Clinical trial NCT04523220
Conditions: End-stage Renal Disease Prevention of Thromboembolic Events Hemodialysis Hemodiafiltration
Keywords: End-stage renal disease (ESRD) Hemodialysis
Sponsor: Bayer
Start date: 2020-08-28; Completion date: 2022-05-30
Enrollment: 704 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study researchers want to learn about the safety of drug Osocimab at lower-dose and higher-doses in adult participants with kidney disease undergoing regular dialysis (a procedure that uses a machine to get rid of toxins and extra fluids in the blood). Patients with kidney disease undergoing regular dialysis are at high risk for heart and blood vessels diseases. Osocimab is a human monoclonal antibody under development for the prevention of events caused by blood clots like heart attack, stroke and death due to heart or blood vessels diseases. It works by binding to and blocking the activated form of clotting factor XI which increases the formation and stability of clots. Researchers also want to find out how drug Osocimab works in human body and how the body absorbs, distributes and excretes the drug.

Participants in this study will receive monthly injection of either Osocimab at a lower-dose or higher-dose or placebo (a placebo looks like a treatment but does not have any medicine in it). Both Osocimab and placebo will be injected into the tissue under the skin of the belly. Observation for each participant will last up to 23 months. Blood samples will be collected from the participants to monitor the safety and measure the blood level of the study drug.

Detailed description:

Arms: arm 1: Participants will receive Osocimab (BAY1213790) 105 mg single loading dose as subcutaneous abdominal injection, followed by monthly maintenance doses of 52.5 mg until the end of the extension treatment period. arm 2: Placebo will be administered subcutaneously in the same manner as Osocimab. arm 3: Participants will receive Osocimab (BAY1213790) 210 mg single loading dose as subcutaneous abdominal injection, followed by monthly maintenance doses of 105 mg until the end of the extension treatment period. arm 4: Placebo will be administered subcutaneously in the same manner as Osocimab.
Interventions: intervention 1: BAY1213790 (Osocimab) intervention 2: Placebo
Intervention descriptions: intervention 1: Single loading dose as subcutaneous abdominal injection followed by monthly maintenance doses. intervention 2: Subcutaneous administration in the same manner as Osocimab.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study protocol 
Official Title: 
A randomized, double-blind, parallel group, placebo-controlled, 
multi-center study to assess the safety and tolerability of monthly 
subcutaneous administrations of a low and high dose cohort of 
osocimab to ESRD patients on regular hemodialysis 
NCT Number: 
NCT04523220 
Document Date: 
16-Mar-2020 
 


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Clinical Study Protocol
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Version 1.0
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Title Page
Protocol Title: 
A randomized, double-blind, parallel group, placebo-controlled, multi-center study to assess 
the safety and tolerability of monthly subcutaneous administrations of a low and high dose
cohort of osocimab to ESRD patients on regular hemodialysis
Protocol Number: 20115
Compound Number: BAY 1213790 / Osocimab
Study Phase: Phase 2b
Short Title: Osocimab in ESRD Phase 2b study
Acronym: CONVERT
Sponsor Name: Bayer AG
Legal Registered Address:
Non-US: Bayer AG, 51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
Regulatory Agency Identifier Number(s):
IND: 141027
EudraCT: 2019-003957-27
Approval Date: 
16 MAR 2020
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 
 M 
Global Clinical Lead 
Clinical Study Protocol 
No. BAY 1213790 / 20115 
Version 1.0 
Date 
Medical Monitor name and contact information will be provided separately. 
Page: 2 of77 
PPD
PPD
PPD


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Table of Contents
Title Page................................................................................................................................... 1
Sponsor Signatory .................................................................................................................... 2
Table of Contents ..................................................................................................................... 3
Table of Tables ......................................................................................................................... 5
Table of Figures........................................................................................................................ 5
1.
Protocol Summary ............................................................................................................ 6
1.1
Synopsis........................................................................................................................... 6
1.2
Schema............................................................................................................................. 8
1.3
Schedule of Activities (SoA) ........................................................................................... 9
2.
Introduction..................................................................................................................... 17
2.1
Study Rationale.............................................................................................................. 17
2.2
Background.................................................................................................................... 17
2.2.1
Cardiovascular Disease in ESRD Patients.................................................................. 17
2.2.2
Cardiovascular Treatment Options for ESRD Patients .............................................. 18
2.2.3
Factor XI..................................................................................................................... 18
2.2.4
Osocimab (BAY 1213790)......................................................................................... 18
2.2.4.1
Preclinical Data ....................................................................................................... 18
2.2.4.2
Human Experience .................................................................................................. 19
2.2.4.3
Rationale for the Development of Osocimab in ESRD Patients............................. 20
2.3
Benefit/Risk Assessment ............................................................................................... 20
2.3.1
Risk Assessment......................................................................................................... 21
2.3.2
Benefit Assessment .................................................................................................... 22
2.3.3
Overall Benefit: Risk Conclusion............................................................................... 22
3.
Objectives and Endpoints............................................................................................... 23
4.
Study Design .................................................................................................................... 24
4.1
Overall Design ............................................................................................................... 24
4.2
Scientific Rationale for Study Design ........................................................................... 25
4.3
Justification for Dose..................................................................................................... 26
4.4
End of Study Definition................................................................................................. 27
5.
Study Population............................................................................................................. 27
5.1
Inclusion Criteria ........................................................................................................... 27
5.2
Exclusion Criteria .......................................................................................................... 28
5.3
Lifestyle Considerations ................................................................................................ 29
5.4
Screen Failures............................................................................................................... 29
6.
Study Intervention .......................................................................................................... 29
6.1
Study Interventions Administered ................................................................................. 29
6.2
Preparation/Handling/Storage/Accountability............................................................... 31
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 31
6.4
Study Intervention Compliance ..................................................................................... 32
6.5
Concomitant Therapy .................................................................................................... 32
6.6
Dose Modification ......................................................................................................... 33
6.7
Intervention after the End of the Study.......................................................................... 33


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 34
7.1
Discontinuation of Study Intervention........................................................................... 34
7.1.1
Temporary Discontinuation........................................................................................ 35
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 35
7.3
Lost to Follow Up.......................................................................................................... 36
8.
Study Assessments and Procedures............................................................................... 36
8.1
Efficacy Assessments .................................................................................................... 37
8.2
Safety Assessments........................................................................................................ 37
8.2.1
Main Safety Assessment............................................................................................. 38
8.2.2
Bleeding Events.......................................................................................................... 38
8.2.2.1
Assessment of AV Access Bleeding....................................................................... 39
8.2.2.2
Recommendations for Bleeding and Surgery Management.................................... 39
8.2.3
Physical Examinations................................................................................................ 41
8.2.4
Vital Signs .................................................................................................................. 41
8.2.5
Electrocardiograms..................................................................................................... 41
8.2.6
Clinical Safety Laboratory Assessments .................................................................... 42
8.2.7
Dialysis Information................................................................................................... 42
8.2.7.1
Renal Replacement Therapy (RRT) Baseline Information (General Dialysis 
Information) ............................................................................................................ 42
8.2.7.2
Dialysis Prescription Changes................................................................................. 43
8.3
Adverse Events and Serious Adverse Events ................................................................ 43
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 43
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 43
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 43
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 43
8.3.5
Pregnancy ................................................................................................................... 45
8.3.6
Cardiovascular and Death Events............................................................................... 45
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs....................................................................................................................... 45
8.3.8
Adverse Events of Special Interest............................................................................. 45
8.3.8.1
Stopping Rule for Study Drug Administration in Case of Thrombocytopenia....... 46
8.3.8.2
Hypersensitivity Reactions...................................................................................... 46
8.3.9
AEs Requiring Submission to the CIAC.................................................................... 48
8.4
Treatment of Overdose .................................................................................................. 48
8.5
Pharmacokinetics........................................................................................................... 48
8.6
Pharmacodynamics ........................................................................................................ 49
8.7
Genetics ......................................................................................................................... 50
8.8
Biomarkers..................................................................................................................... 50
8.9
Immunogenicity Assessments........................................................................................ 50
8.10
Health Economics OR Medical Resource Utilization and Health Economics .............. 51
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


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9.4.3
Secondary Endpoints.................................................................................................. 54
9.4.4
Other Analyses ........................................................................................................... 54
9.5
Interim Analyses............................................................................................................ 55
9.6
Data Monitoring Committee (DMC) ............................................................................. 55
10. Supporting Documentation and Operational Considerations .................................... 56
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 56
10.1.1
Regulatory and Ethical Considerations ...................................................................... 56
10.1.2
Financial Disclosure ................................................................................................... 56
10.1.3
Informed Consent Process.......................................................................................... 57
10.1.4
Data Protection ........................................................................................................... 57
10.1.5
Committees Structure ................................................................................................. 58
10.1.6
Dissemination of Clinical Study Data ........................................................................ 58
10.1.7
Data Quality Assurance.............................................................................................. 58
10.1.8
Source Documents...................................................................................................... 59
10.1.9
Study and Site Start and Closure................................................................................ 59
10.1.10 Publication Policy....................................................................................................... 60
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 60
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 63
10.3.1
Definition of AE......................................................................................................... 63
10.3.2
Definition of SAE....................................................................................................... 64
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 65
10.3.4
Reporting of SAEs...................................................................................................... 68
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 68
10.5
Appendix 5: Genetics..................................................................................................... 71
10.6
Appendix 6: Country-specific Requirements ................................................................ 71
10.7
Appendix 7: Abbreviations and Definitions .................................................................. 72
11. References ........................................................................................................................ 75
Table of Tables
Table 1–1: Schedule of Activities: Main Treatment Period..................................................... 10
Table 1–2: Schedule of Activities – Extension Treatment Period and Follow-up Period ....... 14
Table 2–1: Risk Assessment for Osocimab.............................................................................. 21
Table 3–1: Objectives and Endpoints....................................................................................... 23
Table 6–1: Study Interventions ................................................................................................ 30
Table 8–1: Common Terminology for Adverse Events Related to Immune System Disorders 
(CTCAE v-5.0)...................................................................................................... 47
Table 9–1: Populations for Analyses ....................................................................................... 52
Table 10–1: Protocol-required Laboratory Assessments ......................................................... 62
Table of Figures
Figure 1–1: Study Design Overview.......................................................................................... 8


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1.
Protocol Summary
1.1
Synopsis
Protocol Title: A randomized, double-blind, parallel group, placebo-controlled, multi-center 
study to assess the safety and tolerability of monthly subcutaneous administrations of a low 
and high dose cohort of osocimab to ESRD patients on regular hemodialysis
Short Title: Osocimab in ESRD Phase 2b study
Rationale: It is well known that end-stage renal disease (ESRD) patients on dialysis are at 
high risk for cardiovascular diseases. By targeting FXI, osocimab has the potential to provide 
an efficacious treatment for the prevention of thromboembolic events like myocardial 
infarction (MI), stroke and cardiovascular death with a favorable risk profile for unwanted 
bleeding. This Phase 2b trial will assess the safety and characterize the
pharmacokinetic/pharmacodynamic (PK/PD) profile of two different dose cohorts of 
osocimab given subcutaneously once a month to participants with ESRD.  
Objectives and Endpoints:
Objectives
Endpoints
Primary

To clinically assess the safety of different 
doses of osocimab administered 
subcutaneously once a month during main
treatment period as compared to placebo

Composite of major and clinically-relevant 
non-major bleeding events (in alignment with
ISTH guidelines), as assessed by blinded 
Central Independent Adjudication Committee 
(CIAC)

Composite of moderate and severe AEs and 
SAEs
Secondary

To assess the change of key PD parameter 
from baseline

Activated partial thromboplastin time (aPTT), 
FXIa activity at trough levels after 6 months
Overall Design
Disclosure Statement: This is a covariate-adaptive randomized, double-blind, parallel group, 
placebo controlled, multi-center study with 2 cohorts of osocimab (low and high dose) tested 
against placebo in ESRD patients on hemodialysis. In this protocol, the term hemodialysis 
includes hemodiafiltration. Sponsor, participants and investigators are being blinded with 
respect to active treatment versus matching placebo, but not blinded to dose cohort (low or 
high dose). 
A Data Monitoring Committee will regularly review the safety data of the participants.
Intervention Model: Parallel 
Primary Purpose: Treatment
Number of Arms: 2 dose cohorts, 3 groups, 4 arms
Blinding: Participants, Investigator, Outcome Assessor
Number of Participants: Approximately 600 randomized
Approximately 600 participants (up to 750) will be randomly assigned to study intervention
such that approximately 555 participants complete the main treatment period. 
For details on sample size determination see Section 9.2.


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Intervention Groups and Duration:
The following study interventions will be administered in the study:

Osocimab (BAY 1213790): sponsor’s study drug under investigation

Placebo to osocimab
Different doses will be achieved by administering a different volume. 

