mg to 150 mg have been investigated, as well as a food effect study part 
with 25 mg. No clinically relevant signs or symptoms of bleeding were observed.
The multiple dose escalation study (study 19665) has also been clinically completed and the 
evaluation is still ongoing. Therefore, the results are preliminary. It consisted of three parts: 
Part A, where 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. 

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 single dose (SD) and a 
mean of ~95% (25 mg OD) at steady state. After 50 mg and 100 mg SD and MD, activated 
FXI activity is inhibited by a mean of >95% both after first dose and at steady state. The 
duration of the inhibition of FXI activity (AXIA assay) is dose dependent. Complete 
inhibition was reported for 12 hours for 50 mg at steady state and this is prolonged up to 24 
hours for 100 mg at steady state.
Pharmacodynamic parameters aPTT and FXI activity correlated well with observed plasma 
concentrations of BAY 2433334.
No relevant changes of FXI concentration or PT were observed in either study. 
No clinically relevant changes in bleeding time were observed after single dose application. 
Pharmacokinetics
CCI
CCI
CCI
CCI
CCI
CCI

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

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BAY 2433334 as a FXIa inhibitor in contrast 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. 

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 
inhibition of FXI activity by a mean of > 95% and complete inhibition during 12 hours
of the day. This was combined with a mean prolongation of aPTT of
. 
At this stage of development, the safety profile has not been established. The following 
information related to safety as well as potential risks for participants is available:
1. Bleeding is the main safety concern related to antithrombotic therapies. For an 
inhibitor of FXIa a lower bleeding risk is expected. Data supporting this are listed 
below: 
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 
BAY2433334 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 dosing in participants.
o
Patients with inherited FXI deficiency are typically identified when presenting 
with a prolonged activated partial thromboplastin time (aPTT) in routine 
CCI

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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 no relevant bleeding events were 
reported so far.
A risk for bleeding cannot be excluded in patients after an acute non-cardioembolic 
ischemic stroke included in the Phase 2 study, as many patients with minor strokes 
will be treated on top of dual antiplatelet therapy during the initial phase. Therefore, 
bleeding will be closely monitored in the study and will be adjudicated by an 
independent clinical event committee. In addition, patients after an acute ischemic 
stroke have a risk for a hemorrhagic transformation of the stroke as well as for 
intracranial bleeding in general. Therefore, in patients with acute ischemic stroke, 
anticoagulants are initiated after a delay depending on stroke severity. Based on 
available data a lower risk for bleeding with FXIa inhibition is expected and therefore, 
early initiation is justified. However, in order to maximize the safety of participants 
Part A will be restricted to patients with a minor stroke. Eligibility will be expanded to 
include more severe strokes only after a thorough assessment of bleeding events 
during Part A.
2. In toxicology studies, the liver was identified as a target organ in the rat but not in the 
dog. This included dose-dependent spontaneous, mostly transient increases in liver 
enzymes in single animals without clear correlation to histopathological findings in the 
liver. Based on this participants with a >2.5 ALT or AST increase will be excluded 
from the study and liver findings during the study are defined as AE of special interest 
in the study. 
3. Single doses of BAY 2433334 up to 150 mg and multiple doses up to 100 mg once 
daily for 9 days have been safe and well tolerated. This included general safety, 
laboratory, vital signs and ECGs. The doses were 2 and 3 fold higher than planned in 
this Phase 2 study.
4. Based on preliminary evaluation the strong CYP3A4 inhibitor itraconazole increased 
BAY 2433334 exposure by 100% (2-fold) while maximum plasma concentrations 
were not changed (study 19664). Terminal half-life was prolonged from 16 to 29 
hours. Therefore, strong CYP3A4 inhibitors and inducers should not be taken 
concomitantly with BAY 2433334 in this study until further information is available.
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.
Several Factor XI (FXI) and activated Factor XI (FXIa) inhibitor assets are currently in 
development as antithrombotics, including antisense oligonucleotides (ASOs), antibodies and 
small molecules (SMOLs).
In summary, in this Phase 2 study participants after an acute non-cardioembolic ischemic 
stroke will receive for the first time BAY 2433334. Study drug will be given on top of SoC
therapy with antiplatelet therapy. The main objective of the study is to explore whether the 
addition of BAY 2433334 will lead to a dose response in reducing symptomatic strokes and 
covert brain infarcts and whether this is combined with no relevant increase in bleeding when 

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given on top of antiplatelet therapy. 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, secondary and exploratory) of the study are reported 
below, in Table 3–1. Please refer to Section 9.4 for further details.
Table 3–1 Objectives and Endpoints
Objectives
Endpoints
Primary

to assess the dose response of 3 different 
doses of BAY 2433334 compared to 
placebo in reducing the composite of 
symptomatic ischemic strokes and covert 
brain infarcts detected by MRI as well as 
other cerebro- and cardiovascular endpoints 
in participants with an acute non-
cardioembolic ischemic stroke and who are 
treated with antiplatelet therapy.
Primary Efficacy Endpoint

composite of symptomatic  ischemic stroke 
and covert brain infarcts detected by MRI 
Secondary Efficacy Endpoint

composite of symptomatic ischemic stroke 
and covert brain infarcts detected by MRI, 
CV death, myocardial infarction and systemic 
embolism

symptomatic ischemic stroke

covert brain infarcts detected by MRI

symptomatic ischemic stroke, CV death, 
myocardial infarction 

symptomatic ischemic and hemorrhagic 
stroke

disabling stroke (mRS≥4)

all-cause mortality

to evaluate whether the incidence of 
bleeding is similar for BAY 2433334 
compared to placebo in participants with an 
acute non-cardioembolic ischemic stroke 
and who are treated with antiplatelet 
therapy.
Primary Safety Endpoint

composite of International Society on 
Thrombosis and Hemostasis (ISTH) major 
bleeding and clinically relevant non-major 
(CRNM) bleeding
Secondary Safety Endpoints

all bleeding

ISTH major bleeding

ISTH CRNM bleeding

ISTH minor bleeding

Intracerebral hemorrhage (non-traumatic)
Exploratory Safety Endpoints

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

BARC bleeding definition Type 2, 3, 5

BARC bleeding definition Type 3, 5

BARC bleeding definition Type 1, 2, 3, 5

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Exploratory

to explore additional pharmacokinetic and 
pharmacodynamic parameters, biomarkers 
and genetics

To further investigate the study intervention 
(i.e. mode-of-action-related effects and / or 
safety) and to further investigate 
pathomechanisms deemed relevant to 
cardiovascular diseases and 
associated health problems
Other Exploratory Safety Endpoints

FXIa inhibition, aPTT 

Pharmacokinetics 

Various biomarkers and genetics may be 
explored (e.g. diagnostic, safety, PD, 
monitoring, or potentially predictive 
biomarkers)
Abbreviations: AF = atrial fibrillation, aPTT = activated partial thromboplastin time, BARC = Bleeding 
Academic Research Consortium, CV = cardiovascular, ISTH = International Society on 
Thrombosis and Hemostasis, MI = myocardial infarction, TIMI = thrombolysis in myocardial 
infarction
The primary efficacy estimand is the incidence of symptomatic ischemic stroke or covert 
brain infarcts detected by MRI in 6 months following a non-cardioembolic ischemic stroke in 
adult participants treated with antiplatelet therapy, while alive and regardless of treatment 
discontinuation, for each of the different doses of BAY 2433334 and placebo.
The primary safety estimand is the hazard ratio of the composite of International Society on 
Thrombosis and Hemostasis (ISTH) major bleeding and clinically relevant non-major 
(CRNM) bleeding comparing pooled BAY 2433334 with placebo following a non-
cardioembolic ischemic stroke in adult participants treated with antiplatelet therapy and who 
have taken at least one dose of study medication of BAY 2433334 or placebo and while the 
participant is alive and exposed to study drug.
The secondary efficacy estimand for the following endpoints:

composite of symptomatic ischemic stroke and covert brain infarcts detected by MRI, 
CV death, myocardial infarction and systemic embolism

covert brain infarcts detected by MRI 
is the incidence in six months of each of the individual endpoints following a non-
cardioembolic ischemic stroke in adult participants treated with antiplatelet therapy, while 
alive and regardless of treatment discontinuation, for each of the different doses of BAY 
2433334 and placebo.
The secondary efficacy estimand for the following endpoints:

symptomatic ischemic stroke

symptomatic ischemic stroke, CV death, myocardial infarction 

symptomatic ischemic and hemorrhagic stroke

disabling stroke (mRS≥4)

all-cause mortality
is the hazard ratio of each of the individual endpoints following a non-cardioembolic ischemic 
stroke in adult participants treated with antiplatelet therapy, while alive and regardless of 
treatment discontinuation, comparing each of the different doses of BAY 2433334 with 
placebo. Details are described in Section 9.4.3.
The secondary safety estimand is similar to the primary safety estimand for the following 
endpoints:

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
all bleeding

ISTH major bleeding

ISTH CRNM bleeding

ISTH minor bleeding

Intracerebral hemorrhage (non-traumatic).
Details are described in Section 9.4.3.
4.
Study Design
4.1
Overall Design
Study 19766 is a multicenter, randomized, placebo-controlled, double-blind, parallel group, 
dose-finding Phase 2 study. The overall study design is depicted in Figure 1–1.
The study population includes participants to be randomized within 48 hours of onset of an 
acute non-cardioembolic ischemic stroke who are planned to be treated with antiplatelet 
therapy at the discretion of the investigator. Approximately 1800 participants (450 per arm) 
will be randomized 1:1:1:1 to 1 of the 3 investigational drug arms (BAY 2433334) or the 
placebo arm, in addition to their standard of care antiplatelet background therapy. 
The study will consist of 2 parts, Part A (minor strokes) and Part B (minor and moderate 
strokes) and the following periods:

Screening (Visit 1 until Visit 2): Within 48 hours of the onset of symptoms

Screening and randomization can take place on the same day if all information 
is available (Visits 1 and 2 are combined)

Imaging of brain (CT or MRI) must be available at screening to exclude 
hemorrhagic stroke or other causes of the symptoms. 

All participants must have at least one MRI available meeting study MRI 
manual specifications either before randomization (as a clinically initiated 
MRI) or latest within 72 hours after randomization (as a study initiated MRI).

Participants must be screened, randomized and  study treatment initiated within 
48 hours after the onset of symptoms of the index event or after participants 
were last known to be without symptoms in case of wake-up stroke.

Stratification will be based on whether participants will receive single or dual 
antiplatelet therapy  after the index stroke and randomization.

Treatment Period (Visit 2 through Visit 12): At least 26 weeks up to 52 weeks
Participants are required to receive concomitant antiplatelet therapy. For more details 
see Section 6.5.1.
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.
For details on Part A and B of the treatment phase see Section 4.1.1.

Safety Follow-up (Visit 13): 14 days (+ 7 days) after EOT or ET.