Low dose cohort
105 mg single loading dose as subcutaneous abdominal injection at visit 5, followed 
by monthly (i.e. 30 days ± 3 days) maintenance doses of 52.5 mg starting at visit 8
until the end of the extension treatment period. Placebo will be administered 
subcutaneously in the same manner as osocimab.

High dose cohort:
210 mg single loading dose as subcutaneous abdominal injection at visit 5, followed 
by monthly (i.e. 30 days ± 3 days) maintenance doses of 105 mg starting at visit 8
until the end of the extension treatment period. Placebo will be administered 
subcutaneously in the same manner as osocimab.
The two dose cohorts (low dose and high dose) follow the same treatment schedule:

Screening period (visit 1): up to 14 days 

Randomization (visit 2): 1 day

Pre-treatment period (from visit 2 until visit 4): 7 days

Main treatment period (from visit 5 until EOMT visit): 6 months

Extension treatment period (from visit 19 until EOET visit): up to 12 months

Follow-up period (from visit 32 until visit 35): 4 months after end of treatment 
(EOMT or EOET)
The mandatory extension treatment period is continued until the last study participant has 
completed its 6 months main treatment period or to a maximum of 18 months (i.e. 6 months 
main treatment period + 12 months extension treatment period). When the last participant has 
completed its 6 months main treatment period including EOMT (end of main treatment 
period) visit, all participants who are in extension treatment period at this time point will not 
receive any further dosing and will participate in an EOET (end of extension treatment 
period) visit at the next regular monthly extension visit and will move to the follow-up period. 
The last participant of the whole study will not take part in the extension treatment period. 
Data Monitoring Committee:
Yes
The study will be overseen by a Steering Committee (SC), a Data Monitoring Committee 
(DMC) and a Central Independent Adjudication Committee (CIAC).


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1.2
Schema
Figure 1–1: Study Design Overview
Abbreviations: EOET = end of extension treatment period, EOMT = end of main treatment period, LD = loading 
dose, MD = maintenance/ monthly dose, pts = participants, R = randomization, V = visit
Further details on the randomization schema can be found in Section 6.3.
The follow-up period ends 5 months after last study intervention and 4 months after EOMT or EOET.
I 
Study 
I 
intervention 
Dose [mg] 
Pre-treatment I 
period 
Main treatment period I Extension treatment period 
osocimab 200 pis -----+ : -------------------------------• 
Low dose I LO 105 mg 
: 
Post 
cohort 
MD52.5mg 
: 
treatment 
placebo 100 pis 
-------------------------------• 
: 
follow-up 
Screening {E1 
: 
period 
period 
s 
: 
osocimab 200 pis -----+ -------------------------------• 
High dose I LD210mg 
cohort 
MD 105 mg 
placebo 100 pis -----+ ' -------------------------------• 
creening 2 week 
Randomization 
1 week > ~ __ 
6_m_on_t_h_s_~> I~' __ 
u_p_t_o_1_2_m_o_n_t_hs_~ 
4 months 


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1.3
Schedule of Activities (SoA)
Visit procedures must be completed on a single day, except screening period.
Please note that if screening parameters are available as part of routine medical practice, these are not required to be repeated as long as they 
were measured within 14 days of screening and meet the thresholds defined in the in-/exclusion criteria.
It is not allowed to perform dialyses which are linked to study visits outside of the study center. Participants should come to the same dialysis 
center for each visit. Visits in between dialyses, i.e. not linked to a study visit, can be performed outside of the study center. 
PD and biomarker sampling and analyses are mandatory for all participants except China and have to be done according to the SoA.
Please refer to Table 1–1 for the Schedule of Activities of the main treatment period and to Table 1–2 for the Schedule of Activities of the 
extension treatment period and the follow-up period.


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Table 1–1: Schedule of Activities: Main Treatment Period
Study period
(Duration)
Pre-treatment 
period
(7 days)
Main treatment periodd
(6 months)
Notes
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EOMTb
EDa
Study intervention
LD or MD
SCRc
RND
LD
MD
MD
MD
MD
MD
Day
Day since last study intervention dose
-13 
to 1
1
3
6
8
2
4
30
2
4
30
4
30
4
30
4
30
4
30
Approx. month
-
1
1
1
1
1
1
2
2
2
3
3
4
4
5
5
6
6
7
Window (days)
+3
+3
+3
+ 3
+ 3
± 3
+3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
A deviation of 2-3 days 
equals 1 dialysis 
session. Section 7.1.
Initiation procedures
Informed consent
●
Signed written informed 
consent must be 
available before any 
study procedures are 
conducted.
In/ Exclusion criteria
●
●
Demography
●
Randomization via 
IWRS
●
Clinical procedures / assessments
Complete physical 
examination
●
●
Height, dry body 
weight
●
Vital signs
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Pre-dialysis. See 
Section 8.2.4.
12-lead ECG
●
●
●
●
●
Pre-dialysis. See 
Section 8.2.5.
Prior and 
concomitant 
medication
--------------------------------------------------------------  Continuous reporting  ------------------------------------------------------------------- >


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Table 1–1: Schedule of Activities: Main Treatment Period
Study period
(Duration)
Pre-treatment 
period
(7 days)
Main treatment periodd
(6 months)
Notes
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EOMTb
EDa
Study intervention
LD or MD
SCRc
RND
LD
MD
MD
MD
MD
MD
Day
Day since last study intervention dose
-13 
to 1
1
3
6
8
2
4
30
2
4
30
4
30
4
30
4
30
4
30
Approx. month
-
1
1
1
1
1
1
2
2
2
3
3
4
4
5
5
6
6
7
Window (days)
+3
+3
+3
+ 3
+ 3
± 3
+3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
A deviation of 2-3 days 
equals 1 dialysis 
session. Section 7.1.
Medical history
●
The start of dialysis 
(dialysis vintage) and 
the start of use of the 
current vascular access 
should be documented.
AE/SAE/AESI
--------------------------------------------------------------  Continuous reporting  ------------------------------------------------------------------- >
Heparin dose data 
collection
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Hemodialysis data 
collection (including 
pre-/post-dialysis 
weight, online Kt/V)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
The term hemodialysis 
includes 
hemodiafiltration. Online 
Kt/V if provided by the 
dialysis machine.
AV access bleeding 
assessment
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Not applicable for 
catheter dialysis 
access.
SQCS assessment
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Study intervention
Study intervention 
administered
●
●
●
●
●
●
Administered sc 
abdominally within one 
hour prior to dialysis.


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Table 1–1: Schedule of Activities: Main Treatment Period
Study period
(Duration)
Pre-treatment 
period
(7 days)
Main treatment periodd
(6 months)
Notes
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EOMTb
EDa
Study intervention
LD or MD
SCRc
RND
LD
MD
MD
MD
MD
MD
Day
Day since last study intervention dose
-13 
to 1
1
3
6
8
2
4
30
2
4
30
4
30
4
30
4
30
4
30
Approx. month
-
1
1
1
1
1
1
2
2
2
3
3
4
4
5
5
6
6
7
Window (days)
+3
+3
+3
+ 3
+ 3
± 3
+3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
A deviation of 2-3 days 
equals 1 dialysis 
session. Section 7.1.
Laboratory assessment
Local 
laboratory
Serum 
pregnancy test 
●
●
See Section 10.2.
Screening 
tests
●
See Section 8.2.6 and 
Section 10.2.
Central laboratory
Laboratory 
calculated 
URR and Kt/V
●
●
●
●
●
For BUN a post-dialysis 
sample needs to be 
taken (central lab). 
Local lab values of URR 
and Kt/V ± 7 days are 
accepted. 
Hematology, 
chemistry, 
coagulation 
and serum 
pregnancy
●
●
●
●
●
●
●
●
Pre-dialysis. Prior to 
study intervention.


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Table 1–1: Schedule of Activities: Main Treatment Period
Study period
(Duration)
Pre-treatment 
period
(7 days)
Main treatment periodd
(6 months)
Notes
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EOMTb
EDa
Study intervention
LD or MD
SCRc
RND
LD
MD
MD
MD
MD
MD
Day
Day since last study intervention dose
-13 
to 1
1
3
6
8
2
4
30
2
4
30
4
30
4
30
4
30
4
30
Approx. month
-
1
1
1
1
1
1
2
2
2
3
3
4
4
5
5
6
6
7
Window (days)
+3
+3
+3
+ 3
+ 3
± 3
+3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
+ 3
± 3
A deviation of 2-3 days 
equals 1 dialysis 
session. Section 7.1.
Central laboratory
Biomarker 
geneticse (if 
applicable)
●
Biomarkere: 
FVIII, FIX, 
FXII, vWF 
antigen, vWF 
activity
●
Pre-dialysis. Prior to 
study intervention.
Biomarkerse
●
●
●
●
Main PDe
samples
●
●
●
●
●
●
●
●
●
Additional PDe
samples 
●
●
PK samples
●
●
●
●
●
●
●
●
●
ADA/NAB
●
●
●
●
Abbreviations: ADA = anti-drug antibodies, AE = adverse event, AESI = adverse event of special interest, Approx. = approximately, AV = arteriovenous, BUN = blood urea 
nitrogen, ECG = electrocardiogram, ED = early discontinuation visit, EOET = end of extension treatment period visit, EOMT = end of main treatment period visit,
IWRS = interactive web response system, Kt/V – K = dialyzer urea clearance, t = dialysis time, V = total volume of distribution of urea, LD = loading dose, MD = maintenance/ 
monthly dose, NAB = neutralizing antibodies, PD = pharmacodynamic, PK = pharmacokinetic, RND = randomization, SAE = serious adverse event, sc = subcutaneous, 
SCR = screening, SQCS = semi-quantitative clotting score, URR = urea reduction ratio
a.
It is recommended to perform the ED visit approximately 1 month after last study intervention. After ED the participant moves directly to the follow-up period.
b.
EOMT and visit 19 will be performed at the same day. Both of them are mandatory separate visits and shouldn´t be missed.


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c.
Screening period covers up to 14 days (From Day -13 until Day +1). No Day 0 will occur.
d.
When the last participant completes his 6 months main treatment period including EOMT visit, all participants who are in the extension treatment period at this time 
point will not receive any further dosing and will participate in an EOET visit at the next regular monthly extension visit. They will move to the follow-up period.
e.
Study participating sites in China are excluded from all PD and biomarker sampling and analyses.
Table 1–2: Schedule of Activities – Extension Treatment Period and Follow-up Period
Study period
(Duration)
Extension treatment period
(up to 12 months)
Follow-up period
(For 4 months after 
EOMT or EOET)
Notes
Visit number
19b
20
21
22
23
24
25
26
27
28
29
30
31/
EOET 
EDa
32
33
34
35
Study intervention
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
Day since last study 
intervention dose
30
30
30
30
30
30
30
30
30
30
30
30
30
60
90
120
150
Approx. month 
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Window (days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 5
± 5
± 5
± 5
A deviation of 2-3 days equals 
1 dialysis session. Section 
7.1.
Clinical procedures / assessments
Complete physical 
examination
●
●
●
●
Vital signs
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Pre-dialysis. See Section 
8.2.4.
12-lead ECG
●
●
●
●
●
●
Pre-dialysis. See Section 
8.2.5.
Concomitant 
medication
---------------------------------------------------------  Continuous reporting  ------------------------------------------------------------ >
AE/SAE/AESI
---------------------------------------------------------  Continuous reporting  ------------------------------------------------------------ >
Heparin dose data 
collection
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Hemodialysis data 
collection (including 
pre-/post dialysis 
weight, online Kt/V)
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
The term hemodialysis 
includes hemodiafiltration.
Online Kt/V if provided by the 
dialysis machine.
AV access bleeding 
assessment
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Not applicable for catheter 
dialysis access.
SQCS assessment
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●


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Table 1–2: Schedule of Activities – Extension Treatment Period and Follow-up Period
Study period
(Duration)
Extension treatment period
(up to 12 months)
Follow-up period
(For 4 months after 
EOMT or EOET)
Notes
Visit number
19b
20
21
22
23
24
25
26
27
28
29
30
31/
EOET 
EDa
32
33
34
35
Study intervention
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
Day since last study 
intervention dose
30
30
30
30
30
30
30
30
30
30
30
30
30
60
90
120
150
Approx. month 
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Window (days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 5
± 5
± 5
± 5
A deviation of 2-3 days equals 
1 dialysis session. Section 
7.1.
Study intervention
Study intervention 
administered
●
●
●
●
●
●
●
●
●
●
●
●
Administered sc abdominally 
within one hour prior to 
dialysis.
Laboratory Assessment
Central laboratory
Laboratory 
calculated URR 
and Kt/V
●
●
●
●
For BUN a post-dialysis 
sample needs to be taken 
(central lab). Local lab values 
of URR and Kt/V ± 7 days are 
accepted.
Hematology, 
chemistry, 
coagulation and 
serum 
pregnancy
●
●
●
●
●
Pre-dialysis. Prior to study 
intervention.
Biomarkersd
●c
●c
Pre-dialysis. Prior to study 
intervention.
Main PDd
samples 
●c
●c
●e
●
●e
●
PK samples
●c
●c
●e
●
●e
●
ADA/NAB
●c
●c
●e
●
●e
●
Abbreviations: ADA = anti-drug antibodies, AE = adverse event, AESI = adverse event of special interest, Approx. = approximately, AV = arteriovenous, BUN = blood urea 
nitrogen, ECG = electrocardiogram, ED = early discontinuation visit, EOET = end of extension treatment period visit, EOMT = end of main treatment period visit, IWRS = 
interactive web response system, Kt/V – K = dialyzer urea clearance, t = dialysis time, V = total volume of distribution of urea, MD = maintenance/ monthly dose, 


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NAB = neutralizing antibodies, PD = pharmacodynamic, PK = pharmacokinetic, sc = subcutaneous, SQCS = semi-quantitative clotting score, URR = urea reduction ratio
a.
It is recommended to perform the ED visit approximately 1 month after last study intervention. After ED the participant moves directly to the follow-up period.
b.
EOMT and visit 19 will be at the same day. Both of them are mandatory separate visits and shouldn´t be missed.
c.
Samples are taken prior to study intervention at visit 27 or EOET/ED, whichever comes first.
d.
Study participating sites in China are excluded from all PD and biomarker sampling and analyses.
e.
Samples need to be taken only if no sampling was done approximately 30 days before at a prior visit.