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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), at 
Week 13 (Visit 6), Week 26 (Visit 8), Week 39 (Visit 10) and at Week 52 / EOT ( Visit 12). 
Telephone calls will take place at Week 2 (Visit 3), Week 8 (Visit 5), Week 20 (Visit 7), 
Week 32 (Visit 9), Week 46 (Visit 11) as well as 2 weeks after the EOT visit for participants 
who will take study drug until the planned EOT (i.e. safety follow-up, Visit 13). 
For participants who will prematurely discontinue from study drug, an early termination (ET) 
visit (Visit 12a) will take place as soon as possible at the study site. Participants are asked to 
continue the study schedule of visits until completing all the study visits or end of study is 
declared. Telephone calls will take place 2 weeks after the ET visit (i.e. safety follow-up, Visit 
13). Further details are described in Section 7.1.
Details of study procedures and their timing are summarized in the SoA (Section 1.3).
4.1.1
Study Design: Part A and Part B 
Patients after an acute ischemic stroke have an increased risk for intracranial bleeding and 
hemorrhagic transformation of the ischemic stroke area. Patients may also receive 
thrombolysis as acute therapy. Therefore, in patients who had an ischemic stroke and who 
require anticoagulation therapy for example due to AF, anticoagulation is typically delayed 
with the decision for treatment initiation depending on stroke severity.
In order to address this safety concern (despite that none or only minimal increase in bleeding 
is expected for BAY 2433334) the study will consist of 2 parts with participants with less 
severe strokes to be enrolled in Part A and extended to more severe strokes in Part B if 
warranted by safety documented in Part A. In more detail:
Part A will enroll participants with minor stroke only, defined as NIHSS ≤7 at time of 
randomization, whereas in 
Part B enrollment will be extended to:

Participants with minor or moderate strokes: NIHSS≤ 15 at time of randomization

Participants with thrombolysis or endovascular therapy (mechanical thrombectomy) 
can be randomized >24hr after the intervention; (i.e randomization can take place no 
earlier than 24 hours after having received these treatments).
The decision to initiate Part B will be taken as part of an interim analysis. This will take place
after approximately 50% of participants have been enrolled in the study or MRI data (week 
13) is available for approximately 12.5% of the participants. Besides data from this study, also 
data from the concurrently conducted Phase 2 studies in AF and acute myocardial infarction 
will be considered. For more details on the interim analysis process, see Section 9.5.
If the interim analysis indicates no concern (e.g. no clinically relevant increase in intracranial 
hemorrhage or hemorrhagic transformation of ischemic stroke), Part B will be initiated.
In the event that Part B is not  initiated following the interim analysis, and there is no safety 
concern that warrants a stop of the study, enrolment will continue based on Part A eligibility 
criteria until the end of recruitment.
4.1.2
MRI Procedures
The required study MRI sequences to detect covert brain infarcts are based on brain MRIs 
done for routine clinical care of acute stroke patients. The focus is on the primary study 

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objective of detecting incident covert brain infarcts. MRI data will be transmitted to the 
central MRI Core Laboratory where MRI interpretation will be done blinded to treatment 
assignment to identify incident brain infarcts, comparing the initial study MRI to follow-up 
MRI. Details regarding the procedure, MRI requirements and logistics will be available in a 
MRI procedure manual. 
The required study MRIs are to be performed:

either before randomization (as a clinically initiated MRI) or within 72 hours after 
randomization (as a study initiated MRI) for all participants (Part A and B) and 

a final study MRI will be performed for all participants (Part A and B) at Week 26 
(Visit 8) or ET

a study MRI at Week 13 (Visit 6) will be performed for Part A participants only until 
Part B is open. Once Part B is open neither Part A or Part B participants will require 
the MRI imaging at Week 13.
In summary, all participants are required to undergo at least two MRIs that meet study 
requirements, and most participants enrolled during Part A will undergo a third MRI at 
week 13.
Clinical MRIs are acceptable for study purposes as long as they comply with the minimum 
requirements detailed in the MRI procedures manual. The MRI requirements were designed to 
make it feasible that at most stroke centers the clinical MRIs done for an acute stroke will 
qualify for use in the study and not requiring an additional study MRI. 
If possible, the same MRI machine should be used for all study-related MRIs for an individual 
participant.
Further information is available in Section 10.9 and in a separate MRI procedures manual.
4.2
Scientific Rationale for Study Design
Study 19766 is a multicenter, randomized, placebo controlled, double-blind, parallel group, 
dose-finding Phase 2 study in 1800 patients (450 patients per arm) with an acute non-
cardioembolic ischemic stroke. The study will apply the principles of randomization, 
stratification (by antiplatelet therapy; single vs. dual antiplatelet therapy) 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 
BAY 2433334 there are no safety concerns related to the highest dose of 50 mg once daily 
tested in the study. 
Treatment duration is planned for at least 26 and up to 52 weeks in this Phase 2 study in order 
to enable collection of sufficient number of bleeding events as well as efficacy events i.e. 
stroke events, over time. In addition, the longer treatment duration allows to identify signals 
on delayed adverse drug reaction. 
Based on our assumptions, 7.5% of participants will experience a symptomatic stroke during 
the study conduct and in addition twice as many covert brain infarcts (15%) are expected 
leading to overall 22.5% at 6 months. During the whole study duration ~ 100 symptomatic 
strokes and ~ 200 covert brain infarcts (total ~ 300) are expected to be observed in the study 

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cohort. At the same time, ~ 70 major or CRNM bleeding are expected. This number of events 
is required to provide a signal of efficacy, reassurance about safety, and allow determination 
of the optimal dose to be selected for Phase 3.
The study is separated into 2 parts (Part A and Part B). In Part A, only patients with a minor 
stroke will be enrolled, whereas in Part B, the study will also be opened up to patients with 
moderate stroke and patients who have undergone thrombolysis or endovascular therapy. This
approach has been chosen to address the increased risk of patients with ischemic stroke for 
hemorrhagic transformation of the ischemic stroke area, and a generally higher risk for 
intracranial bleeding. For more details, see section 4.1.1. 
In this study, treatment initiation with BAY 2433334 is planned within 48 hours of onset of an 
acute ischemic stroke, as the risk for a recurrent stroke is highest during the early phase after a 
stroke with almost 7% risk at 48 hours and a 10% risk by 7 days, even for patients with initial 
mild clinical presentation (Johnston et al. 2016, Johnston et al. 2018, Wang et al. 2013). Early 
initiation is regarded as acceptable, because the oral FXIa inhibitor BAY 2433334 is expected 
to not increase the bleeding risk.
BAY 2433334 will be given on top of standard of care with background antiplatelet therapy. 
The decision on type of antiplatelet therapy will be left to the discretion of the treating 
physician, as there is variance in the current clinical practice. Mandating a single antiplatelet 
regimen might not be widely acceptable according to local practices or regional guidelines, 
but also not scientifically required, as the primary comparison will be BAY 2433334 versus 
placebo.
The current clinical development of BAY 2433334 is conducted with three Phase 2 studies in 
parallel. Apart from participants with non-cardioembolic ischemic stroke, other studies are 
being conducted in patients with AF as well as acute myocardial infarction (AMI). A common 
Independent Data Monitoring Committee (IDMC) will keep oversight of each one of the 
studies individually and as overall for Phase 2 studies of BAY 2433334.
The aim of these individual Phase 2 studies is to gain knowledge of the bleeding profile. It is 
not planned to perform hypotheses testing. However, this study (19766) is powered to detect a 
dose-response relationship for the primary efficacy outcome. Pooled data across the studies
should will add precision concerning safety in terms of bleeding and general safety. For this 
purpose, data will be pooled within and across studies.
4.3
Justification for Dose
The study will test the once daily doses of 10 mg (low dose), 20mg (mid dose) and 50 mg 
(high dose) BAY 2433334. 
The selection of the high dose in this study was not limited by the safety and tolerability data 
from toxicology studies, nor from the results of the human Phase 1 studies conducted in 
healthy volunteers. Single doses up to 150 mg or multiple doses up to 100 mg for 9 days were 
tested in the Phase 1 studies. Due to these favorable results, the dose selection for the Phase 2 
studies was primarily based on pharmacodynamic assays (preclinical and Phase 1 studies) 
including aPTT and FXIa activity. 
Modeling approaches of the available Phase 1 data were used to predict the doses for Phase 2 
studies with the goal to select doses that cover a broad range of inhibition of FXIa and lead to 
different degrees of increases in aPTT (Table 4–1).

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
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 dose linear 
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: doses selection for Phase 2
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
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 within 48 hours of the onset of symptoms of an acute 
non-cardioembolic ischemic stroke (index event) documented to be not hemorrhagic by 
neuroimaging and with intention to be treated with antiplatelet therapy. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Male and female participants are eligible to be included in the study only if all of the 
following criteria apply:
Age
1. Participant must be 45 years of age and older at the time of signing the informed 
consent
Type of Participant and Disease Characteristics
2. Non-cardioembolic ischemic stroke with
a.
persistent signs and symptoms of stroke lasting for ≥ 24 hours OR
b. acute brain infarction documented by computed tomography (CT) or MRI
AND
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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c.
with the intention to be treated with antiplatelet therapy during the study 
conduct1
3. Imaging of brain (CT or MRI) ruling out hemorrhagic stroke or another pathology 
that could explain symptoms (e.g. brain tumor, abscess, vascular malformation)
4. Severity of index event nearest the time of randomization:
a.
Part A:  minor stroke (defined as NIHSS ≤ 7)  can be enrolled
b. Part B: participants with  minor or moderate stroke and NIHSS ≤ 15 can be 
enrolled. Participants undergoing thrombolysis or endovascular therapy 
(mechanical thrombectomy) can be enrolled but at the earliest 24 hours after 
the intervention 
5. Randomization within 48 hours after the onset of symptoms of the index event (or 
after patients were last known to be without symptoms in case of wake-up stroke)
6. Ability to conduct an MRI either before randomization or within 72 hours after 
randomization
Informed Consent
7. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. Written informed consent has to be signed 
before any study procedure.
5.2
Exclusion Criteria 
Participants are excluded from  study participation if any of the following criteria apply:
Medical Conditions
1. Prior ischemic stroke within last 30 days of index event 
2. History of atrial fibrillation* or suspicion of cardioembolic source of stroke (*12-lead 
ECG or documented during cardiac rhythm monitoring)
3. Dysphagia with inability to safely swallow study medication at time of randomization
4. Contraindication to perform brain MRI (e.g. certain types of aneurysm clips, 
claustrophobia, patients that cannot lie supine for 30 minutes, patients whose body 
structure exceeds the restrictions of the local MRI instrument) 
5. Part A only: thrombolysis or endovascular therapy (mechanical thrombectomy)
                     performed for index event
6. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg) at randomization
7. Active bleeding; known bleeding disorder, history of major bleeding (intracranial, 
retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 6 
months of randomization
                                                
1 any antiplatelet therapy recommended by regional guidelines for secondary stroke prevention, single or dual, is 
permitted based on the choice of the treating physician see Section 6.5.1.

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8. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or 
hepatic insufficiency classified as Child-Pugh B or C (see Section 10.7), or ALT or AST 
> 2.5 x the upper limit, measured between enrollment and randomization 
9. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 calculated by 
Modification of Diet in Renal Disease (MDRD) (see Section 10.7), determined between 
enrollment and randomization.
10. Major surgery during last 30 days or planned major surgery or intervention within study 
period (e.g. Carotid endarterectomy, CABG)
11. Known allergy, intolerance or hypersensitivity to the study intervention (active substance 
or excipients).
Prior/Concomitant Therapy
12. Planned use or requirement of full dose and long term anticoagulation therapy during 
study conduct2
13. Anticipated need for chronic (more than 4 weeks) therapy with NSAIDs
14. Concomitant use of any of the following therapies within 14 days (or at least five half-
lives of the active substance whatever is longer) before randomization and first study 
intervention administration (see Section 6.5):

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 
15. Known current alcohol and/or illicit drug abuse that may interfere with the participant’s 
safety and/or compliance at the discretion of the investigator 
16. Women of childbearing potential (women are considered of childbearing potential if they 
are not surgically sterile or postmenopausal, defined as amenorrhea for > 12 months). 
Male participants not willing to use condoms when sexually active with a woman of 
childbearing potential
17. Close affiliation with the investigational site or sponsor; e.g. a close relative of the 
investigator, or a dependent person (e.g. employee or student of the investigational site or 
the sponsor)
18. Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) 
or concomitant participation in another clinical study with investigational medicinal 
product(s) or device(s). Registries and observational studies are allowed.
19. Any condition or therapy, which would make the participant unsuitable for the study (e.g. 
non-compliance) or otherwise vulnerable (e.g. participant in custody by order of an 
authority or a court) or life expectancy < 6 months.
                                                
2 venous thromboembolism prophylaxis with LMWH or unfractionated heparin for short periods of time is 
allowed.

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5.3
Lifestyle Considerations
No restrictions during any of the study periods pertaining to lifestyle (except for the above 
mentioned substance abuse) and / or diet apply.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details and eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Interventions Administered
The following study interventions will be administered in the study:

BAY 2433334: sponsor’s study drug under investigation

Placebo to BAY 2433334
BAY 2433334 is supplied in various strengths as film-coated, immediate-release tablets with 
identical appearance. BAY 2433334 is taken orally once a day in the morning, preferably 
around the same time each day. The immediate release tablets will be provided as pink, oval, 
film-coated tablets containing either 5 mg, 15 mg or 25 mg of BAY 2433334 (Table 6–1) .
The study interventions (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 immediately 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 
low dose
BAY 2433334 
medium dose
BAY 2433334 
high 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
5 mg
5 mg and 15 mg
25 mg
NA
Dosage Level(s)
10mg
20mg
50mg
NA
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 all administered study interventions a system of numbering in accordance with all 
requirements of Good Manufacturing Practice (GMP) will be used, ensuring that each dose 
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 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation, and final disposition records).

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4. Further guidance and information for the final disposition of unused study 
interventions are provided in the Investigator Site File. 
6.3
Measures to Minimize Bias: Randomization and Blinding
All participants will be centrally assigned to randomized study intervention using an 
Interactive Web Response System (IWRS). To accomplish random assignments, computer-
generated randomization lists specified by the sponsor's responsible statistician will be 
prepared by Randomization Management at the study sponsor. The randomization lists are 
provided to an IWRS vendor. Before the study is initiated, the log in information & directions 
for the IWRS will be provided to each site.
The randomization will be stratified based on whether participants will receive single or dual 
antiplatelet therapy after the index stroke and randomization.
Study intervention will be dispensed at the study visits summarized in SoA (see Section 1.3). 
Returned study intervention should not be re-dispensed to the participants.
Participants will be randomly assigned in a [1:1:1:1] ratio to receive study intervention. 
Investigators will remain blinded to each participant’s assigned study intervention throughout 
the course of the study. 
Tablets containing 5 mg, 15 mg or 25 mg of BAY 2344443 and corresponding placebo are 
identical in appearance (size, color, shape). In order to maintain the blind, study interventions 
will be packaged in bottles labeled with a unique number which will be preprinted 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 participant’s treatment 
assignment is warranted. If the investigator is unavailable, and a treating physician not 
associated with the study requests emergency unblinding, the emergency unblinding requests 
are forwarded to the study specific emergency medical advice 24 hours/7 day service. 
Participant safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a participant’s treatment assignment unless this could 
delay emergency treatment of the participant. If a participant’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and case 
report form, as applicable. 
BAY 2433334 is known to prolong the activated partial thromboplastin time (aPTT) in a dose 
dependent manner.  aPTT is a commonly used functional coagulation test widely used in 
clinical practice in patients using anticoagulants and is as well commonly used during acute 
hospitalizations, and as a pre-procedural screening test.  Thus, inadvertent unblinding of the 
participant or investigator might take place in cases where aPTT test results are known. 
Therefore, the measurement of aPTT during the study conduct is strongly discouraged and 
should only be done in case of (emergency) situations where aPTT may help to guide 
treatment decision.  aPTT determinations obtained as part of the study protocol will not be 
reported to investigators during the study in order to maintain the blinding.

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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 drug 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 drug and empty packages at study 
Visit 6, 8 10 and EOT (or ET) visit if applicable for accountability purposes. Any 
discrepancies between actual and expected amount of returned study medication must be 
discussed with the participant at the time of the visit, and any explanation must be 
documented in the source documents.
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

Careful recording of medication received during the index event is required especially 
any thrombolysis and antithrombotic medication
The Medical Monitor (sponsor’s Study Medical Expert) should be contacted if there are any 
questions regarding concomitant or prior therapy.
Special focus needs to be on antiplatelet, thrombolytics and anticoagulant medications. Any 
use of these medications in the week before the index stroke 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 specified concomitant medication page.
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

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
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
The choice of antiplatelet therapy as standard of care background treatment during the study 
treatment period will be left to the discretion of the investigators and/or treating physician and 
should follow local standard of care guidelines. Antiplatelet therapy can include single and 
dual therapy with ASA, clopidogrel, dipyridamole or cilostazol. Dual antiplatelet therapy 
with ASA and clopidogrel may only be given for the first weeks after the index stroke. 
Anticipated use of anticoagulants or/and other drugs that affect the coagulation system and 
specifically drugs that affect platelets other than the allowed background therapy exclude 
participation. 
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 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).

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 in the support of use of these agents.
6.5.3
Guidance for Management of Participants who Have Surgery or 
Percutaneous/Endoscopic Procedures 
When possible, surgery and percutaneous/endoscopic procedures should be planned and 
delayed for at least 24 hours to allow for a 24-hour washout period after temporary 
discontinuation of randomized study drug to mitigate risks of bleeding.
For urgent or emergent surgery or percutaneous/endoscopic procedures, when waiting for 24 
hours is not an option to allow for study drug wash out after temporary discontinuation, the 
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based upon the clinical situation. Peri-procedure management may in part, depend on the 
randomized treatment assignment (BAY 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 et al. 2013). 
The procedure should be conducted in such a way to minimize the risk of bleeding.
Treatment of participants receiving BAY 2433334 during urgent or emergency procedures 
may be guided by published data regarding patients with an inherited FXI deficiency. Apart 
from giving FXI concentrate (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 Recurrent 
Ischemic Stroke
For participants who experience ischemic stroke during the study, a complete diagnostic 
work-up including brain and arterial imaging, at least 24-hour cardiac rhythm monitoring, and 
echocardiography is encouraged (but neither required by the study protocol nor reimbursed 
by the sponsor). 
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.
Mechanical clot removal (thrombectomy) without thrombolysis may be performed in any 
case.
6.5.5
Guidance for Management of Participants who Experience new
Myocardial Infarction During the Study
For participants who experience a suspected new, acute cardiac ischemic event requiring 
unplanned hospitalization (unstable angina or acute MI), standard of care medications should 
be administered according to local practice guidelines and based upon the chosen invasive 
procedure (dual antiplatelet therapy, if not already being used, intravenous / subcutaneous 
anticoagulants, or intravenous antiplatelet therapies such as glycoprotein IIb/IIIa inhibitors or 
cangrelor). Study drug should be temporarily discontinued upon hospital presentation for a 
suspected acute cardiac ischemic event to mitigate potential bleeding risks. Cardiac ischemic 
event (acute MI) endpoint reporting guidelines and processes should be followed for these 
situations.

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For participants who undergo urgent or emergent coronary angiography (with or without PCI) 
as treatment for the new ischemic event, study drug should be restarted no earlier than 24 
hours after the arterial sheath has been removed and / or no earlier than 24 hours after the last 
dose of intravenous / subcutaneous anticoagulant or intravenous antiplatelet agent has been 
administered. For participants who are treated with urgent or emergent CABG surgery for the 
new ischemic event after coronary angiography, 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.
6.6
Dose Modification
This protocol does not allow any alteration from the outlined dosing schedule (Section 4.3).
6.7
Intervention after the End of the Study
No further study intervention is planned following the End of the Study. For the definition of 
“End of Study” please refer to Section 4.4. 
Any further therapy at the end of the study is at the discretion of investigator/treating 
physician. 
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for bleeding and efficacy outcome events 
until the planned regular end of treatment. See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need 
to be completed.
An ET visit is only applicable to participants who prematurely discontinue intake of study 
intervention; such participants should undergo the ET visit as soon as possible, after 
permanent discontinuation of study intervention. A safety follow up visit (telephone call) will 
occur 14 days after the day of the premature discontinuation of study intervention (+ 7 days 
window). If the ET visit falls into the time window for the safety follow up visit (≥2 weeks 
after permanent discontinuation of study intervention), a safety follow up visit will not be 
performed.
In this study, outcome events and vital status data are crucial to the primary analysis and must 
be collected until the end of the study, as participants will still be part of the study even if they
are no longer taking study medication. Therefore, all efforts will be taken to motivate 
participants to comply with all study procedures and to continue to be followed until the end 
of the study for each participant (i.e. 26 to 52 weeks).

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Study intervention will not be routinely discontinued in participants reaching a potential 
outcome event or in case of unblinding, unless there is a safety concern or a clear indication 
for an alternative antithrombotic therapy as determined by the local investigator.
Specifically, a permanent discontinuation of study 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).