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2.
Introduction
Osocimab is a novel long-acting anticoagulant targeting the activated form of FXI with the 
potential to exhibit lower risk of bleeding events than currently available anticoagulants. 
2.1
Study Rationale
It is well known that ESRD patients on dialysis are at high risk for cardiovascular diseases. 
By targeting FXI, osocimab has the potential to provide an efficacious treatment for the 
prevention of thromboembolic events like MI, stroke and cardiovascular death with a 
favorable risk profile for unwanted bleeding. This Phase 2b trial will assess the safety and 
characterize the PK/PD profile of two different dose cohorts of osocimab given 
subcutaneously once a month to participants with ESRD.  
2.2
Background
2.2.1
Cardiovascular Disease in ESRD Patients
Cardiovascular disease is the leading cause of death in adults around the world. World Health 
Organization (WHO) data show that an estimated 17.7 million people died from 
cardiovascular disease in 2015, which represents 31% of all deaths worldwide. Of these 
deaths, an estimated 6.7 million were due to stroke and 7.4 million were due to coronary heart 
disease (1).
It is well known that patients with ESRD have very high cardiovascular morbidity and 
mortality rates. Cardiovascular disease (e.g., coronary artery disease [CAD] and acute 
coronary syndrome, arrhythmia, chronic heart failure, cerebrovascular events [i.e., stroke]) is 
the leading cause of death in ESRD patients and accounts for 53% of all deaths with a known 
cause in patients on hemodialysis (2). In a large prospective United States–based study, the 5-
year survival rate for hemodialysis patients was only 40%, with 40% of the deaths being 
cardiac (3). The annual cardiovascular mortality in the general population increases with age, 
rising from 0.01% in 30-year-old patients to 0.1% in 80-year-old patients (4). In contrast, 
there is only a modest age-related increase in cardiovascular mortality in hemodialysis 
patients, and the annual cardiovascular mortality in a 40-year-old hemodialysis patient is 
comparable with the mortality observed in an 80-year-old individual in the general 
population.
CAD incidence among patients initiating hemodialysis is up to 38%, with a relative risk that 
is 5 to 20fold higher than that in the general population. The uremic environment due to 
the underlying renal disease may accelerate the progression of atherosclerosis and may 
influence the prevalence of CAD (5). Similarly, ESRD itself is seen as a risk factor for 
peripheral artery disease (PAD) as an additional expression of the underlying 
atherothrombosis/atherosclerosis, which often leads to complications such as non-healing 
ulcers and lower limb amputation (6- 7).
High levels of Creactive protein and pro-inflammatory cytokines have been reported in 
patients with ESRD, as well as endothelial dysfunction and increased oxidative stress, which 
are exacerbated in the setting of ESRD. Atherosclerosis and subsequent atherothrombosis are 
the drivers of CAD and PAD. These are inflammatory processes and the pro-inflammatory 
environment in patients with ESRD predisposes them to accelerated plaque formation and 
rupture, which contributes to thromboembolic events such as acute coronary syndrome/MI,
stroke and cardiovascular death. 


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2.2.2
Cardiovascular Treatment Options for ESRD Patients
Treating patients with ESRD is challenging owing to competing mortality risks. Patients with 
chronic kidney disease (CKD) and ESRD are at an increased risk for both thromboembolic 
events and bleeding (8) and treatment options need to be carefully evaluated against their 
benefits and risks. Furthermore, the relative benefit-risk profile of anticoagulation in ESRD 
patients is different from that in patients with normal kidney function. In the non-ESRD 
population, current anticoagulation therapies have been shown to be efficacious for 
prevention of thromboembolic events (9-11). However, their use is associated with a variable 
bleeding risk and ESRD patients have a much higher risk for severe bleeding events than the 
non-ESRD population (12). 
Although there are numerous high-quality randomized clinical trials (RCTs) supporting 
therapeutic cardiovascular interventions in the general population (13), the vast majority of 
these studies specifically excluded patients with severe renal impairment. In contrast, very 
few RCTs have evaluated cardiovascular therapies in hemodialysis. Because of the paucity of 
RCTs in hemodialysis patients, most cardiovascular therapies in this population are based on 
observational studies or results extrapolated from studies that excluded hemodialysis patients. 
Hence, due to the much higher bleeding risk of ESRD patients and the unproven benefits of 
anticoagulation therapy in these patients, most hemodialysis patients are not treated with 
respect to the prevention of thromboembolic events. 
2.2.3
Factor XI
Factor XI (FXI) is a new target for anticoagulants that have the potential to be associated with 
a lower risk of bleeding events than currently available anticoagulants. The identification of 
FXI as a safer target is supported by epidemiological data, studies in FXI deficient mice, 
studies with FXI knockdown or inhibition, and animal bleeding models (14).
The formation and the stability of clots are enhanced by FXI in in-vitro experiments (15- 16). 
Furthermore, FXI amplifies thrombin generation when coagulation is initiated by low levels 
of tissue factor (TF) or thrombin. FXI-dependent amplification of thrombin generation also 
leads to activation of thrombin-activatable fibrinolysis inhibitor, which renders clots resistant 
to fibrinolysis. Therefore, FXI inhibitors might also indirectly enhance clot dissolution.
The most solid evidence in support of FXI as a potential therapeutic target came from 
epidemiological data. Observational studies in patients with congenital factor XI deficiency 
suggested that these patients are at reduced risk of ischemic stroke, myocardial infarction, and 
venous thromboembolism (VTE) compared with those with normal factor XI levels (14-19). 
Furthermore, a second-generation antisense oligonucleotide (ASO) that specifically reduces 
FXI levels (ISIS 416858) yielded promising results when compared with enoxaparin for 
thromboprophylaxis in patients undergoing elective total knee arthroplasty (TKA) (20). 
2.2.4
Osocimab (BAY 1213790)
Osocimab is a fully human monoclonal immunoglobulin G1 (IgG1) antibody that binds 
specifically to activated factor XIa (FXIa) (21) and exhibits a terminal half-life in plasma
ranging from approximately 30 to 44 days after intravenous administration.
2.2.4.1
Preclinical Data
Preclinical pharmacology experiments indicated a profound antithrombotic effect, both in 
arterial and in venous thrombosis models, in the absence of significantly prolonged bleeding 
times or increased blood loss. In line with the mechanism of action, the activated partial 


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thromboplastin time (aPTT) increased in a dose-dependent manner and in parallel with the 
antithrombotic effect. Osocimab had no effect on the prothrombin time (PT), confirming that 
the effects of Osocimab were limited to the intrinsic pathway of coagulation.
As with any protein product, Osocimab may induce immune responses affecting safety and 
product efficacy. However, the compound is a fully human monoclonal IgG1 antibody that 
has been optimized for affinity and low immunogenicity. The immunogenic potential of 
Osocimab was tested in silico and showed a favorable overall score, similar to other marketed 
monoclonal antibodies. Furthermore, toxicological studies have not identified relevant 
hypersensitivity effects in Cynomolgus monkeys after intravenous (iv) or subcutaneous (sc)
injections. Nevertheless, injection and hypersensitivity reactions may occur and the possibility 
of hitherto unforeseen side effects and allergic reactions to interventions, which can result in 
severe damage and even death, must always be considered.
2.2.4.2
Human Experience
So far osocimab has been tested in 4 Phase 1 studies (Studies #17188, 17956, 17780, 19513)
with either iv or sc administration in healthy volunteers (175 participants received osocimab 
up to 10 mg/kg iv), as well as in a study in patients undergoing total knee arthroplasty for the 
prevention of VTE (#17664 FOXTROT study, 587 participants received osocimab up to 1.8 
mg/kg).
In the single dose Phase 1 studies #17188 (study report available) and #17780 and #17956 
(clinically completed, reporting ongoing), osocimab administrations were safe and well 
tolerated. No drug related serious adverse events (SAEs) were reported. Further details can be 
found in Section 5.2.3 of the Investigator’s Brochure (IB).
There were no clinically relevant bleeding events, no relevant bleeding time prolongations 
and no signs or symptoms for hidden bleedings in the single dose Phase 1 studies.
In the multiple dose study #19513, which investigated two dose steps, two bleeding events of 
a moderate severity were reported in the dose step 1 (loading dose 100 mg sc; maintenance 
dose 35 mg sc) of the study: bleeding hemorrhoids and rupture of tympanic membrane of the 
right ear. These hematomas were also assessed as not related to the study intervention. In dose 
step 2 (loading dose 210 mg sc; maintenance dose 105 mg sc), an intra-cranial hemorrhage 
was observed. The sponsor together with external experts performed a thorough evaluation of 
the case including follow-up Magnetic Resonance Imaging (MRI). In conclusion, and 
although the contribution of osocimab cannot be excluded, the overall benefit risk assessment
for osocimab has not changed according to the data generated so far, specifically as from the 
image interpretation there is a greater than 50% likelihood for an underlying arteriovenous 
(AV)-malformation/cavernoma as the underlying cause for the bleeding event. 
In summary, bleeding events in the single dose studies and in the multiple dose study in 
healthy volunteers did not indicate any increased risk of bleeding. 
In a Phase 2a study (#17664, FOXTROT), osocimab was administered in patients undergoing 
elective TKA. This was a randomized, active comparator controlled, multicenter study to 
assess the safety and efficacy of different doses of osocimab for the prevention of VTE in 
comparison to enoxaparin and apixaban (22).  
In the FOXTROT study, 2 different administration schemes of osocimab were assessed: post-
surgery administration (part A) and pre-surgery administration (part B).  A total of 813
patients were randomized in the overall study.


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Part A investigated osocimab at single iv doses of 0.3, 0.6, 1.2, and 1.8 mg/kg. Part B 
investigated osocimab at single iv doses of 0.3 and 1.8 mg/kg.
Overall, FOXTROT showed that FXIa inhibition is effective for the prevention of VTE in 
patients undergoing TKA whether administered post- or pre-operatively. Osocimab
demonstrated good hemorrhagic as well as non-hemorrhagic safety and good tolerability (22). 
Further details can be found in the latest available version of the Investigator's Brochure, 
which contains comprehensive information on the test drug.
Furthermore, a small Phase 1, observer-blind, multicenter, placebo-controlled study is 
ongoing in patients with ESRD to assess the safety and tolerability and to characterize the PK 
and the PD of different doses of osocimab (sc and iv) in this patient population (Study 
#20046). So far 13 patients with ESRD received a single iv dose of osocimab (0.3 mg/kg or 
1.2 mg/kg). No clinically significant bleeding events (i.e. major or clinically relevant non-
major bleeding) occurred after study drug administration nor were any treatment-emergent 
SAEs reported, so far.
2.2.4.3
Rationale for the Development of Osocimab in ESRD Patients
The aim for the development of osocimab in patients with ESRD is to prevent 
thromboembolic events without increasing the risk for bleeding events, as it is known from 
currently available anticoagulation therapies, which could provide a favorable benefit risk 
profile in patients with ESRD on hemodialysis. Due to the characteristics of osocimab as a 
monoclonal antibody targeting FXIa additional benefits suit very well to the ESRD patient 
population:

Low dosing frequency of once a month subcutaneous injection, which does not add to 
the already high pill-burden in this patient population.

Low risk for drug-drug interaction via Cytochrome P450 (CYP) enzymes in the liver. 
Generally, monoclonal antibodies are metabolized to peptides and amino acids in 
several tissues, by circulating phagocytic cells or by their target antigen-containing 
cells (23). In contrast to many other drugs that are taken by ESRD patients, osocimab 
will not interfere with other drugs that are metabolized in the CYP system of the liver 
as it is metabolized via other pathways. 