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 (i.e, 
ET visit) and follow-up and for any further evaluations that need to be completed. 
At the time of permanent discontinuation of the study intervention, the participant is expected 
to continue regular study clinic visits at the investigator’s site as outlined in the protocol.
If this is not possible for any reason, the investigator and participant must discuss and 
determine further follow-up options, as listed below, in descending order of preference: 
1. Participant will be contacted by phone at the regular follow-up intervals
2. Participant allows his / her treating physician, e.g. general practitioner or a family 
member, to be contacted or his medical file checked at the regular follow-up interval, 
or at least once at study end (if allowed in respective country) 
3. Participant will be contacted only once at the planned End of Treatment period 
(planned regular EOT visit for the participant)
After permanent discontinuation of the study intervention the following will need to be 
collected at the regular study visits and up to the regular end of treatment visit, preferentially 
directly from the participant and as agreed to by the participant during the initial informed 
consent process:

Vital Status

Antiplatelet and anticoagulant medications

Outcome events (MI, stroke, systemic embolism, death, bleeding).
If a participant is unwilling or unable to return for follow-up visits in person or have follow-
up contacts, sites should collect as much follow-up visit information as possible, including 
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 

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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).
7.1.1
Temporary Discontinuation 
In the event of a temporary interruption of study drug for any reason, study drug will be 
restarted as soon as medically justified in the opinion of the investigator. There is no 
predefined maximum limit for temporary treatment interruption. 
If study interventions 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 the SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need 
to be completed.

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:

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
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow up.

In order to reduce risk for lost to follow-up the site should collect 2 alternative means 
of contact for each participant e.g. contact information of family members, caretaker, 
legal representative, or treating physician. The correctness of these contact details 
should be checked regularly at the study visits.

A patient locator service may be used to re-establish contact with a participant in case 
the site has exhausted all means of regaining contact, if the participant will agree to 
this in the ICF.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (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 endpoint is the composite of symptomatic ischemic stroke and covert
brain infarcts detected by MRI.
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.

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8.1.1.1
Stroke
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by an
injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction.
Differentiation is made regarding ischemic stroke and hemorrhagic stroke.
Hemorrhagic stroke:
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. 
Ischemic stroke:
Either of the following is considered to be an ischemic stroke: 

Rapid onset (or present on awakening) of a new focal neurological deficit with clinical 
(>24 hours symptoms/signs) or imaging evidence of infarction that is not attributable 
to a non-ischemic cause (i.e. not associated with infection, tumor, seizure, severe 
metabolic disease) 

Acute worsening of an existing focal neurological deficit (e.g., the qualifying stroke) 
that is judged to be attributable to a new infarction or extension of the previous 
infarction in the same vascular territory, based on persisting symptoms/signs or 
imaging evidence of infarction and no evidence of a non-ischemic etiology. If imaging 
is inconclusive, persistent symptoms/signs must be significant (worsening of NIHSS 
score of 4 or more) and sustained (duration of ≥24 hours or until death).
The term undetermined stroke will apply when sudden focal neurological deficits persist for 
24 hours (or death if occurs before 24 hours), but without neuroimaging or autopsy.
8.1.1.1.1
Covert Brain Infarcts
Covert brain infarcts are defined as incident infarcts detected by serial MRI in the absence of 
an adjudicated stroke consistent with the location of the infarct. MRI criteria for brain 
infarction will be available in the MRI procedures manual.
8.1.2
Secondary efficacy endpoints
A definition of the secondary efficacy outcome events is provided as follows, and further 
specified in the charter of the clinical event committee (CEC).
Secondary efficacy endpoints are:

composite of symptomatic ischemic stroke and covert brain infarcts detected by MRI, 
CV death, myocardial infarction and systemic embolism

symptomatic ischemic stroke

covert brain infarcts detected by MRI

symptomatic ischemic stroke, CV death, myocardial infarction 

symptomatic ischemic and hemorrhagic stroke 

disabling stroke (mRS ≥4)

all-cause mortality.

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8.1.2.1
Systemic Embolism
Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or 
radiological evidence of arterial occlusion in the absence of other likely mechanisms (this 
does not include thromboembolism of the pulmonary vasculature or venous thrombosis, e.g. 
pulmonary embolism or deep venous thrombosis).
8.1.2.2
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
8.1.2.3
Cardiovascular Death
Cardiovascular death includes death due to stroke, myocardial infarction, heart failure or 
cardiogenic shock, sudden death or any other death due to other cardiovascular causes.  In 
addition, death due to non-traumatic hemorrhage will be included.
8.2
Safety Assessments 
The safety 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 safety endpoint
The primary safety endpoint includes the analysis of the composite of ISTH major bleeding 
(Section 8.2.1.1) and clinically relevant non-major bleeding (Section 8.2.1.2).
8.2.1.1
ISTH Major Bleeding
An event that meets at least one of the below criteria for a major bleeding event according to 
the definition given by the ISTH:

Fatal bleeding, and/or

Symptomatic  bleeding in a critical area or organ (intracranial, intraocular, intraspinal, 
pericardial, retroperitoneal, intraarticular, or intramuscular with compartment 
syndrome), and/or 

Clinically overt* bleeding associated with a recent decrease in the hemoglobin level of 
≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value 
available before the event, and/or 

Clinically overt* bleeding leading to transfusion of 2 or more units of packed red 
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*overt bleeding requires the identification of the bleeding location and the hemoglobin 
drop and/ or transfusion needs to be related to the bleeding
8.2.1.2
ISTH Clinically Relevant Non-Major Bleeding
Clinically relevant non-major bleeding is considered any sign or symptom of hemorrhage that 
does not fit the criteria for the ISTH definition of major bleeding, but does meet at least one of 
the following criteria (Kaatz et al. 2015):

requiring medical intervention by a healthcare professional

leading to hospitalization or increased level of care

prompting a face to face (i.e. not just a telephone or electronic communication) 
evaluation
8.2.2
Secondary safety endpoints
The secondary safety endpoints include the analysis of the following outcome events:

all bleeding

ISTH major bleeding (Section 8.2.1.1)

ISTH CRNM bleeding (Section 8.2.1.2)

ISTH minor bleeding (Section 8.2.2.1)

Intracerebral hemorrhage (non-traumatic)
8.2.2.1
ISTH Minor bleeding
All other overt bleeding episodes not meeting the above criteria for ISTH major or clinically 
relevant non-major bleeding will be classified as minor bleeding (e.g. bleeding from a minor 
wound that does not prompt a face-to-face evaluation for a physical examination or laboratory 
testing).
8.2.3
Exploratory safety endpoint
The exploratory safety endpoints include the analysis of the following outcome events:

TIMI clinically significant bleeding

TIMI major bleeding

TIMI minor bleeding

BARC bleeding definition Type 2, 3, 5

BARC bleeding definition Type 3, 5

BARC bleeding definition Type 1, 2, 3, 5
8.2.3.1
TIMI Bleeding Definitions
The non-CABG related TIMI clinically significant bleeding definition encompasses the 
following bleeding types excluding events that are related to a CABG procedure:

TIMI Major Bleeding

Any symptomatic intracranial hemorrhage

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
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).
8.2.3.2
BARC Bleeding Definition
The BARC bleeding definition encompasses the following bleeding types (type 4: CABG-
related bleeding is not applicable to this study):

Type 0: no bleeding

Type 1: bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a healthcare 
professional; may include episodes leading to self-discontinuation of medical therapy 
by the patient without consulting a healthcare professional

Type 2: any overt, actionable sign of hemorrhage (e.g. more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, or 5 but does meet at least one of the following 
criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, 
(2) leading to hospitalization or increased level of care, or (3) prompting evaluation

Type 3:
Type 3a

Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided 
hemoglobin drop is related to bleed)

Any transfusion with overt bleeding
Type 3b

Overt bleeding plus hemoglobin drop ≥ 5 g/dL* (provided hemoglobin 
drop is related to bleed)

Cardiac tamponade

Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid)

Bleeding requiring intravenous vasoactive agents
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
Intracranial hemorrhage (does not include microbleeds or hemorrhagic
transformation, does include intraspinal); subcategories confirmed by 
autopsy or imaging or lumbar puncture

Intraocular bleed compromising vision

Type 5: fatal bleeding
Type 5a

Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious
Type 5b

Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1g/dL
  hemoglobin)
8.2.4
Physical Examinations

Height and weight (also referred to as biometrics in the SoA) will be measured and 
recorded at screening (see Section 1.3).
8.2.5
Vital Signs

Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.

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 
include temperature, systolic and diastolic blood pressure, and pulse.
8.2.6
Electrocardiograms

A single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.
8.2.7
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.

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o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
o
If laboratory values from non-protocol specified laboratory assessments performed 
at the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.
Events identified as Adverse Events of Special Interest (AESI) for the study are specified in 
Section 8.3.7.
AEs that are outcome events according to the study protocol are further described in Section 
8.3.6 and Section 10.3.5.
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 study procedures, 
or those that caused the participant to discontinue the study intervention and/or study. AESIs 
have to be followed up regardless of causality or relationship to study intervention.
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 AEs will be collected from the start of the intervention until the 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 
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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.

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 partners of male participants will be collected after 
the start of study intervention and until 4 days after the last dose intake.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours
of learning of the pregnancy and should follow the procedures outlined in Section 
10.4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
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 related to the blinded 
treatment, the participant’s treatment code will usually be unblinded before reporting to the 

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Health Authorities. Notifications of IECs / IRBs and investigators will be done according to 
all applicable regulations (see Section 8.3.4).
The following disease- and treatment-related events are common in participants with stroke 
who are being treated with an anticoagulant:
a.
Bleeding
b. Death
c.
Myocardial Infarction
d. Ischemic stroke
e.
Systemic embolism
These events will be recorded on the corresponding CRF page in the participant’s CRF.
These events will also be monitored and adjudicated by a Central Event Committee (CEC) on 
an ongoing basis. 
In addition, these events require reporting to the sponsor according to the standard process of 
expedited reporting of SAEs within 24 hours of the investigator’s awareness of the event, 
along the timelines set for reporting of SAEs and AESIs.
However, due to their expectedness, efficacy endpoints listed above (b-e: death, myocardial 
infarction, ischemic stroke and systemic embolism), including events indicative of those 
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 Event 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 the initial laboratory value 
elevation) with or without symptoms such as e.g. nausea, vomiting, right upper quadrant 
abdominal pain, fatigue, weakness, weight loss and jaundice. Re-testing of lab values can be 
performed at the local lab and needs to be documented in the eCRF.
AESIs have to be reported to the sponsor within 24 hours of the investigator’s awareness, i.e. 
along the timelines set for SAEs (even though they may not be classified as serious), as 
described in Section 8.3.1.
8.4
Treatment of Overdose
For this study, any dose of BAY 2433334 greater than 3 assigned daily 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 6.5.1 should be followed.
In the event of an overdose, the investigator/treating physician should:

Contact the Medical Monitor immediately.

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
Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study drug can no longer be detected systemically (at least 5 days.). 