No influence of plasma concentrations is expected with impaired kidney function as 
the drug is not excreted via this pathway. Furthermore, due to the large size of 
osocimab it not expected to be dialyzable.
2.3
Benefit/Risk Assessment
Due to the higher bleeding risk of ESRD patients and the unproven benefits of currently 
available anticoagulation therapy in these patients, most hemodialysis patients are not treated
for the prevention of thromboembolic events. 
Targeting factor XI may attenuate thrombosis without increasing the risk for bleeding. The 
separation of bleeding and efficacy might be explained by the fact that inhibition of FXIa 
affects the intrinsic and propagation pathways, but keeps the extrinsic pathway unaffected, 
which is activated in case of vessel injury.
Based on the results of relevant animal models, known cases of human FXI deficiency, 
clinical experience with compounds with a similar mode of action (second-generation 
antisense oligonucleotide), initial clinical testing in healthy volunteers, and most importantly 


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patients undergoing TKA and receiving osocimab post- and pre-surgery, osocimab is a 
promising new drug candidate with the potential to prevent thromboembolic events with a 
low risk for bleeding. Potential risks such as bleeding, thrombocytopenia, hypersensitivity/ 
injection-related reactions will be closely monitored during this trial. Strict inclusion and 
exclusion criteria are applied to exclude ESRD patients who are at higher risk for bleeding 
events. Due to the long half-life of the compound in plasma, participants will be kept under 
observation for approximately 5 months after the last administration of osocimab. 
A DMC will frequently review safety data to ensure the safety of the participants in the 
ongoing study. Further details can be found in the DMC charter.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of osocimab may be found in the Investigator’s Brochure.
2.3.1
Risk Assessment
Risk assessment for osocimab is described in Table 2–1.
Table 2–1: Risk Assessment for Osocimab
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Hemorrhage (Bleeding)

Risk factor associated with 
ESRD due to uremia-induced 
endothelial dysfunction

Increased bleeding risk due to 
routinely administered 
anticoagulant and antiplatelet 
agents to reduce risk of 
thromboembolic events and for 
dialysis maintenance

So far, no increased risk of 
bleeding across studies and 
doses for osocimab was 
identified

Specific in-and exclusion 
criteria to be applied

Reporting as primary safety 
outcome 

Regular hematological
laboratory assessment (see 
Section 1.3)

DMC will frequently review all 
safety events including bleeding 
events

CIAC will adjudicate all 
suspected bleeding events
Thrombocytopenia

Osocimab reduces dose and 
concentration-dependently FXI 
activity and prolongs aPTT
(expected mode of action)

Specific in- and exclusion 
criteria to be applied

Regular safety laboratory 
assessment (see Section 1.3)

Reporting as adverse event of 
special interest and stopping 
rule for drug administration (see 
Section 8.3.8)

DMC will frequently review all 
safety events laboratory results
Hypersensitivity

Observed cases of infusion or 
hypersensitivity reactions were 
rare and of mild degree in 
healthy volunteers

In participants undergoing TKA, 
frequency of hypersensitivity 
and infusion-related reactions 
were low and comparable 
across treatment groups
including comparators 
(enoxaparin and apixaban)

Reporting as adverse event of 
special interest (see Section 
8.3.8)

DMC will frequently review all 
safety events


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Table 2–1: Risk Assessment for Osocimab
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Development of anti-
drug antibodies (ADA) 
and neutralizing 
antibodies (NAB)

In two Phase 1 studies (#17188 
and #17780) the majority of 
participants did not develop anti-
osocimab antibodies;
participants with ADA- or NAB-
positive samples had low titers 
and did not show altered plasma 
concentrations of osocimab or 
unexpected PD or safety 
findings. In participants 
undergoing TKA, a small 
number of anti-osocimab 
antibodies (ADAs) and NABs
were detected

Measurements of ADA/NAB
formation over the course of 
the study (see Section 8.9)
Abbreviations: ADA = anti-drug antibodies, aPTT = activated partial thromboplastin time, CIAC = Central 
Independent Adjudication Committee, DMC = Data Monitoring Committee, ESRD = end-stage renal disease, 
NAB = neutralizing antibodies, PD = pharmacodynamic(s), TKA = total knee arthroplasty
Currently available preclinical and clinical data regarding the important potential risks 
including the assessment of the safety from the clinical studies do not indicate an unfavorable 
risk profile for osocimab.
2.3.2
Benefit Assessment
The potential benefit of receiving study intervention during study duration may already be a 
reduced risk for thromboembolic events in participants with ESRD, although this has not yet 
been proven clinically. Furthermore, this study will contribute to develop new therapies in an 
area of high medical need, specifically as patients with ESRD are often excluded from clinical 
trials due to their specific risk profile.
2.3.3
Overall Benefit: Risk Conclusion
Taking into account the potential benefits of this new compound, the potential risks identified 
in association with osocimab are justified by the anticipated benefits that may be afforded to 
participants with ESRD. Currently available preclinical and clinical data do not indicate an 
unfavorable risk profile for osocimab.


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3.
Objectives and Endpoints
Objectives and endpoints are listed in Table 3–1. 
Table 3–1: Objectives and Endpoints
Objectives
Endpoints
Primary

To clinically assess the safety and 
tolerability of different doses of osocimab 
administered subcutaneously once a month 
during main treatment period as compared 
to placebo

Composite of major and clinically-relevant 
non-major bleeding events (in alignment with 
ISTH guidelines) as assessed by blinded 
CIAC

Composite of moderate and severe AEs and 
SAEs
Secondary

To assess the change of key PD parameter 
from baseline

aPTT, FXIa activity at trough levels after 6 
months
Tertiary/Exploratory

To clinically assess the efficacy of osocimab 
during main treatment period

To evaluate the anticoagulant effect of 
osocimab on the extracorporeal blood circuit 
by the assessment of a semi-quantitative 
clotting score (SQCS) 

To evaluate the impact of osocimab on the 
AV access for participants with fistulas or 
grafts

To assess key PK parameter

To explore additional PK/PD parameters, 
biomarkers and biomarker 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 and renal diseases and
associated health problems

Composite endpoint consisting of: vascular 
death [due to MI, stroke, PE and SE], non-
fatal stroke, non-fatal MI, major amputation 
of vascular etiology, acute limb ischemia and 
symptomatic VTE as assessed by blinded 
CIAC

Incidence of thrombosis of the arteriovenous 
fistulas or grafts 

SQCS

AV access bleeding score

Osocimab trough levels

Various biomarkers and biomarker genetics 
may be explored (e.g., diagnostic, safety, 
population PK, PD, monitoring, or potentially 
predictive biomarkers)
Abbreviations: AE = adverse event, aPTT = activated partial thromboplastin time, AV = arteriovenous, 
CIAC = Central Independent Adjudication Committee, ISTH = International Society on Thrombosis and 
Hemostasis, MI = myocardial infarction, PD = pharmacodynamic(s), PE = pulmonary embolism, 
PK = pharmacokinetic(s), SAEs = serious adverse events, SE = systemic embolism, SQCS = semi-quantitative 
clotting score, VTE = venous thromboembolism
The primary objective is to assess the safety under an osocimab concentration which is 
expected to be maintained during a chronic treatment. Thus the attributes constituting the 
primary estimand are the following:


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Population: The population consists of ESRD patients, further defined by the in- and 
exclusion criteria, who received study intervention at least once.
Variable:
a.
Time from first dose of intervention to treatment emergent major and clinically-
relevant non-major bleeding events (in alignment with ISTH guidelines) up until 30 
days after last study intervention
b. Time from first dose of intervention to moderate or severe AEs and SAEs up until 30 
days after last study intervention
Treatment: Low/high-dose osocimab or matching placebo on top of standard of care
Intercurrent events: Of interest is the response to treatment while the participant is

alive (intercurrent event “death”) and 

exposed to study intervention ( intercurrent event “premature discontinuation of 
treatment”),
i.e. both intercurrent events are handled using the same strategy “while alive” or “while on 
treatment”.
Population-level summary: Hazard ratios comparing each of the osocimab dose groups with 
the placebo group as estimated from Cox proportional hazards models.
Please refer to Section 9.4 for further details.
4.
Study Design
4.1
Overall Design
Study 20115 is a covariate-adaptive randomization, double-blind, parallel group, placebo-
controlled, multi-center study to assess the safety and tolerability of monthly administrations 
of a low and high dose cohort of osocimab given subcutaneously in ESRD patients on 
hemodialysis. In this protocol, the term hemodialysis includes hemodiafiltration. The overall 
study design is depicted in Figure 1–1.
Approximately 600 participants (up to 750) from approximately 150 sites are planned to be 
randomized and will receive either osocimab (200 participants on each dose arm), or placebo 
(200 participants, i.e. 100 participants receiving low dose volume placebo and 100 
participants receiving high dose volume placebo).
The following regions are planned to be included: North America, Europe, Asia Pacific.
The planned study will consist of:

Screening period (visit 1): up to 14 days

Randomization (visit 2): 1 day

Pre-treatment period (from visit 2 until visit 4): 7 days

Main treatment period (from visit 5 until EOMT visit): 6 months

Extension treatment period (from visit 19 until EOET visit): up to 12 months

Follow-up period (from visit 32 until visit 35): 4 months after end of treatment 
(EOMT or EOET)


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Informed consent form will be obtained at the beginning of the screening period. During the 
screening period, participant’s eligibility evaluations will be performed. Participants will be 
randomized either to osocimab or to placebo using a covariate-adaptive randomization 
technique (minimization methods) (for details see Section 6.3).
During the pre-treatment period, which will serve as a baseline period, a series of 3 
hemodialysis sessions will be performed. Unfractionated or low molecular weight heparin 
(UFH/LMWH) is allowed as anticoagulation for maintenance of hemodialysis treatment
during the whole study duration.
The study intervention will be administered subcutaneously abdominal with one single 
loading dose at visit 5 and monthly maintenance doses from visit 8 onwards until the end of 
the extension treatment period with an overall maximum of 18 months of treatment. The main 
treatment period consists of 6 months of treatment as this time frame is deemed to be the 
minimum clinically relevant treatment time to assess osocimab as chronic life-time treatment 
in an appropriate manner and in preparation for Phase 3. 
Study intervention will be administered during the extension treatment period for up to a 
maximum of 12 months or until the last participant randomized to the study has performed the 
EOMT visit (whichever comes first).
The treatment period (main or extension) will end with the study assessments performed 30 
days after the last study intervention administration.
The follow-up period is an observational period of 4 months, i.e. ends approximately 5 
months after the administration of the last dose of osocimab.
All suspected bleeding and cardiovascular (CV) or thromboembolic (TE) events occurring 
after signing informed consent (randomized participants only) will be adjudicated by the
CIAC in a blinded fashion; blinded to treatment allocation and dose cohort (details are 
described in the CIAC charter).
The procedures followed by the CIAC are detailed in the CIAC charter. Detailed instructions 
regarding documentation, reporting and transferal of adjudication dossiers will be provided in 
a study specific guidance document.
A DMC will frequently review safety data to ensure the safety of the participants in the 
ongoing study. Further details can be found in the DMC charter.
Details of study procedures and their timing are summarized in the SoA (see Section 1.3).
4.2
Scientific Rationale for Study Design
This is the first multiple dose study of osocimab in ESRD patients with the aim to investigate 
the safety, tolerability and PK/PD after chronic monthly treatment with subcutaneous 
administrations in comparison to placebo. No established treatment exists for the prevention 
of thromboembolic events in patients with ESRD.
The selection criteria were chosen to exclude patients from the study, who may potentially be 
exposed to specific risks after administration of osocimab, as well as all patients with
conditions that may have an impact on the objectives of the study.
A main treatment period of 6 months until the primary endpoint assessment is deemed to be 
appropriate to assess the safety, tolerability and efficacy of osocimab for an envisaged chronic 
treatment regimen. However, participants will receive osocimab for a maximum of 18 months 