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  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 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 the 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 intervention. At this visit, study 
intervention will be administered at the study center by study personnel and the exact time of 
study intervention intake on the day before the visit and on the day of the visit and the exact 
sampling time will be recorded in the eCRF. Ideally, the study personnel should contact the 
participant prior to the respective Visit to remind them not to take the study intervention as 
usual in the morning at home. At Visit 4 additional post-dose samples will be taken like 
indicated in the SoA (Section 1.3).
The PK data and the relationship of the BAY 2433334 exposure parameters (e.g. Cmax, AUC) 
with treatment effects might be evaluated using population approaches (e.g. non-linear mixed 
effect modeling) including potential influence of relevant participant co-variables. Analysis 
and report will be done under a separate cover. This evaluation might be started prior to 
database lock: if this is applicable, appropriate measures will be taken to maintain blinding of 
the study team. 
PK samples will be analyzed using validated analytical methods. Quality control (QC) and 
calibration samples will be analyzed concurrently with study samples. The results of 
calibration samples and QC samples will be reported in the Bioanalytical Report which will 
be included in the CSR for this study.
8.6
Pharmacodynamics
Blood sampling for PD parameters is scheduled for the time points as given in Section 1.3. 
The actual date and time of blood sampling will be documented in the eCRF. 
All PD parameters will be measured using validated methods.

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Quality control and calibration samples will be analyzed concurrently with study samples. For 
selected PD parameters, the results of QC samples will be reported together with analyte 
concentrations in the Clinical Study Report (CSR) of this study.
Concentrations of the analyte are calculated according to the method description. Detailed 
method descriptions of all PD methods will be filed with the study report.
The following parameters will be used to assess the PD effects after administration of the 
investigational drug, but will be performed optionally and/or only in a subset of participants:

aPTT will be measured using a coagulation assay via kaolin-trigger

Activated Factor XIa activity (AXIA) will be analyzed using a kaolin-trigger and a 
fluorogenic substrate readout

D-Dimer will be measured using an immunoturbidometric method

Fibrinogen will be measured using a coagulation assay

FXI concentration will be measured via ELISA using polyclonal antibodies

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 
analyses.
In addition, blood samples will be taken for exploratory biomarker work (see Section 8.8).
Detailed information about the collection, processing, storage and shipment of the samples 
will be provided separately (e.g. sample handling sheets and / or laboratory manual).
8.7
Genetics
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study. See Section 8.8 for details.
8.8
Biomarkers
Exploratory biomarker analyses (scheduled for the time points as given in Section 1.3), that 
might be performed optionally and/or only in a subset of participants are:

NT-proBNP will be measured using an electrocheminulescence assay (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 
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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 laboratory manual). Samples 
may be stored for a maximum of 15 years (or according to local regulations) following the 
end of the study at a facility selected by the sponsor to enable further analyses.
8.9
Immunogenicity Assessments
Not applicable.
8.10
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 primary efficacy objective is the assessment of the overall dose-response effect (evidence 
for effectiveness) based on the incidence proportions observed for the primary efficacy 
outcome at Day 180. To detect a dose-response signal, the null hypothesis: “The response 
(incidence proportion) at all four doses is equal” will be tested against the alternative “There 
is a dose-response relationship” for each of M=3 assumed potential dose-response shapes 
prespecified in a candidate set as described below. For each of the dose-response shapes a 
contrast test based on contrast coefficients optimized for the pre-specified dose-response 
shapes will be applied, taking the actual estimated treatment effect per treatment group into 
account. For each of the  = 4 treatment arms (i.e. the placebo group and the 3 active 
treatment arms of BAY 2433334) the response is denoted by , 
 = 1, … , .
For each model ,  = 1, … , 3, in the candidate set
the null hypothesis
:    = 0 
will be tested against
the respective 1-sided alternative hypothesis
:      >  0,
where  = (, … ,  )′ is an optimized contrast vector for the doses 
 = , … ,   
 = (   (,    ), … ,    (,    ))′ and 
is the dose-response 
model   =  (,  ) + ". A more detailed description of the MCP-Mod approach and the 
models used will be provided in Section 9.4.2.
9.2
Sample Size Determination
Sample size calculations were performed for establishing evidence of a drug effect across the 
doses, that is, detecting a statistically significant dose response signal for the primary efficacy 
outcome in this study using the MCP-Mod approach.

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Assuming a true incidence for the primary efficacy outcome of 22.5% at Day 180 under 
placebo, a maximum relative risk reduction of 25% for BAY 2433334 relative to placebo, a 
set of plausible dose-response shapes including Emax and logistic models (chosen based on 
FXIa inhibition data, see Section 9.4.2), random allocation of participants to dose groups 
according to a 1:1:1:1 ratio and about 1% of participants without post-randomization data on 
the occurrence of the primary outcome, a sample size of 450 participants per dose groups will 
have at least 80% power to demonstrate a dose-response relationship, using a one-sided test at 
a type I error rate of α=0.10. Approximately 1900 patients will be screened to achieve 1800 
randomized participants for an estimated total of 450 evaluable participants per intervention 
group.
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
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the intervention they actually 
received.
Pharmacokinetic Analysis Set
All BAY 2433334-treated patients 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)
9.4
Statistical Analyses
9.4.1
General Considerations
The statistical analysis plan (SAP) will be developed and finalized before the first interim 
analysis and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a summary 
of the planned statistical analyses of the primary and secondary endpoints and estimands. 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. The cumulative incidence 
risk will be estimated for time to event variables. The hazard ratios and the corresponding 
confidence intervals will be estimated on separate Cox proportional hazards models for each 
comparison of a BAY 2433334 dose versus placebo. No comparison of the different doses of 
BAY 2433334 is planned.
All collected events will be analyzed summarized using methods like frequency tables and 
other descriptive statistics.
Analyses will be stratified will be stratified based on whether participants will receive single 
or dual antiplatelet therapy after the index stroke and randomization. The statistical analyses 
will be performed using SAS; the version used will be specified in the SAP.

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9.4.2
Primary Endpoints
Efficacy analyses
The primary efficacy estimand is the incidence of symptomatic ischemic stroke or covert 
brain infarcts detected by MRI in 6 months following a non-cardioembolic ischemic stroke in 
adult participants with background antiplatelet therapy, while alive and regardless of 
treatment discontinuation, for each of the different doses of BAY 2433334 and placebo.
The primary efficacy analysis will be using the Full Analysis Set. All participants with a 
primary efficacy outcome up to Week 26 will be counted in the analysis. Of note the brain 
infarct component of the primary efficacy outcome can only be detected based on MRI.
Note that a study participant who dies before week 26 without having experienced a 
symptomatic ischemic stroke may not have had a post-randomization MRI performed to 
assess if s/he experienced a covert brain infarct before death. This data would be meaningful 
for the analysis but can no longer be collected due to death. The same holds true for 
participants who refuse to undergo a second MRI and/or that have a missing MRI at 
randomization.
For the main estimator corresponding to the primary efficacy estimand missing values for 
covert infarcts detected by MRI at week 26 will be handled as follows: 
For participants in Part A who have a MRI at week 13, the result of that MRI will be used if a 
covert infarct was detected.
For participants without a symptomatic stroke and missing MRI evaluation (up to or) at week 
26 it will be assumed that the proportion of participants with a covert infarct is the same as in 
participants without a symptomatic stroke with a MRI evaluation at week 26 (Quan et al. 
2007). 
The MCP-Mod method combining MCP (multiple comparison procedures) principles with 
modeling techniques will be used for the primary statistical analysis. This method allows the 
flexibility of modeling for dose estimation, while preserving the robustness to model 
misspecification associated with MCP procedures.
3 active doses of BAY 2433334 will be used in this study: 10 mg, 20 mg, and 50 mg, with an 
additional placebo arm, corresponding to a 0 mg dose. The incidence proportion at dose $ will 
be transformed to a normal distributed variable %, the estimated logit of the incidence
proportion at dose $. For the dose-response relationship the functional relationship is
% = ($,  ) + ".
It is assumed that the relative incidence risk is 22.5% at Day 180 under placebo and there is a 
relative risk reduction of 25% under the highest dose.
The candidate set of models for ($,  ) consists of three models, two (standardized) Emax 
models with parameter &'(= 6 and &'(= 29 and a (standardized) logistic model with the 
parameter &'( = 0.05 and * = 8.25. All three candidate models assume a monotonically 
decreasing dose-response. The parameter of the models are based on pharmacokinetic data. 
The dose-response candidate models are shown in the Table below.

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Model
Response as function of dose d
Emax1
–1.24 – 0.40d / (6 + d)
Emax2
–1.24 – 0. 57d / (29 + d)
Logistic 
–0.88 – 0.72d / (1 + exp((0.05 - d) / 8.25))
The corresponding dose-response relationships of the candidate models are shown in the 
Figure below.
Based on these models and the observed data optimal contrasts  and the corresponding 
critical value will be calculated. (For a detailed description see the SAP).
Based on the optimal contrast and the critical values a one-sided test with - = 0.1 based on 
the maximum value of the test statistics for the models in the candidate set will be performed. 
The MCP-Mod method takes multiplicity into account. Thus no further multiplicity 
adjustments has to be performed.
If for at least one contrast the test is statistically significant, a dose-response signal is 
established. Out of the statistically significant models in the candidate set a best model can be 
selected for the next step: modeling and estimation. The selection of the dose-estimation 
model will be based on an assessment of the p value. If no candidate model is statistically 
significant, the procedure stops indicating that a dose-response relationship cannot be 
established from the observed data. The modelling of the dose-response relationship will be 
done using least-squares parameter estimation.
For the primary efficacy estimand sensitivity analyses are planned to investigate the impaction 
of potentially missing values due to missing MRI scans. Assumptions made for participants 
with a missing MRI are described in the following:
1. Assume these participants had no covert infarct.
2. Assume these participants had a covert infarct.
3. Assume only those participants in the BAY 2433334 treatment arms had a covert 
infarct while the participants in placebo arm did not have a covert infarct (worst 
case analysis).
As supplementary analysis only the participants who have a MRI at randomization and at 
week 26 will be analyzed, i.e. the population in the primary efficacy estimand is changed.

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This also excludes participants in Part A, who have an MRI at randomization and week 13, 
but not at week 26.
There will be no formal comparison of the different doses of BAY 2433334.
Safety analyses
The primary safety estimand is the hazard ratio of the composite of International Society on 
Thrombosis and Hemostasis (ISTH) major bleeding and clinically relevant non-major 
(CRNM) bleeding comparing pooled BAY 2433334 with placebo following a non-
cardioembolic ischemic stroke in adult participants treated with antiplatelet therapy and who 
have taken at least one dose of study medication of BAY 2433334 or placebo and while the 
participant is alive and exposed to study drug.
The primary safety estimator will be hazard ratio for the composite in a Cox proportional 
hazards model comparing the pooled BAY 2433334 treatment arms with placebo. All events 
from first intake of study drug up until 2 days after permanent study drug discontinuation will 
be counted. As supplementary analyses the analyses will be done on the ITT data set and 
counting all events from randomization until final follow-up.
These analyses will be replicated for the comparison of each dose of BAY 2433334 and 
placebo.
In addition, incidence proportions for the primary safety endpoint will be reported.
9.4.3
Secondary Endpoints
Efficacy analyses
The secondary efficacy analyses for the endpoints that include the evaluation of the MRI will 
be different from those that will be performed for the endpoints that do not include it. 
The secondary efficacy estimand for the following endpoints:

composite of symptomatic ischemic stroke and covert brain infarcts detected by MRI, 
CV death, myocardial infarction and systemic embolism

covert brain infarcts detected by MRI 
is the incidence in 6 months of each of the individual endpoints following a non-
cardioembolic ischemic stroke in adult participants treated with antiplatelet therapy while 
alive and regardless of treatment discontinuation, for each of the different doses of BAY 
2433334 and placebo.
The secondary efficacy estimand for the following endpoints:

symptomatic ischemic stroke

symptomatic ischemic stroke, CV death, myocardial infarction 

symptomatic ischemic and hemorrhagic stroke

disabling stroke (mRS≥4)

all-cause mortality
is the hazard ratio of each of the individual endpoints following a non-cardioembolic ischemic 
stroke in adult participants treated with antiplatelet therapy, while alive and regardless of 
treatment discontinuation, comparing each of the different doses of BAY 2433334 with 
placebo. The endpoints will be analyzed with point estimators and confidence intervals for the 
proportion of participants with an event.

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Time to event endpoints will be analyzed as described in 9.4.1.
Sensitivity analyses will be done similar as for the primary efficacy outcome and described in 
the SAP.
Safety endpoints
The secondary safety estimand is the hazard ratio of each of the individual endpoints
comparing pooled BAY 2433334 with placebo in adult participants after non-cardioembolic 
ischemic stroke and who have taken at least one dose of study medication of BAY 2433334 or 
placebo and while the participant is alive and exposed to study drug for the endpoints:

all bleeding

ISTH major bleeding

ISTH CRNM bleeding

ISTH minor bleeding

Intracerebral hemorrhage (non-traumatic).
The analyzes will follow those of the primary safety estimand.
9.4.4
Tertiary/exploratory Analyses
Exploratory safety endpoints are: TIMI clinically significant bleeding, TIMI major bleeding, 
TIMI minor bleeding, BARC bleeding definition Type 2, 3, 5, BARC bleeding definition 
Type 3, 5 and BARC bleeding definition Type 1, 2, 3, 5.
Exploratory other endpoints are FXIa inhibition, aPTT and various biomarkers.
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, as well as the mandatory pharmacodynamic markers will be described in the statistical 
analysis plan finalized before database lock. Optional pharmacodynamic markers as well as 
exploratory biomarkers may be described in the statistical analysis plan finalized before 
database lock, if they are available in time. Otherwise they may be reported under separate 
cover. The population PK analysis and exploratory or optional biomarkers may 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 2 other ongoing Phase 2 studies will be reviewed together when 
the pre-defined criteria for the 2 interim analyses have been reached. The overall approach of 
the 2 interim analysis 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 

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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 may also be included in this review. The data will be kept strictly confidential by 
this group and will not be shared with the study team and the SC. Thus, the study integrity 
will not be impacted and the study conduct will otherwise not be altered by the results of this 
interim analysis.
The interim analysis will include selected and predefined study data primarily as aggregated 
data for this individual study but may also include pooling of some data across all 3 ongoing 
Phase 2 studies.
The first interim analysis will be conducted once about 50% of the participants (800 
participants) with a minor non-cardioembolic ischemic stroke (NIHSS ≤ 7) are enrolled in the 
study 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 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 the
interim analysis is specific for the decision for this study only, data and especially bleeding 
data from the other 2 studies will be taken into consideration. 
The second interim analysis will occur when sufficient data are available from all 3 Phase 2 
studies. This interim analysis may occur, when approximately 80% of all planned participants, 
taken all 3 studies together, are randomized. This meeting will aim to assess whether the 
interim data support decision making on dose and design for a potential Phase 3 clinical 
development program while the Phase 2 studies are still ongoing and may allow interaction 
with Health Authorities before final data from the studies are available. 
The timepoints when these two interim analyses occur are difficult to predict and will depend 
e.g. on study start time, number of sites and countries, on the enrollment rate and other factors 
in all three studies. In case the timepoints for the 2 interim analysis may be close together, the 
decision could be taken to just conduct one interim analysis.
As part of the 2 interim analyses the additional objective to potentially change the dose during 
the ongoing Phase 2 studies will be assessed. This will allow flexibility in case of unexpected 
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 
efficacy and safety data for study 19766, and of the overall safety data across all 3 Phase 2 
studies with BAY 2433334 (Section 10.1.5.3). Detailed information on the roles and 
responsibilities of the IDMC will be described in the IDMC Charter. 

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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 (e.g., 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 modification of 
the protocol will be submitted to the competent authorities as substantial amendments 
for approval, in accordance with ICH Good Clinical Practice and national and 
international regulations.

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. 

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, 

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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 who will be required to give consent for their 
data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
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 3 Phase 2 studies with BAY 
2433334, as well as 2 sponsor representatives, will ensure the overarching integrity of the 3 
studies. Details of the committee will be specified in the Executive Committee Charter. 
10.1.5.2
Steering Committee (SC)
The main task of the Steering Committee is to support protocol development, to facilitate the 
conduct of the study, to advise the sponsor on clinical, medical, and scientific questions and to
initiate publications. The Steering Committee will consist of the National Leaders from the 
participating countries, three physicians from the clinical coordinating center (Population 
Health Research Institute, Canada), the director of the MRI Core Lab, and two Bayer 
representatives. Additional details of the committee will be specified in the Steering 
Committee charter.

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10.1.5.3
IDMC
Ongoing safety monitoring during the conduct of the study will be performed by an external 
and unblinded IDMC. An independent statistical analysis center (SAC) will be involved in 
processing unblinded safety data for the IDMC. Analysis periods and procedures will be 
defined in an operational charter (IDMC Charter) filed in the study file. Following data 
review, the IDMC will provide written recommendations that will be transferred to Bayer. All 
other definitions will be provided in the IDMC charter.
10.1.5.4
Clinical Events Committee (CEC)
Potential pre-specified clinical outcome events will be submitted for adjudication to an 
independent CEC. Adjudication of all bleeding events as well as efficacy events will be 
performed by members of the CEC who will review events in a blinded fashion and will 
adjudicate and classify the following events in a consistent and unbiased manner according to 
definitions contained in the CEC charter. The adjudication will also include algorithm 
approaches:

Bleeding events according to the following classifications:

ISTH (major, clinically relevant non-major and minor)

TIMI (major, minor, requiring medical attention, minimal)

BARC (type 1, 2, 3, 5)

Death (CV death [including death with unknown cause] or non-CV death)

MI

Stroke (ischemic, hemorrhagic, undetermined)

Systemic embolism
In addition, events that might be indicative of a potential outcome event will be reported as 
outcome events to ensure that no outcome event is missed. This includes for example TIA and 
hospitalization for cardiac chest 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 
in patients for medicines and indications approved in the United States (US) and European 
Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.

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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 (e.g., 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 (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
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 
TrialMaster. Participant data necessary for analysis and reporting will be entered/transmitted 
into a validated database or data system (SPECTRUM).
Data required according to this protocol will be recorded by study site personnel via data entry 
into the internet based EDC software system TrialMaster, which the ARO (Academic 
Research Organization) has licensed from OmniComm. TrialMaster has been validated by 
OmniComm and the ARO for use in its clinical studies. TrialMaster 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/ARO 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 

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data are stored at a secure host facility maintained by PHRI and transferred on a periodic basis 
to Bayer's internal computer system via a secure Virtual Private Network.
All access to the TrialMaster system is through a password-protected security system that is 
part of the TrialMaster software. All internal Bayer and external investigator site personnel 
seeking access must go through a thorough TrialMaster training process before they are 
granted access to TrialMaster for use in Bayer's clinical studies. Training records are 
maintained.
All personnel with access to the TrialMaster 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 TrialMaster 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 
ARO/Bayer. Data entries made in the TrialMaster 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, GCP, and sponsor’s procedures, monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of participants are being protected

Study is conducted in accordance with the currently approved protocol
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.

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10.1.7.3
Data processing
Data will be collected as described in Section 10.1.7.1. Clinical data management will be 
performed in accordance with applicable sponsor’s standards and data cleaning procedures. 
This is applicable for data recorded on eCRF as well as for data from other sources (e.g. IxRS, 
laboratory, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, additional data release for analysis is possible, 
to include, for example, the following data: pharmacokinetic data, pharmacodynamic data, 
anti-drug antibody data etc.
10.1.7.4
Missing data
All efforts will be made to collect complete data for all participants randomized in this study. 
Participants will be followed up to the study end and all required data will be collected, 
regardless of participants’ compliance with study 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 GCP and regulatory requirements, a member of the sponsor’s 
quality assurance unit may arrange to conduct an audit to assess the performance of the study 
at the study site and of the study documents originating there. The investigator/institution will 
be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
10.1.7.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Participant (hospital) files will be archived according to local regulations and in accordance 
with the maximum period of time permitted by the hospital, institution or private practice. 
Where the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.

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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.
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. 

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
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 Section 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)
Investigators must document their review of each laboratory safety report.
The name and address for the central laboratory service provider can be found in the 
documentation supplied by the vendor. In the event of implausible results, the laboratory may 
measure additional parameters to assess the quality of the sample (e.g. clotted or hemolyzed) 
and to verify the results. The results from such additional analyses may neither be included in 
the clinical database of this study nor evaluated further. If the results are relevant, the 
investigator will be informed to determine follow-up activities outside of this protocol. 
All exploratory biomarkers are not used routinely in practice and will be analyzed in batches. 
Therefore, timely reporting of the results will not be possible during the study and review of 
the results will not assist participant care.

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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
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 (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.

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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 

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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 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) 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 

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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 
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.

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
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide 
 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 
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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

SAE reporting via email transmission of the scanned paper CRF is the preferred 
method to transmit this information to the Sponsor via 
.  