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which will generate additional long-term safety data and allow participants to potentially 
benefit from long-term treatment.
The study procedures were planned to be as close as possible aligned with the usual dialysis 
procedures in order to limit the extra burden for participants.
The envisaged indication for osocimab is prevention of thromboembolic events in male and 
female patients with ESRD undergoing hemodialysis.
4.3
Justification for Dose
The medium doses (0.6 and 1.2 mg/kg iv single dose administration) tested in the FOXTROT 
study were identified as the most promising doses to be tested in further studies, as they 
showed efficacy numerically comparable to that with enoxaparin and apixaban and were not 
associated with any primary safety event, i.e. clinical significant bleeding event (22) (further 
details on FOXTROT can be found in the current version of the IB). The doses tested in 
FOXTROT were substantially lower than the doses that were administered during the first
Phase 1 study (up to 10 mg/kg iv). It is currently assumed that the dose levels which were 
efficacious and safe in the FOXTROT trial will be safe and efficacious for the prevention of 
thromboembolic events in ESRD patients as well. The selected single iv doses from 
FOXTROT were translated into comparable sc doses independent from body weight (i.e.
fixed dosing) taking into account the bioavailability of sc administration. It was the aim to 
achieve with monthly fixed sc doses similar trough levels (plasma concentration 
approximately one month after dosing) as in FOXTROT at the primary endpoint assessment 
(approx. 10-14 days after dosing). Therefore, osocimab doses needed to be adapted to achieve 
the FOXTROT exposure level after that longer period of one month. Furthermore, therapeutic
drug level should be reached as soon as possible after initiation of treatment to allow for an 
immediate treatment effect. Therefore, a loading dose concept was developed and tested in a
multiple dose Phase 1 study (#19513). This loading dose concept provides with a single 
(higher) loading dose (compared to the maintenance doses) a rapid achievement of a 
therapeutic drug concentration and ensures steady state exposure already from study drug 
initiation.
As already tested in multiple dose study #19513, in this study the sc dose administration will 
be independent from the body weight (BW) (fixed dose concept). This is supported by 
preliminary population PK analyses of Phase 1 data indicating that BW-adjusted dosing and 
flat dosing provide similar exposure distributions, with no clear advantage to both dosing 
approaches with respect to reducing variability in pharmacokinetics.
When the fixed doses of the high dose cohort of 210 mg (LD) and 105 mg (MD) and are 
back-converted to BW-adjusted dosing, the corresponding sc doses for a participant of 80 kg 
will be 2.625 mg/kg and 1.3125 mg/kg BW, respectively. This is below 6 mg/kg BW sc, a
dose already shown to be safe in a Phase 1 study (#17780).
In an alternative scenario of administering fixed doses to a light weight participant of 50 kg, 
the calculated BW-adjusted sc doses would be 4.2 mg/kg BW for a flat dose of 210 mg and
2.1 mg/kg BW for 105 mg. For both, the low and high dose cohort, and both BWs the loading
and maintenance doses are below 6 mg/kg BW sc that were tested in the Phase 1 study 
(#17780). Additionally, the sc doses of the high dose cohort of 105 mg (MD) and 210 mg 
(LD) have already been tested in multiple dose study #19513 (administration on study days 1, 
29, 57 and 85). Importantly, all doses intended for the current study are considerably lower 


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than the highest tested iv dose of 10 mg/kg BW, which was has been shown to be safe and 
well tolerated in healthy volunteers (#17188).
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed at least the 
main treatment period of the study including the last visit (EOMT).
The primary completion of the study is defined as the date of the last visit of the last 
participant in the main treatment period. 
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
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
The study population will consist of stable end-stage-renal disease patients requiring 
hemodialysis (including hemodiafiltration) sessions for approx. 3 times per week at least 9 
hours a week with no restriction to vascular access (e.g., catheter, AV fistulas and graft are 
allowed).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1.
Participants must be at least 18 years of age
Type of Participant and Disease Characteristics
2.
Patients with end-stage renal disease on hemodialysis (including 
hemodiafiltration) for ≥3 months, receiving dialysis at least 9 hours a week and 
stable in the view of the investigator
Weight
3.
Body weight of at least 50 kg
Sex
4.
Male and/or female 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
For details see Section 10.4.
Informed Consent
5.
Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol


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5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Recent (<6 months before screening) clinically significant bleeding
2.
Hemoglobin (Hb) < 9.0 g/dL
3.
Platelet count < 100 x 109/L 
4.
aPTT or PT > ULN (upper limit of normal)
5.
Hepatic disease associated with ALT > 3x ULN, or total bilirubin >2x ULN with 
direct bilirubin > 20% of the total
6.
Sustained uncontrolled hypertension (diastolic blood pressure ≥100 mmHg and/or 
systolic blood pressure ≥ 180 mmHg) 
7.
Known intracranial neoplasm, arteriovenous malformation or aneurysm
8.
Known bleeding disorders e.g., von-Willebrand disease or Hemophilia A, B or C
9.
Recent (<3 months before screening) thromboembolic event, e.g., acute coronary 
syndrome, stroke or VTE (except dialysis access thrombosis)
10.
Recent (<3 months before screening) major surgery or scheduled major surgery 
during study participation
11.
Scheduled living donor renal transplant during study participation 
12.
Persistent heart failure as classified by the New York Heart Association (NYHA) 
classification of 3 or higher
13.
Receiving antiplatelet therapy except daily ASA (acetylsalicylic acid)
≤150 mg/day
14.
Receiving anticoagulation in therapeutic doses, other than standard 
anticoagulation during the hemodialysis procedure
15.
Life expectancy less than 6 months
16.
Active malignancy requiring treatment during study participation (except non-
melanoma skin cancer, or cervical carcinoma in situ)
17.
Known hypersensitivity to the investigational drug or to inactive constituents of 
the study drug
Prior/Concurrent Clinical Study Experience
18.
Participation in another clinical study with an investigational medicinal product
within 30 days or within 5 half-lives of such, whichever is longer, prior to 
randomization and during the study
Other Exclusions
19.
Any other conditions, which, in the opinion of the investigator or sponsor would 
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5.3
Lifestyle Considerations
No restrictions during any of the study periods pertaining to lifestyle 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 randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, and 
eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants should be assigned a new participant identification 
code (PID) and sign a new informed consent form.
Re-screening is allowed only if any of the following applies: 

The participant had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule. 

The in- / exclusion criteria preventing the participant’s initial attempt to participate 
have been changed (via protocol amendment). 

The participant suffered from a temporary and not clinical relevant disease, e.g., a 
common cold.
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the participant to an unjustifiable health risk. Also, for re-screening, the participant has 
to re-sign the informed consent form, even if it was not changed after the participant’s 
previous screening.
Suspected events of screen failures will not be submitted to the CIAC.
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:

Osocimab (BAY 1213790): sponsor’s study drug under investigation

Placebo to osocimab
Different doses will be achieved by administering a different volume:

Low dose cohort
105 mg single loading dose as subcutaneous abdominal injection at visit 5, followed 
by monthly (i.e. 30 days ± 3 days) maintenance doses of 52.5 mg starting at visit 8
until the end of the extension treatment period. Placebo will be administered 
subcutaneously in the same manner as osocimab.


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
High dose cohort:
210 mg single loading dose as subcutaneous abdominal injection at visit 5, followed 
by monthly (i.e. 30 days ± 3 days) maintenance doses of 105 mg starting at visit 8 
until the end of the extension treatment period. Placebo will be administered 
subcutaneously in the same manner as osocimab.
Participants will be treated up to 18 months.
Osocimab/ placebo is administered within one hour (60 minutes) prior to start of dialysis 
session by site personnel at site.
Further details for study interventions are described in Table 6–1.
Table 6–1: Study Interventions
Study 
Intervention
Osocimab
low dose
Osocimab
high dose
Placebo to osocimab 
Intervention 
Name
osocimab
osocimab
placebo to osocimab
Type
drug
drug
placebo
Dose 
Formulation
solution
solution
solution
Unit Dose 
Strength(s)
150 mg/mL
150 mg/mL
NA
Dosage Level(s)
105 mg (LD) once,
52.5 mg (MD) monthly
210 mg (LD) once, 
105 mg (MD) monthly 
NA
Route of 
Administration
sc injection
sc injection
sc injection
Use
experimental
experimental
Placebo
Packaging and 
Labeling
Study intervention will 
be provided in 6 mL 
glass vials. Each vial 
will be labeled as 
required per country 
requirement.
Study intervention will 
be provided in 6 mL 
glass vials. Each vial 
will be labeled as 
required per country 
requirement.
Study intervention will 
be provided in 6 mL 
glass vials. Each vial 
will be labeled as 
required per country 
requirement.
Current/Former 
Name(s) or 
Alias(es)
BAY 1213790
BAY 1213790
NA
Abbreviations: LD = loading dose, MD = maintenance/ monthly dose, NA = not applicable


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6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. The investigator or the head of the institution (where applicable) is responsible for 
study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the Investigator Site File. 
Osocimab is supplied in 6 mL clear, single-use injection glass vials as a solution. Osocimab is 
a solution with a concentration of 150 mg/mL at pH 5.0. The total content of the glass vial is 
2.3 mL, corresponding to 345 mg of osocimab. From the total 2.3 mL, 2.0 mL (i.e. 300 mg) 
are the extractable volume and 0.3 mL (i.e. 45 mg) are overfill. Placebo to osocimab is 
supplied in 6 mL clear, single-use glass vials as a solution. Further details can be found in the 
handling instruction provided separately.
6.3
Measures to Minimize Bias: Randomization and Blinding
After a participant has signed an informed consent form,  the unique participant identification 
number (PID) will be assigned via Interactive Web Response System (IWRS). If a participant 
is re-screened, a new PID will be assigned. The PID is a 9-digit number consisting of: 
Digits 1 to 5 = Unique site number 
Digits 6 to 9 = Unique participant number (current participant number within the study site)
The unique participant number will start with 5 for each participant.
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Study intervention will be administered at the study visits summarized in SoA (Section 1.3). 
Before the study is initiated, the log in information and directions for IWRS will be provided 
to each site.
Covariate-adaptive randomization techniques (minimization methods) will be utilized taking 
into account the following baseline covariates (weights of the baseline covariates for the 
calculation of imbalance in brackets):

Region (categorical) (17.0%)

Age (17.0%)

Prior major adverse cardiovascular event (MACE) (17.0%)

Dialysis access via catheter (17.0%)

Low-dose ASA use (Yes/No) (17.0%)

Diabetes (Yes/No) (7.5%)


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
Atrial fibrillation (Yes/No) (7.5%)
Sponsor, participants and investigators are being blinded with respect to active treatment 
versus placebo, but not blinded to dose cohort (low or high dose). The CIAC will be blinded 
to the participant’s treatment allocation and dose cohort. The DMC will review blinded data 
and will have access to unblinded data as outlined in the DMC charter.
In order to maintain the blind, osocimab and matching placebo will be packaged in identical 
vials and each vial will be labeled with a unique, pre-printed number.
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 intervention 
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 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 intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s intervention assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and case 
report form, as applicable.
Bioanalytics and pharmacometrics staff will be unblinded according to Bayer SOPs. 
Bioanalysis and population PK (popPK) evaluation might be started prior to database lock: if 
this is applicable, appropriate measures will be taken to maintain blinding of the study team, 
e.g., data will be stored separately, and members of the study team will not have access to 
unblinded data.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the electronic case report form (eCRF). The 
vial number(s) and study participant identification will be confirmed at the time of dosing. To 
monitor compliance, drug accountability information will be documented for each participant.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving between signing of the ICF and 
the end of the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Specifically, medications influencing coagulation or platelet aggregation even if taken before 
the informed consent was signed should also be recorded in the eCRF (up to 6 months prior to 
randomization).
Prior and concomitant medications that should be stopped at least 10 days prior to start of 
study intervention, i.e. 3 days prior to randomization and not allowed during the study are:


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1. Antiplatelets (e.g., clopidogrel, ticagrelor, dipyridamole, acetylsalicylic acid 
>150 mg/day) 
2. Vitamin K antagonists (e.g., phenprocoumon, warfarin-sodium) 
3. Unfractionated heparins and LMWH other than for dialysis maintenance
4. Direct oral anticoagulants (e.g., rivaroxaban, apixaban, dabigatran, edoxaban).
Participants who cannot stop the respective treatment have to be excluded from the 
study.
5. Thrombolytic drugs for systemic use (e.g., streptokinase, alteplase, tenecteplase, etc.)
For participants, who are receiving ASA ≤ 150 mg/day, any dose adaptation should be 
avoided if possible. Especially, during the main treatment period any adaptation of the current
ASA dose or any initiation of ASA should be avoided and should only be done if medically 
necessary.
Surgery, which is deemed necessary should be performed under general anesthesia only. 
Spinal or epidural anesthesia is not allowed during the study. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.6
Dose Modification
This protocol does not allow any pre-planned alteration from the currently outlined dosing 
schedule (Section 6.1).
6.7
Intervention after the End of the Study
No further intervention is planned after the end of the study. No long-term effects are 
expected that would need any additional care or intervention.  


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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 until the end of the follow-up period. 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.
A participant must permanently discontinue study intervention for any of the following: 

The participant becomes pregnant. The pregnancy will be reported per reporting 
procedures in Section 8.3.5.

The participant is unwilling to continue study intervention.

The participant experiences an AE (including clinically significant bleeding 
[Sections 8.2.2 and 8.3]) or requires surgery (Section 8.2.2.2) that in the judgment of 
the investigator necessitates permanent discontinuation of study intervention.

The participant develops laboratory test abnormalities that meet the stopping rule 
outlined in Section 8.3.8.1.