In rare circumstances and in the absence of email transmission tools or 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.
10.3.5
Event Reporting Process Overview 
If an AE or SAE is a potential outcome event (all bleeding, death, MI, stroke, TIA and 
systemic embolism [Section 8.3.6]), it must be collected and reported on the dedicated forms 
on an ongoing basis, until the participant has completed the study. Thus, even if a participant 
is no longer taking study medication this would be until the end of the regular, planned end of 
treatment for this participant (i.e. until the participant’s last visit). After completion of SFU 
visit, for participants that prematurely discontinued study intervention, there is no further 
requirement for reporting AEs. Only potential outcome events are to be reported (refer to 
Section 8.3.1 and Section 10.9).
All bleeding events including fatal bleeding will be captured in the eCRF. SAE which are 
bleeding terms will also be reported to the sponsor’s PV Department in an expedited manner. 
Symptomatic intracerebral / intraparenchymal hemorrhages as well as symptomatic 
subarachnoid hemorrhages will be captured as bleeding and as stroke. All subdural / epidural 
hematoma and asymptomatic intracranial bleeding are only reported as bleeding.
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).
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If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g. Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview.
Postmenopausal Female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement (> 40 IU/L) is 
required. 

Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance

Female participants must be of non-child bearing potential as per Clinical Trial 
Facilitation Group (CTFG) guidelines.

Male participants must agree to use condoms when sexually active with a woman of 
childbearing potential from the time of the first dose to 7 days after the last dose of 
study intervention. This is in line with the CTFG guideline, as BAY 2433334 is non 
genotoxic but data related to teratogenicity/fetotoxicity in early pregnancy (Segment 2 
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 
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pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 

Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting. 

Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
10.5
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Any participant with an ALT or AST > 3 x ULN must be re-tested as soon as possible, at the 
latest within 48-72 hours of the investigator becoming aware of the result. This re-testing and 
any subsequent testing based on elevated levels should include measurement of ALT, AST, 
total and direct bilirubin, AP and INR, and will be assessed by local laboratory. There also 
should be inquiry made about symptoms.
Every effort should be made to clarify the etiology of elevated levels and laboratory testing 
may include, but not be limited to, testing for viral hepatitis, cytomegalovirus, Epstein-Barr 
virus, human immunodeficiency virus (once the participant has provided written consent), 
ferritin levels, iron, iron binding capacity, antinuclear antibody, and smooth muscle 
antibodies. Participant management is at the discretion of the treating physician but the 
investigator may continue the study 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 

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or returned to participant’s baseline. If close liver monitoring is not possible, then the 
participant should discontinue study medication.
For ALT or AST > 3 x ULN concurrent with a total bilirubin > 2 x ULN, every effort should 
be made to promptly clarify any possible underlying disease(s).
The frequency of liver function tests based on re-test values is shown in Table 10–2. 
Table 10–2
Liver function monitoring 
ALT, AST level at re-test
Frequency
Further notice
ALT or AST > 3 x ULN
2-3 times a week
Obtain details on liver related symptoms and 
exclude other causes of liver enzyme elevations
ALT or AST ≤ 3 x ULN
Once a week
Until return to normal or participant baseline levels
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
Discontinuation of treatment should be considered if: 

ALT or AST > 8 x ULN 

ALT or AST > 5 x ULN for more than 2 weeks 

ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN or INR > 1.5) 

ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and / or eosinophilia (> 5%).
10.6
Appendix 6: Calculating the Child-Pugh Score
The severity of liver disease (Table 10–3) will determine the Child-Pugh score (Table 10–4).
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
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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).
10.8
Appendix 8: Outcome Events: Data Collection
All outcome events (efficacy and safety) are to be captured and reported from randomization 
until the regular last scheduled study visit  (ie, Safety Follow-up Visit; in case of permanent 
discontinuation of study intervention, the planned 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 AEs 
subpage for outcome events.

Outcome events occurring after SFU visit through the end of the study (for 
participant who discontinue study intervention): the outcome events should be 
collected until completion of participant´s regular scheduled study visits, and should 
be reported in the outcome event eCRF page.
10.9
Appendix 9: Study MRI procedure
The minimum requirements for the study MRIs are outlined in the table below. In addition, it 
is encouraged to also collect T1- and T2 weighted sequences and have a slice gap ≤ 1mm in 
order to detect smaller infarcts. However, this is optional and not required.
Minimum Requirements
Preferred / Optional
Sequences
FLAIR
DWI
ADC
SWI, SWAN, GRE or equivalent 
per local MRI routine protocol
T1-weighted
T2-weighted
Field strengths
≥ 1 Tesla
Slice thickness
1 - 5 mm
Slice gap
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Study sites will be required to demonstrate that study-sponsored MRIs that meet the minimum 
study criteria outlined above can be obtained in advance of enrolling participants. Detailed 
instructions will be provided to sites, followed by submission to the central MRI Core Lab of 
an MRI of an inanimate phantom object. 
The study MRIs will be transmitted to the central MRI Core Lab that will be responsible for 
analyzing all MRIs blinded to treatment assignment.
More detailed information regarding image acquisition and processing will be found in a 
separate MRI procedures manual.
10.10
Appendix 10: Modified Ranking Score
Modified ranking score (mRS)
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; despite symptoms, able to carry 
out all usual duties and activities
2
Slight disability; unable to carry out all previous activities but able to look after 
own affairs without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to 
attend to own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care 
and attention
6
Death
TOTAL (0–6): _______
Source: adapted from (Banks and Marotta 2007, van Swieten et al. 1988).
10.11
Appendix 11: NIH Stroke Scale
NIH stroke scale (NIHSS)
Administer stroke scale items in the order listed. Record performance in each category after 
each subscale exam. Do not go back and change scores. Follow directions provided for each 
exam technique. Scores should reflect what the patient does, not what the clinician thinks the 
patient can do. The clinician should record answers while administering the exam and work 
quickly. Except where indicated, the patient should not be coached (i.e., repeated requests to 
patient to make a special effort). 
At the end the scores of all items need to be summed up.

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Instructions
Scale Definition
Score
1a. Level of Consciousness: The 
investigator must choose a response if a 
full evaluation is prevented by such 
obstacles as an endotracheal tube, 
language barrier, orotracheal 
trauma/bandages. A 3 is scored only if the 
patient makes no movement (other than 
reflexive posturing) in response to noxious 
stimulation. 
0 = Alert; keenly responsive. 
1 = Not alert; but arousable by minor 
stimulation to obey, answer, or respond. 
2 = Not alert; requires repeated 
stimulation to attend, or is obtunded and 
requires strong or painful stimulation to 
make movements (not stereotyped). 
3 = Responds only with reflex motor or 
autonomic effects or totally unresponsive, 
flaccid, and areflexic.
______
1b. LOC Questions: The patient is asked 
the month and his/her age. The answer 
must be correct - there is no partial credit 
for being close. Aphasic and stuporous 
patients who do not comprehend the 
questions will score 2. Patients unable to 
speak because of endotracheal intubation, 
orotracheal trauma, severe dysarthria from 
any cause, language barrier, or any other 
problem not secondary to aphasia are 
given a 1. It is important that only the initial 
answer be graded and that the examiner 
not "help" the patient with verbal or non-
verbal cues. 
0 = Answers both questions correctly. 
1 = Answers one question 
correctly. 
2 = Answers neither question 
correctly. 
______
1c. LOC Commands: The patient is asked 
to open and close the eyes and then to 
grip and release the non-paretic hand. 
Substitute another one step command if 
the hands cannot be used. Credit is given 
if an unequivocal attempt is made but not 
completed due to weakness. If the patient 
does not respond to command, the task 
should be demonstrated to him or her 
(pantomime), and the result scored (i.e., 
follows none, one or two commands). 
Patients with trauma, amputation, or other 
physical impediments should be given 
suitable one-step commands. Only the first 
attempt is scored. 
0 = Performs both tasks correctly. 
1 = Performs one task correctly. 
2 = Performs neither task correctly. 
______

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Instructions
Scale Definition
Score
2. Best Gaze: Only horizontal eye 
movements will be tested. Voluntary or 
reflexive (oculocephalic) eye movements 
will be scored, but caloric testing is not 
done. If the patient has a conjugate 
deviation of the eyes that can be overcome 
by voluntary or reflexive activity, the score 
will be 1. If a patient has an isolated 
peripheral nerve paresis (CN III, IV or VI), 
score a 1. Gaze is testable in all aphasic 
patients. Patients with ocular trauma, 
bandages, pre-existing blindness, or other 
disorder of visual acuity or fields should be 
tested with reflexive movements, and a 
choice made by the investigator. 
Establishing eye contact and then moving 
about the patient from side to side will 
occasionally clarify the presence of a 
partial gaze palsy.
0 = Normal. 
1 = Partial gaze palsy; gaze is 
abnormal in one or both eyes, but forced 
deviation or total gaze paresis is not 
present. 
2 = Forced deviation, or total 
gaze paresis not overcome by the 
oculocephalic maneuver. 
______
3. Visual: Visual fields (upper and lower 
quadrants) are tested by confrontation, 
using finger counting or visual threat, as
appropriate. Patients may be encouraged, 
but if they look at the side of the moving 
fingers appropriately, this can be scored as 
normal. If there is unilateral blindness or 
enucleation, visual fields in the remaining 
eye are scored. Score 1 only if a clear-cut 
asymmetry, including quadrantanopia, is 
found. If patient is blind from any cause, 
score 3. Double simultaneous stimulation 
is performed at this point. If there is 
extinction, patient receives a 1, and the 
results are used to respond to item 11.
0 = No visual loss. 
1 = Partial hemianopia. 
2 = Complete hemianopia. 
3 = Bilateral hemianopia (blind including 
cortical blindness). 
______
4. Facial Palsy: Ask – or use pantomime 
to encourage – the patient to show teeth or 
raise eyebrows and close eyes. Score 
symmetry of grimace in response to 
noxious stimuli in the poorly responsive or 
non-comprehending patient. If facial 
trauma/bandages, orotracheal tube, tape 
or other physical barriers obscure the face, 
these should be removed to the extent 
possible. 
0 = Normal symmetrical movements. 
1 = Minor paralysis (flattened nasolabial 
fold, asymmetry on smiling). 
2 = Partial paralysis (total or near-total 
paralysis of lower face). 
3 = Complete paralysis of one or both 
sides (absence of facial movement in the 
upper and lower face). 
______

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Instructions
Scale Definition
Score
5. Motor Arm: The limb is placed in the 
appropriate position: extend the arms 
(palms down) 90 degrees (if sitting) or 45 
degrees (if supine). Drift is scored if the 
arm falls before 10 seconds. The aphasic 
patient is encouraged using urgency in the 
voice and pantomime, but not noxious 
stimulation. Each limb is tested in turn, 
beginning with the non-paretic arm. Only in 
the case of amputation or joint fusion at the 
shoulder, the examiner should record the 
score as untestable (UN), and clearly write 
the explanation for this choice. 
0 = No drift; limb holds 90 (or 45) degrees 
for full 10 seconds. 
1 = Drift; limb holds 90 (or 45) degrees, 
but drifts down before full 10 seconds; 
does not hit bed or other support. 
2 = Some effort against gravity; limb 
cannot get to or maintain (if cued) 90 (or 
45) degrees, drifts down to bed, but has 
some effort against gravity. 
3 = No effort against gravity; limb falls. 
4 = No movement. 
UN = Amputation or joint fusion, explain: 
_____________________ 
5a. Left Arm 
5b. Right Arm 
______ 
______
6. Motor Leg: The limb is placed in the 
appropriate position: hold the leg at 30 
degrees (always tested supine). Drift is 
scored if the leg falls before 5 seconds. 
The aphasic patient is encouraged using 
urgency in the voice and pantomime, but 
not noxious stimulation. Each limb is tested 
in turn, beginning with the non-paretic leg. 
Only in the case of amputation or joint 
fusion at the hip, the examiner should 
record the score as untestable (UN), and 
clearly write the explanation for this choice.
0 = No drift; leg holds 30-degree position 
for full 5 seconds. 
1 = Drift; leg falls by the end of the 5-
second period but does not hit bed. 
2 = Some effort against gravity; leg falls 
to bed by 5 seconds, but has some effort 
against gravity. 
3 = No effort against gravity; leg falls to 
bed immediately. 
4 = No movement. 
UN = Amputation or joint fusion, explain: 
________________ 
6a. Left Leg 
6b. Right Leg 
______ 
______
7. Limb Ataxia: This item is aimed at 
finding evidence of a unilateral cerebellar 
lesion. Test with eyes open. In case of 
visual defect, ensure testing is done in 
intact visual field. The finger-nose-finger 
and heel-shin tests are performed on both 
sides, and ataxia is scored only if present 
out of proportion to weakness. Ataxia is 
absent in the patient who cannot 
understand or is paralyzed. Only in the 
case of amputation or joint fusion, the 
examiner should record the score as 
untestable (UN), and clearly write the 
explanation for this choice. In case of 
blindness, test by having the patient touch 
nose from extended arm position. 
0 = Absent. 
1 = Present in one limb. 
2 = Present in two limbs. 
UN = Amputation or joint fusion, explain: 
________________ 
______

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Instructions
Scale Definition
Score
8. Sensory: Sensation or grimace to 
pinprick when tested, or withdrawal from 
noxious stimulus in the obtunded or 
aphasic patient. Only sensory loss 
attributed to stroke is scored as abnormal 
and the examiner should test as many 
body areas (arms [not hands], legs, trunk, 
face) as needed to accurately check for 
hemisensory loss. A score of 2, “severe or 
total sensory loss,” should only be given 
when a severe or total loss of sensation 
can be clearly demonstrated. Stuporous 
and aphasic patients will, therefore, 
probably score 1 or 0. The patient with 
brainstem stroke who has bilateral loss of 
sensation is scored 2. If the patient does 
not respond and is quadriplegic, score 2. 
Patients in a coma (item 1a=3) are 
automatically given a 2 on this item. 
0 = Normal; no sensory loss. 
1 = Mild-to-moderate sensory loss; 
patient feels pinprick is less sharp or is dull 
on the affected side; or there is a loss of 
superficial pain with pinprick, but patient is 
aware of being touched. 
2 = Severe to total sensory loss; patient 
is not aware of being touched in the face, 
arm, and leg. 
______
9. Best Language: A great deal of 
information about comprehension will be 
obtained during the preceding sections of 
the examination. For this scale item, the 
patient is asked to describe what is 
happening in the attached picture, to name 
the items on the attached naming sheet 
and to read from the attached list of 
sentences. Comprehension is judged from 
responses here, as well as to all of the 
commands in the preceding general 
neurological exam. If visual loss interferes 
with the tests, ask the patient to identify 
objects placed in the hand, repeat, and 
produce speech. The intubated patient 
should be asked to write. The patient in a 
coma (item 1a=3) will automatically score 3 
on this item. The examiner must choose a 
score for the patient with stupor or limited 
cooperation, but a score of 3 should be 
used only if the patient is mute and follows 
no one-step commands. 
0 = No aphasia; normal. 
1 = Mild-to-moderate aphasia; some 
obvious loss of fluency or facility of 
comprehension, without significant 
limitation on ideas expressed or form of 
expression. Reduction of speech and/or 
comprehension, however, makes 
conversation about provided materials 
difficult or impossible. For example, in 
conversation about provided materials, 
examiner can identify picture or naming 
card content from patient’s response. 
2 = Severe aphasia; all communication is 
through fragmentary expression; great 
need for inference, questioning, and 
guessing by the listener. Range of 
information that can be exchanged is 
limited; listener carries burden of 
communication. Examiner cannot identify 
materials provided from patient response. 
3 = Mute, global aphasia; no usable 
speech or auditory comprehension. 
______
10. Dysarthria: If patient is thought to be 
normal, an adequate sample of speech 
must be obtained by asking patient to read 
or repeat words from the attached list. If 
the patient has severe aphasia, the clarity 
of articulation of spontaneous speech can
be rated. Only if the patient is intubated or 
has other physical barriers to producing 
speech, the examiner should record the 
score as untestable (UN), and clearly write 
an explanation for this choice. Do not tell 
the patient why he or she is being tested. 
0 = Normal. 
1 = Mild-to-moderate dysarthria; patient 
slurs at least some words and, at worst, 
can be understood with some difficulty. 
2 = Severe dysarthria; patient's speech is 
so slurred as to be unintelligible in the 
absence of or out of proportion to any 
dysphasia, or is mute/anarthric. 
UN = Intubated or other physical barrier, 
explain:____________________________
______

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Instructions
Scale Definition
Score
11. Extinction and Inattention (formerly 
Neglect): Sufficient information to identify 
neglect may be obtained during the prior 
testing. If the patient has a severe visual 
loss preventing visual double simultaneous 
stimulation, and the cutaneous stimuli are
normal, the score is normal. If the patient 
has aphasia but does appear to attend to 
both sides, the score is normal. The 
presence of visual spatial neglect or 
anosagnosia may also be taken as 
evidence of abnormality. Since the 
abnormality is scored only if present, the 
item is never untestable. 
0 = No abnormality. 
1 = Visual, tactile, auditory, spatial, or 
personal inattention or extinction to 
bilateral simultaneous stimulation in one of 
the sensory modalities. 
2 = Profound hemi-inattention or 
extinction to more than one modality; 
does not recognize own hand or orients to 
only one side of space. 
______
Source: adapted from (Brott et al. 1989, Lyden et al. 1994, Pugh et al. 1973)
10.12
Appendix 12: Abbreviations
AE
Adverse Event
AESI
Adverse event of special interest
ACC
American College of Cardiology
AF
Atrial fibrillation
AG
Joint stock company, Aktiengesellschaft
AHA
American Heart Association
ALT
Alanine aminotransferase
AMI
Acute myocardial infarction 
AP
Alkaline phosphatase
APCC
Activated prothrombin complex concentrate
aPTT
Activated partial thromboplastin time
ARC
Academic Research Consortium
ASA
Acetylsalicylic acid
ASO
Antisense oligonucleotide
AST
Aspartate aminotransferase
AUC
Area under the curve
AXIA
Activated Factor XIa activity
AxMP
Auxiliary medicinal product
BARC
Bleeding Academic Research Consortium
BID
Twice a day, Bis in die
BL
Baseline
BMS
Bristol-Myers Squibb
BP
Blood pressure
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CEC
Clinical Events Committee
CFR
Code of Federal Regulations
CHEST
American College of Chest Physicians
CIOMS
Council for International Organizations of Medical Sciences

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CHMP
Committee for Medicinal Products for Human Use
CK
Creatinine kinase
CL/F
Apparent oral plasma clearance
Cmax
maximum observed concentration reached after administration
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTFG
Clinical Trial Facilitation Group
CV
Cardiovascular
CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
e.g.
For example, exempli gratia
ECG
Electrocardiogram
ECLIA
Electrochemiluminescence Immunoassay
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
End of Treatment
ESC
European Society of Cardiology
ESUS
Embolic stroke of undetermined source
ET
Early termination
EU
European Union
EudraCT
European Clinical Trials Database
F1.2
F1.2 fragment of prothrombin
FAS
Full Analysis Set
FeCl
Ferric chloride
FEIBA
Factor eight inhibitor bypass activity
FiM
first in man
FFP
Fresh frozen plasma
4F-PCC
4-factor Prothrombin complex concentrate
FSH
Follicle stimulating hormone
γGT
Gamma glutamyl transpeptidase
GCP
Good Clinical Practice
geoCV
Geometric coefficient of variation
GFR
Glomerular filtration rate
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HDL
High-density lipoprotein
HDPE
High-density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HR
Heart rate
HRS
Heart Rhythm Society
HRT
Hormonal replacement therapy
hsCRP
High-sensitivity C-reactive protein
i.e.
That is, id est

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IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IDMC
Independent data monitoring committee
IDMS
Isotope dilution mass spectroscopy
IEC
Independent Ethics Committee
IMP
Investigational medical product
IND
Investigational New Drug
INN
International non-proprietary name
INR
International normalized ratio
ISTH
International Society on Thrombosis and Hemostasis 
IR
Immediate-release
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Hemostasis
ITT
Intent-to-treat
IV
Intravenous(ly)
IVRS/IWRS, IxRS
Interactive Voice/Web Response System
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LSH
Life Science Data Hub
LV
Left ventricular
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MD
Medical doctor
MD / MDE
Multiple dose/ multiple dose escalation
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic resonance imaging
N
Total number of participants
NA
Not applicable
NIHSS
National Institutes of Health Stroke Scale
NJ
New Jersey
NOAC
Non-Vitamin K oral anticoagulant
NSAID
Nonsteroidal anti-inflammatory drug
NT-proBNP
N-terminal pro B-type Natriuretic Peptide
OD
Once a day
P2Y12
Gi-coupled platelet receptor for adenosine diphosphate
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PT
Prothrombin time
QC
Quality control
RAAUC
Accumulation ratio for AUC
RACmax
Accumulation ratio for Cmax
RAVE
Data collection tool
RBC
Red blood cell (count)

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RND
Randomization
ROTEM
Rotational thromboelastometry
SAC
Statistical analysis center
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical analysis software
SC
Steering Committee
SCR
Screening
SD
Single dose
SFU
Safety follow-up
SMOL
Small molecule
SoA 
Schedule of activities
SUSAR
Suspected unexpected serious adverse reaction
TAFI
Thrombin-activatable fibrinolysis inhibitor
TAT
Thrombin-antithrombin complex
TIA
Transient ischemic attack
TIMI
Thrombolysis in myocardial infarction
TKA
Total knee arthroplasty
TM
Trademark
tmax
Time to reach maximum drug concentration in plasma
TMF
Trial Master File
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US/USA
United States/United States of America
VKA
Vitamin K antagonist
VTE
Venous thromboembolism
vWF
Von Willebrand Factor
W
Week
WBC
White blood cell (count)
WOCBP
Woman of Childbearing Potential
11.
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