The participant moves their dialysis care to a different hemodialysis facility where the 
study team cannot regularly follow the participant. All efforts should be made to 
conduct the post-treatment follow-up visits in person to complete all study procedures. 
If in-person visits by the participant are impossible, limited remote contact visits (e.g.,
phone) may be conducted recording as much information as possible for eCRF entry.

At the discretion of the investigator due to participant non-compliance, or major 
protocol deviation(s) 

The sponsor has the right to withdraw a participant from the study due to non-
compliance, major protocol deviations or for safety reasons
A participant may permanently discontinue study intervention for any of the following at the 
discretion of the investigator: 

The participant begins treatment with a disallowed concomitant medication as 
described in Section 6.5. 

The participant is no longer on regular maintenance hemodialysis of at least 3-times 
per week for a minimum of 9 hours per week, including a change in dialysis modality.
If a participant permanently discontinues study intervention and is unwilling or unable to 
attend regular study visits at the study site, all possible efforts should be made to obtain 
information on the health status of the participant.
A participant may be withdrawn from study intervention at the discretion of the investigator 
for safety, behavioral, compliance, or administrative reasons. 
The reason for discontinuation of study intervention must be recorded in the eCRF and source 
documentation. 


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7.1.1
Temporary Discontinuation 
This protocol does not allow any pre-planned alteration from the currently outlined dosing 
schedule. However, there may be rare circumstances due to which the investigator may need 
to temporarily discontinue study intervention for an adverse event (Section 8.3), bleeding 
event (Section 8.2.2), or surgery (Section 8.2.2.2) and any other reason not listed as reasons 
for discontinuation of study intervention (Section 7.1) or withdrawal from the study 
(Section 7.2). 
The following guidance should be observed in case maintenance dosing cannot be 
administered according to dosing schedule.
Delayed maintenance dosing:
A dose is delayed if it is given up to 4-7 days from the original schedule. The dose should be 
administered at the next possible time point, but not later than 7 days than originally 
scheduled.
Missed maintenance dosing:
Any dose which is delayed for more than 7 days will be considered as missed dose. The dose
should be administered at the next possible time point, but not later than 60 (+3) days after the 
last given dose. There should be also minimum 30 days ± 3 days between the doses. If the 
dose is delayed more than 60 (+3) days after the last given dose, the participant will need to
move into the follow-up period. Only one maintenance dose can be missed (i.e. given > 7 
days after the originally scheduled dosing and not later than 60 (+3) days after the last 
actually administered dose) per main treatment or per extension treatment period. Between 
missed doses at least 5 regular maintenance doses should have been administered according to 
protocol, otherwise the participant will also need to move into the follow-up period. Obtain 
blood samples for PK/PD analysis 30 (±3) days after the date of the delayed dose, if not 
already scheduled according to the study protocol. 
7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 

At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA (Section 1.3) 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.
If a participant permanently discontinues/withdraws from the study and is unwilling or unable 
to attend regular study visits at the study site, all possible efforts should be made to obtain 
information on the health status of the participant.


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7.3
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
Data that have been collected until the time the participant is considered to be lost to follow
up may be retained and continued to be used.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g.,
platelet 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.

If deemed necessary for an individual participant, the investigator or designee, at 
his/her discretion, may arrange visits in addition to the scheduled study visits. 
Relevant unscheduled visits will be documented in the eCRF.


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8.1
Efficacy Assessments 
The efficacy will be assessed by analyzing exploratively the incidence of the following 
components

Death due to MI, stroke, pulmonary embolism (PE) and systemic embolism (SE)

Non-fatal stroke

Non-fatal MI

Major amputation of vascular etiology

Acute limb ischemia

Symptomatic VTE 

Thrombosis of AV fistulas or grafts
Furthermore, the effect of osocimab on the clotting in the dialysis circuit will be assessed by 
the SQCS. At the end of the hemodialysis procedure, the filter and line (including drip 
chamber/air trap) will be examined by the hemodialysis nurse (or respective appropriate 
personnel) after rinsing the circuit. If possible the same rinsing volume should be used within 
one participant throughout the course of the study. Clotting scores will be assigned as follows:

“0” clean filter and no visible clots in the drip chamber/air trap

“1” traces of coagulation in the filter and/or in the drip chamber/air trap

“2” intermediate state between “1” and “3”

“3” fully clotted extracorporeal system resulting in an interruption of the 
hemodialysis session
Adequate anticoagulation is defined by a SQCS of less or equal “1”.
Additional details for assessment of SQCS can be found in a study specific guidance 
document .
8.2
Safety Assessments 
During all contacts with the participant from signing the informed consent form, investigators 
will check for and record the following in the eCRF:

Bleeding events

Adverse events, including adverse events of special interest

Concomitant medication changes

Changes in dialysis prescription
Planned time points for all safety assessments are provided in the SoA in Section 1.3.. 
Abnormal safety findings which have started after signing of informed consent should be 
reported as an AE/SAE. Clinically significant abnormal findings will be reported as AEs in 
the eCRF.
AEs requiring submission to the CIAC are listed in Section 8.3.9.


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8.2.1
Main Safety Assessment
Incidence, severity and seriousness of AE, and SAE, including bleeding events, as well as the 
causal relationship between an AE/SAE and the administration of the study intervention will 
be assessed throughout the study.
In order to evaluate the safety and tolerability of osocimab, AEs will be assessed as the main 
safety endpoint. See Section 8.3 for further information.
8.2.2
Bleeding Events
Major bleeding (MB) and clinically-relevant non-major bleeding (CRNMB) events, as 
assessed by CIAC, will be the primary safety endpoint in this study. 
Randomized participants will be evaluated for occurrence of bleeding events continuously 
after signing informed consent up to the end of the post-treatment follow-up for all cohorts. 
All bleeding events (other than the normal bleeding from AV graft or fistula post-dialysis) 
will be reported as AE or SAE per Section 8.3 and submitted to the CIAC.
However, bleeding after dialysis from AV graft or fistulas is expected and will only be 
reported as an AE/SAE and submitted to CIAC if there is a change in the pattern, duration or 
intensity of bleeding in a participant, or if exceptional measures are taken for hemostasis 
beyond normal, relative to post-dialysis bleeding that was observed in that participant over
(approximately) the prior 4 weeks.  
Bleeding after dialysis from the AV fistula have also to be assessed by the AV bleeding score 
(Section 8.2.2.1).
The CIAC will classify bleeding events primarily in alignment with the ISTH definitions (24):
Definitions in alignment with ISTH (Please refer to the adjudication charter for details):
Major bleeding (MB) is defined as symptomatic bleeding with one of the following:

Bleeding that contributed to death

Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome

Bleeding causing a fall in hemoglobin level of 2 g/dL(1.24 mmol/L) or more, or 
leading to transfusion of two or more units of whole blood or red cells
Clinically relevant non-major (CRNM) bleeding is any sign or symptom 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 the ISTH definition of major bleeding but 
does meet at least one of the following criteria:

Requiring medical intervention by a healthcare professional

Leading to hospitalization or increased level of care

Prompting a face to face evaluation (i.e. not a telephone or electronic communication)


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8.2.2.1
Assessment of AV Access Bleeding
Severity of bleeding at the dialysis access will be assessed approx. 15 minutes after removal 
of the dialysis needle(s) from the AV access according to the following categories 
(exploratory bleeding score):

“0” no access bleeding

“1” slow oozing

“2” overt bleeding
In case the AV access exhibits overt bleeding 15 minutes after removal of the dialysis
needle(s) (AV access bleeding score of 2), the investigator may consider the reduction of
heparin (i.e. UFH, LMWH) for the subsequent dialysis sessions during the treatment and
follow-up period. For such decision, the investigator should take all available participant
information into account (e.g., laboratory values, concomitant medication, details of
hemodialysis session, adverse events etc.).
In case catheter is used, the AV access bleeding is not applicable.
8.2.2.2
Recommendations for Bleeding and Surgery Management 
Bleeding
In general, the management of bleeding is at the discretion of the treating physician and local 
prescribing information should be consulted for usage in ESRD for any drug administered. 
Evidenced-based treatment recommendations for uremic bleeding in patients with ESRD are 
summarized in Hedges et al, 2007 (25).
In case a participant experiences a severe bleeding event (e.g., bleeding that leads to surgical 
procedures or transfusion of blood components or to prolonged hospitalization or bleeding  
into a critical organ or in close space) and further treatment of the participant is harmful in the 
view of the investigator, treatment should be discontinued and participants should be treated 
as medically indicated. So far no data for management of bleeding and surgery under 
osocimab have been gathered.
The following measures may be considered by the investigators to control bleeding and are at 
the discretion of the treating physician:

Mechanical compression or surgical intervention

Delay of the next injection or discontinuation of treatment

Review and discontinue concomitant medications that could exacerbate bleeding

General volume management: fluid replacement & hemodynamic support.

Transfusion (e.g., whole blood/packed cells/fresh frozen plasma [FFP]/platelets) with 
careful volume management

Antifibrinolytics (e.g., aminocaproic acid or tranexamic acid, consult local prescribing 
information for guidance on usage in patients with severe renal impairment/ESRD)

Desmopressin

Conjugated estrogens


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If bleeding cannot be controlled by these measures, administration of the following may be 
considered, if used as part of local practice (consult local prescribing information for guidance 
on usage in patients with severe renal impairment/ESRD) and are under discretion of the 
treating physician:

Recombinant Factor VIIa (NovoSeven)

FEIBA

4-factor concentrate (prothrombin complex concentrate)
In vitro data with osocimib showed that the prolongation of aPTT and ROTEM CT induced 
by osocimab can be fully reversed by recombinant FVIIa (NovoSeven) or factor eight 
inhibitor bypass activity (FEIBA). In in vitro experiments PCC (prothrombin complex 
concentrate) was not able to normalize aPTT and ROTEM CT. However, this may be due to 
the inability to show effects on the coagulation tests by these measures (further details may be 
found in the current version of the IB).
As coagulation parameters are potentially unblinding these should only be reviewed if 
medically indicated. 
Surgery
Major surgery (e.g., surgical procedure involving an organ within the cranium, chest, 
abdomen, or pelvic cavity) or major procedures in tissue with high fibrinolytic activity (e.g.,
gynecologic, urologic, or surgeries of the nasal and oral cavities) or surgeries with high risk 
for perioperative bleeding, should not be performed during the trial. However, if deemed 
medically necessary and surgery cannot be postponed until the end of the follow-up period, 
the surgery is only allowed to be performed under general anesthesia. Spinal or epidural 
anesthesia/analgesia is not allowed during the study. Investigators are encouraged to postpone 
surgeries whenever possible until the end of the study including the 4 months follow-up 
period or at least as long as possible after the last study intervention. Hence, study 
intervention should be immediately discontinued if a participant is scheduled for the above 
mentioned surgeries. Participants who permanently discontinue study intervention due to a 
surgery will enter the post-treatment follow-up period (Section 7.1).
Minor surgeries or surgeries with low bleeding potential (e.g., knee replacement surgery) may 
be performed during the trial if deemed necessary and can’t be postponed. Of note, during the 
FOXTROT trial participants have been operated for total knee replacement under full anti-
coagulation with osocimab (doses up to 1.8 mg/kg). Study interventions may be further 
administered after such surgery if deemed appropriate by the investigator and after careful 
post-operative assessment. Before restarting study intervention administration of prohibited 
concomitant medication needs to be taken into account (Section 6.5).
If knowledge of treatment assignment will influence the choice of intervention to manage 
bleeding risk prior to or during the surgery the investigator may immediately obtain the 
participant’s treatment assignment by contacting IWRS.  In this setting, it is appropriate to 
monitor coagulation parameters.  
Management of bleeding and surgery of study participants may further be guided by 
published data regarding patients with inherited FXI deficiency. There have been reports in 
the literature about the successful use of tranexamic acid or ε-amino caproic acid in the 
management of non-ESRD, hemophilia C patients when undergoing surgery (26). The local 
package insert need to be consulted for usage in patients with ESRD on dialysis. In patients 


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undergoing tooth extractions, i.e. an invasive procedure in tissue with high fibrinolytic 
activity in the oropharynx, Berliner et al. reported uneventful extractions in 19 patients with 
severe FXI deficiency treated with tranexamic acid alone (1 g q.i.d.) started 12 h prior to 
surgery and continued for 7 days after surgery (27). The administration of recombinant FVIIa 
in addition to tranexamic acid was also reported as a therapeutic option in patients with severe 
FXI deficiency undergoing surgery (28- 29). O’Connell et al. reported effective hemostasis 
when a dose of 90 μg/kg of recombinant FVIIa given every two hours in the first 24 hours 
and every 4 hours in the second 24 hours, followed by postoperative tranexamic acid for 7 
days, was used in patients undergoing major surgery. Subsequently, Livnat et al. showed that 
even a single dose of recombinant FVIIa at a dose of 15-30 μg/kg, along with 1 g of 
tranexamic acid given before surgery and then every 6 hours post-surgery for 7-14 days 
achieved satisfactory hemostasis in patients with FXI inhibitors undergoing major surgery 
(30). 
Please consider that for severe renal impairment/ESRD specific limitation or even 
contraindications for use of certain agents may apply. This may differ between countries.
8.2.3
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems and will follow standard 
practice of the site. Height will only be measured at screening visit. Weight will be measured 
pre- and post-hemodialysis (dry-weight).
8.2.4
Vital Signs

Vital signs will consist of 1 pulse and 1 blood pressure measurements. Vital signs will 
be measured after 5 minutes rest. 

Blood pressure and pulse measurements will be assessed pre-dialysis (with the 
exception of the screening visit), either in a supine or sitting position (preferably in the 
same position for all visits), on the same arm at each visit, and using the appropriate 
size cuff. These measurements will be performed at the time points specified in the 
SoA (see Section 1.3). 
NOTE: The AV graft or fistula arm cannot be used to measure blood pressure.
8.2.5
Electrocardiograms

Single standard electrocardiograms (12 lead ECG) according to Goldberger / 
Einthoven and Wilson will be recorded pre-dialysis after resting for at least 5 min at 
the time points specified in the SoA (see Section 1.3).

All ECG print-outs will be identified with the PID as well as date and time of 
recording and will be attached to the participant’s file.

ECG printouts will be examined locally by the investigator on the day of recording for 
safety and quality. Any clinically relevant abnormality will be documented as an AE.

All suspected acute coronary syndrome events need to be submitted to the CIAC for 
evaluation.


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8.2.6
Clinical Safety Laboratory Assessments

See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA
(Section 1.3) for 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 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or until the end of study should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the 
investigator or the medical monitor.

If 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.

All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 

If laboratory values from non-protocol specified laboratory 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 eCRF.

Appropriate blood draws from the dialysis access for any type of blood sampling, 
collected from the hemodialysis line (not directly from the fistula, nor from any vein 
on the fistula arm), or tunneled catheters are permitted. Whenever possible, the blood 
should be drawn under the same conditions (details are depicted in the laboratory 
manual). 

Where possible for safety laboratory, pediatric-sized blood volumes (as opposed to 
adult-sized blood volumes) are to be taken and blood collections should be combined 
to minimize the number of needle punctures.

During the screening visit, only local laboratory samples will be assessed to check the 
eligibility of the patient. For details see Section 10.2.
Central lab results for PD parameters including coagulation parameters will not be provided to 
the sites, as these are potentially unblinding. Investigators should also avoid local testing of
coagulation parameters, as these may be unblinding, unless clinically indicated.
8.2.7
Dialysis Information
8.2.7.1
Renal Replacement Therapy (RRT) Baseline Information (General 
Dialysis Information)
Current dialysis prescription will be collected on the appropriate eCRF.
Note: anticoagulation use during hemodialysis must be reported in the Concomitant 
Medication page in the eCRF.


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8.2.7.2
Dialysis Prescription Changes
Changes to the dialysis prescription and compliance with dialysis will be recorded on the 
appropriate eCRF at visits specified in the SoA.
Note: changes in anticoagulation use during hemodialysis must be reported on the appropriate 
eCRF page.
8.3
Adverse Events and Serious Adverse Events
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 and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or study (see 
Section 7).
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs/SAEs will be collected from signing of informed consent until the last follow-up visit 
at the time points specified in the SoA (Section 1.3).
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AESIs (as defined in Section 8.3.8),
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. 


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
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.
Reporting of Disease-Related Events
Overall, in compliance with applicable regulations, in the event of a SUSAR related to the 
blinded treatment, the participant’s treatment code will usually be unblinded before reporting 
to the health authorities. Notifications of IEC/IRB and investigators will be done according to 
all applicable regulations (see Section 8.3.4) with the restrictions described below.
During the study there will be instances where AEs are also potential efficacy or safety 
endpoints.
The following efficacy and pre-defined disease-related outcome events are expected in 
patients with ESRD
i.
Bleeding
ii.
Death due to MI, stroke, PE and SE
iii.
Non-fatal stroke
iv.
Non-fatal MI
v.
Major amputation of vascular etiology
vi.
Acute limb ischemia
vii.
Symptomatic VTE 
viii.
Thrombosis of AV fistulas or grafts
These will be recorded on the corresponding CRF page in the participant’s eCRF.
If any of the above listed outcome events fulfil the definition of SAEs as given in 
Section 10.3, the investigator must report them immediately (within 24 hours of the 
investigator’s awareness) to the sponsor’s pharmacovigilance department as described in 
Section 10.3. However, SUSARs that derive from these efficacy outcome events (as specified
above ii – viii: Death due to MI, stroke, PE and SE, non-fatal stroke, non-fatal MI, major 
amputation of vascular etiology, acute limb ischemia, symptomatic VTE, thrombosis of AV 
fistulas or grafts), including events indicative of those outcome events (details will be 
described in the adjudication charter and additional study specific guidance documents) will 
be waived from unblinding and are not subject to expedited reporting to health authorities. In 
case of unblinding, SUSARs may be submitted blinded, either expedited or aggregated, to 


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investigators and IEC/IRB. Unblinded SUSAR reports are submitted only when required by 
local legislation.
8.3.5
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after signing of informed consent and until the last
follow-up visit (visit 35). 

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.

As serum beta human chorionic gonadotropin (βhCG) levels are high in pregnant and 
may be elevated in non-pregnant women with ESRD undergoing hemodialysis, one 
measurement of high βhCG may not be sufficient to establish pregnancy. Only 
sequential increasing levels of βhCG may be considered for further investigation on 
pregnancy. If deemed necessary, a follow-up ultrasound may be performed to confirm 
pregnancy. If a female participant becomes pregnant, she must permanently 
discontinue study intervention.
8.3.6
Cardiovascular and Death Events
Not applicable.
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Bleeding after dialysis from AV graft or fistulas is expected and will only be reported as an 
AE or SAE if there is a change in the pattern or intensity of bleeding in a participant, or if 
exceptional measures are taken for hemostasis beyond normal, relative to post-dialysis 
bleeding that was observed in that participant over the prior 4 weeks.
8.3.8
Adverse Events of Special Interest 
Adverse events of special interest have to be reported to the sponsor along the timelines set 
for SAEs, i.e. within 24 hours of the investigator’s awareness, as described in Section 8.3.1.
Declaration of an event as serious should only occur if one or more of the serious criteria is 
applicable. Non-serious adverse events of special interest should not automatically be 
upgraded to serious by the reporting investigator.
Adverse events of special interest are:

Decrease in platelets below 75 x 109/L or > 50 % decrease in platelet count from 
baseline 

Hypersensitivity (i.e. any allergic reactions of ≥ CTCAE criteria 2 [Common 
Terminology Criteria for Adverse Events] or anaphylaxis)


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8.3.8.1
Stopping Rule for Study Drug Administration in Case of 
Thrombocytopenia
In the event of a platelet count that is < 75,000mm3, or > 50% decrease in platelet count from 
baseline the initial measurement should be confirmed by drawing repeat measurement(s)
within 2 weeks. The repeat measurement(s) must occur before further study intervention (i.e. 
study drug administration). In the event that the platelet count has not recovered to 
> 100,000 mm3 within 2 weeks , dosing of the participant will be postponed until the platelet 
has increased at least above 100,000 mm3. In the event that after resumed dosing 
thrombocytopenia (< 75,000 mm3) occurs again, study drug administration will be stopped 
permanently. A participant may be withdrawn from study intervention at any time at the 
discretion of the investigator for safety reasons (Section 7.1). 
8.3.8.2
Hypersensitivity Reactions
Hypersensitivity reactions will be assessed according the Common Terminology Criteria for 
Adverse Events of the National Cancer Institute (CTCAE v5.0), see Table 8–1. 


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Table 8–1: Common Terminology for Adverse Events Related to Immune System 
Disorders (CTCAE v-5.0)
Immune system disorders
Adverse 
Event
Grade
1
2
3
4
5
Allergic 
reaction
Systemic 
intervention not 
indicated
Oral intervention 
indicated
Bronchospasm; 
hospitalization 
indicated for clinical 
sequelae; 
intravenous 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
intervention 
indicated; allergy-
related edema/ 
angioedema; 
hypotension
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it 
presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to 
death.
Autoimmune 
disorder
Asymptomatic; 
serologic or other 
evidence of 
autoimmune 
reaction, with 
normal organ 
function; 
intervention not 
indicated
Evidence of 
autoimmune 
reaction 
involving a non-
essential organ 
or function (e.g., 
hypothyroidism)
Autoimmune 
reactions involving 
major organ (e.g., 
colitis, anemia, 
myocarditis, kidney)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by loss of function or tissue destruction of an organ or multiple organs, 
arising from humoral or cellular immune responses of the individual to his own tissue constituents.
Cytokine 
release 
syndrome
Fever with or 
without 
constitutional 
symptoms
Hypotension 
responding to 
fluids; hypoxia 
responding to 
<40% O2
Hypotension 
managed with one 
pressor; hypoxia 
requiring ≥40% O2
Life-threatening
consequences; 
pressor or 
ventilatory 
support 
indicated
Death
Definition: A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or 
hypoxia caused by the release of cytokines.
Serum 
sickness
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; intervention 
not indicated
Moderate 
arthralgia; fever, 
rash, urticaria, 
antihistamines 
indicated
Severe arthralgia or 
arthritis; extensive 
rash; steroids or iv 
fluids indicated
Life-threatening 
consequences; 
pressor or 
ventilatory 
support 
indicated
Death
Definition: disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from 
an animal serum. It occurs approximately six to twenty-one days following the administration of the foreign 
antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked 
discomfort and dyspnea.
CTCAE=  common terminology criteria for adverse events; iv= intravenous
Depending on the observed grade of reaction, respective measures like general and specific 
drug treatment (e.g., anti-histamines) as well as temporary or permanent stop of study drug 
administration in the affected participant will be applied. In case of a mild (grade 1-2
according to CTCAE v5.0) hypersensitivity reaction and an apparent symptoms relief, the 


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investigator may decide to cautiously continue further dosing. If any hypersensitivity 
symptom re-occurs dosing will be stopped permanently.
In case of hypersensitivity reactions of ≥ 3 dosing will be directly stopped permanently.
Anaphylaxis is strongly suspected when respiratory symptoms or hypotension occurs within 
10 minutes of injection. All measures at site will be performed according the S2 Guideline for 
acute therapy and management of anaphylaxis (31). 
8.3.9
AEs Requiring Submission to the CIAC
All deaths, and events suspected to be related to cardiovascular disease, or other arterial or 
venous thrombosis (including AV access thrombosis), but not limited to these and starting 
after signing informed consent (randomized participants only), will be submitted to the CIAC 
for adjudication. Similarly, all bleeding events in randomized participants (except a 
participant’s normal/expected post-dialysis bleeding from AV access) will be submitted to the 
CIAC for adjudication. Details of the adjudication process will be described in the 
adjudication charter and additional study specific guidance documents.
8.4
Treatment of Overdose
In the event of an overdose, the investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically (approx. 5 months).
3. Obtain blood samples for PK/PD analysis within 4 to 10 days and an additional one 
around 30 days from the date of the last dose of study intervention if not already 
scheduled according to the study protocol.
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
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 of osocimab and its relationship with treatment 
effects, the plasma concentrations of osocimab will be determined at different time points 
using a sparse sampling approach in all participating subjects. Details about the collection, 
processing, storage and shipment of samples will be provided separately (e.g., in the 
laboratory manual). Analysis of samples from participants not treated with osocimab 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 time points will be documented and taken into account for the PK analysis. Date and 
time of the PK sample collection and date and time of most recent study drug administration
must be documented accurately in the eCRF.
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 


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calibration samples and QC samples will be reported in the Bioanalytical Report which will 
be included in the clinical study report (CSR) for this study.
Pharmacokinetic and exposure-response analysis might be performed using population 
approaches (popPK and popPK/PD, e.g., by non-linear mixed effect modeling). Analysis and 
report will be done under separate cover (see Section 6.3).
Exploratory analysis of unbound osocimab or of the complex of osocimab bound to FXI(a) 
might be done if applicable.
8.6
Pharmacodynamics
For the investigation of the pharmacodynamic response to osocimab and its relationship with 
treatment effects, pharmacodynamic parameters detailed below will be determined at different 
time points using a sparse sampling approach in all participating subjects. Details about the 
collection, processing, storage and shipment of samples will be provided separately (e.g., in 
the laboratory manual). Samples from participants not treated with osocimab will also be 
analyzed. 
Blood samples will be collected at the time points indicated in the SoA (Section 1.3). Blood
samples obtained at additional time points based on the investigator’s discretion will not 
qualify as a protocol deviation and will be used for the PD analysis as well. Deviations from 
the specified time points will be documented and taken into account for the PD analysis. Date 
and time of the PD sample collection and date and time of most recent study drug 
administration must be documented accurately in the eCRF.
For PD evaluation of osocimab the last sample taken prior to first drug administration will be 
defined as reference time point (i.e., will be assigned to a relative time of 00d00h00m). 
The actual date and time of blood sampling will be collected in the eCRF. All PD parameters 
will be measured using validated methods. Quality control and calibration samples will be 
analyzed concurrently with study samples. For selected parameters, results of QC samples 
will be reported together with analyte concentrations in the Clinical Study Report (CSR) for 
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 CSR for this study. 
The following parameters will be used to assess the PD effects after administration of the 
investigational drug:
Main pharmacodynamic parameters:

aPTT will be measured via the kaolin-trigger method (clotting assay). Furthermore, 
the aPTT assay will be conducted after in vitro-neutralization of heparin in order to 
separate potential heparin effects from the PD effect of osocimab.

Factor XI activity will be assessed with an aPTT-based coagulation test using FXI 
deficient plasma. Furthermore, the assay will be conducted after in vitro-neutralization 
of heparin in order to separate potential heparin effects from the PD effect of 
osocimab.
Other pharmacodynamic parameters:

Activated Factor XIa activity (AXIA) will be analyzed using a kaolin-trigger and a 
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
Factor XI concentration will be analyzed using an enzyme-linked immunosorbent
assay (ELISA).

D-dimer will be analyzed using a particle-enhanced immunoturbidimetric method.

TAT (thrombin-antithrombin complex) will be analyzed using ELISA.

F1.2 will be analyzed using ELISA.
The study sponsors reserve the right not to conduct all or part of the above-mentioned 
analysis.
8.7
Genetics
Genetic as well as non-genetic analyses may be part of the biomarker investigations in this 
study. Genetic investigations may be of any kind, except for whole genome sequencing. See 
Section 8.8 for details.
8.8
Biomarkers
Genetic as well as non-genetic biomarkers will be investigated. Biomarker analyses might be 
performed optionally and/or only in a subset of participants.
Exploratory biomarkers: FVIII activity, FIX activity, FXII activity, von Willebrand factor 
antigen level, ristocetin cofactor (i.e. von Willebrand factor) activity.
Furthermore, some PD markers listed under Section 8.6 might also be analyzed using 
alternative reagent/analyzer manufacturers in order to assess potential systematic influences 
of the analysis technology. 
In addition to the biomarkers described above, further biomarkers related to, e.g., the mode of 
action or the safety of the study intervention and similar drugs may be investigated. The same 
applies to further biomarkers deemed relevant to cardiovascular and renal diseases and 
associated health problems. These investigations may include e.g., diagnostic, safety, 
pharmacodynamic, monitoring, or potentially predictive biomarkers.
Timing
See SoA (Section 1.3) for planned time points of sample collection.
Sample handling and storage
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.
Reporting
Some of the results of biomarker investigations may be reported separately (e.g., in a 
biomarker evaluation report).
8.9
Immunogenicity Assessments
The development of anti-drug antibodies (ADAs) to osocimab will be investigated in plasma
samples from all participants taken at the time points indicated in the SoA (Section 1.3). 
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participants´ safety in this respective study setting. In case of any hypersensitive AE of life-
threatening consequences the ADA measurement will be carried out at short notice.
Plasma samples will be screened for ADAs to osocimab and the result as well as the titer of 
confirmed positive ADA samples will be reported. ADA positive samples will be further 
characterized for their ability to neutralize the activity of osocimab (i.e. Neutralizing antibody 
(NAB) analysis). Other analyses may be performed to further characterize the 
immunogenicity of osocimab. Analysis of samples from participants not treated with 
osocimab is optional.
Further details on collection, labeling, storage, and shipping of samples are provided in a 
separate laboratory manual. Immunogenicity samples will be analyzed using validated 
analytical methods. Positive controls will be analyzed concurrently with study samples. The 
results of samples and positive control samples will be reported in the Bioanalytical Report 
which will be included in the CSR for this study.
8.10
Health Economics OR 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 objective of this study is a qualitative assessment of safety. All analyses are 
performed in a descriptive manner and thus no formal hypothesis is defined. 
9.2
Sample Size Determination 
Assuming 25% screen failure proportion as based on historic operational experience, 
approximately 800 participants will be screened to achieve an estimated total of
approximately 600 participants randomly assigned to study intervention. Of those, 555
participants are expected to complete the main treatment period assuming a true incidence rate 
of 15 participants with LTFU (lost to follow-up) (including e.g., withdrawal of consent) per 
100 participant-years across all groups.
As a participant will be evaluated once he was randomized and received at least one dose of 
study intervention, the number of evaluable and randomized participants can be assumed to be 
similar.
In case that the observed overall incidence rate of participants with LTFU after the 400th
participant is significantly higher than expected, the number of randomized participants may 
be increased (max. of 750 participants) to ensure a sufficient number of participants 
completing the main treatment period.
As all analyses will be performed in a descriptive manner, no statistically driven sample size 
calculation was performed.
The expected 90% confidence interval for the hazard ratio of the primary safety outcome is 
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1.
a true incidence rate of 10 participants with a major or clinically-relevant non-major 
bleeding event (in alignment with ISTH guidelines) per 100 participant-years in the 
placebo group (see below for definition)
2.
a true hazard ratio of 1.0 (i.e. no change in relative risk) in both osocimab groups as 
compared to placebo
3.
6 months of treatment with a true incidence rate of 15 participants with LTFU per 100 
participant-years across all groups.
The corresponding expected 90% confidence interval for the hazard ratio of the primary 
efficacy outcome is given by [0.44; 1.53]. while additionally assuming  
1.
a true incidence rate of 13 participants with a primary efficacy outcome per 100 
participant-years in the placebo group.
2.
a true hazard ratio of 0.75 in both osocimab groups as compared to placebo
For details on screen failures see Section 5.4.
9.3
Populations for Analyses 
The populations are defined in Table 9–1.
Table 9–1: Populations for Analyses
Population
Description
Enrolled
All participants who sign the ICF
Full analysis set
All participants randomly assigned to study intervention.
Safety
All participants randomly assigned to study intervention who
received at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they actually received.
Pharmacokinetic analysis set
All osocimab-treated participants with at least 1 PK sample in 
accordance with the PK sampling schedule (Section 1.3 and 8.5) 
and without deviation from the protocol that would interfere with the 
evaluation of the PK data will be included in the PK analysis.
Pharmacodynamic analysis set
All participants with at least 1 PD sample in accordance with the PD 
sampling schedule and without deviation from the protocol that 
would interfere with the evaluation of the PD data will be included in 
the PD analysis.
Listing only set
All participants who signed consent but are not randomized.
Abbreviations: ICF = Informed consent form, PD = pharmacodynamic(s), PK = pharmacokinetic(s)
9.4
Statistical Analyses
The statistical analysis plan will be finalized prior to FPFV (first patient first visit) and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.
9.4.1
General Considerations
The statistical analysis will be performed using SAS; the version used will be specified in the 
statistical analysis plan. In general, all variables including demography and baseline 
characteristics will be summarized by treatment group and by providing frequency tables for 
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For the primary analysis, only the main treatment period will be considered. The partial data
of a participant’s extended treatment period up until primary completion may be presented in 
separate tables. Furthermore, the primary analysis will be performed on the safety analysis set 
in accordance with the “population” attribute of the primary estimand.
In general, participants receiving placebo in either the low-dose or the high-dose cohort will 
be analyzed in a pooled manner. This group will be referred to as placebo group. The group of 
participants receiving osocimab in the high dose cohort (or low dose cohort) will be referred 
to as high dose (or low dose osocimab) group.
Where appropriate, the osocimab groups will be additionally displayed in a pooled manner.
9.4.2
Primary Endpoints
The primary safety analysis is a descriptive time to first primary safety event (for both 
endpoints: composite of major and clinically-relevant non-major bleeding events [in 
alignment with ISTH guidelines] and moderate and severe AEs and SAEs). 
The primary objective is to assess the safety under an osocimab concentration which is 
expected to be maintained during a chronic treatment. Thus the aim it to assess the response to 
treatment while the participant is

alive (intercurrent event “death”) and 

exposed to study intervention (intercurrent event “premature discontinuation of 
treatment”).
Therefore, the time to the first primary safety event is defined as time from first dose of study 
intervention to the first event of the endpoint of interest up until 30 days after last study 
intervention in the main treatment period. The time under risk for a participant without a 
primary safety event will be censored at the date of the EOMT visit, or 30 days after study 
intervention discontinuation, or at the last date data was collected for a participant (e.g., for 
participants lost to follow-up) in the main treatment period, whatever occurs first.
The cumulative incidence risk for the primary safety event together with its confidence 
interval will be estimated. Each of the osocimab groups will be compared to the placebo 
group using two-sided log-rank tests at a type I error rate of α=10%. Due to the explorative 
nature of these analyses, no multiplicity adjustment will be done.
Hazard ratios comparing each of the osocimab groups with the placebo group and 
corresponding 90% (and 95%) confidence intervals will be estimated, as appropriate, from 
Cox proportional hazards models.
Hazard ratio, relative risk reduction (RRR; RRR = 100 × [1 – hazard ratio]%), and 
corresponding 2-sided 90% and 95% confidence intervals comparing each of the osocimab 
groups with the placebo group will be estimated based on two separate Cox proportional 
hazards models. Censoring will be assumed independent of the randomized group assignment.
For the analysis of the primary endpoint in this study, the hazard function h(t) is the chance 
that an individual experiences an event of the primary safety outcome in the next instant in 
time, given that the individual has not had such an event up to time t. For example, for the 
comparison of the osocimab high dose group with the placebo group, the corresponding Cox 
proportional hazards model can be described by the following equation:


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h(t,xi) = h0(t) exp(β xi),
where 
h(.)
hazard function for primary safety outcome, as a function of time and participant’s 
covariates
h0(.)
unspecified underlying baseline hazard function for primary safety outcome; hazard 
of an individual with xi = 0
t
time (in days) relative to the date of first study intervention
xi
treatment group of participant i
(0 corresponds to “placebo group” and
1 corresponds to “osocimab high dose group”)
β
unknown parameter (to be estimated); hazard ratio = exp(β)
Only events that started after the first dose of study treatment and during the main treatment 
period are considered for the primary analysis. Events that occurred during the pre-treatment 
period will be displayed in an exploratory manner.
9.4.3
Secondary Endpoints
The activated partial thromboplastin time (aPTT) and FXIa activity at trough levels after 6 
months will be analyzed as ratio to baseline by providing the mean and median, together with 
the standard deviation and quantiles, respectively.
The exploratory composite efficacy endpoint will be analyzed using a time to event analysis 
similarly to the primary safety endpoints. Thus, the descriptive analysis focuses on estimating 
the efficacy under an osocimab concentration which is expected to be maintained during a 
chronic treatment.
Only events that started after the first dose of study treatment and during the main treatment 
period are considered for the primary analysis. Events that occurred during the pre-treatment 
period will be displayed in an exploratory manner.
The endpoint of thrombosis of the arterio-venous grafts or fistulas will be handled similar.
9.4.4
Other Analyses
The difference in the median of SQCSs during main treatment period between each of the 
osocimab groups and the placebo group will be displayed together with the corresponding 
90% (and 95%) confidence intervals based on a T-test.
Furthermore, the difference of the proportion of hemodialysis sessions with adequate 
anticoagulation during main treatment period between each of the osocimab groups and the 
placebo group will be summarized with the corresponding 90% (and 95%) confidence 
intervals based on a proportion test.
The difference in the median of AV access bleeding score during main treatment period
between each of the osocimab groups and the placebo group will be displayed with the 
corresponding 90% (and 95%) confidence intervals based on a T-test.
Furthermore, the difference of the proportion of hemodialysis sessions with no AV access 
bleeding during main treatment period between each of the osocimab groups and the placebo 
group will be summarized with the corresponding 90% (and 95%) confidence intervals based 
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Both the safety and efficacy analyses will be repeated based on the full data to also include 
events that occurred during the extension treatment period and during the follow-up period.
PK variables
For the investigation of PK, the plasma concentrations of osocimab will be determined at the 
times given in Section 1.3 using a sparse sampling approach.
The data processing and the statistical analysis will be performed in accordance with the 
sponsor’s current guidelines.
Osocimab concentrations will be summarized by visit, separated according to actual dose
cohort. Descriptive statistics of plasma concentrations [geometric mean and percent 
coefficient of variation (%CV), arithmetic mean and %CV, median and range] will be 
presented by treatment group and time in tabular form. Means at any time will only be 
calculated if at least 2/3 of the individual data were measured and were above the lower limit 
of quantification (LLOQ). For the calculation of the mean value, a data point below LLOQ 
will be substituted by one half of this limit. In tables showing mean values, where values 
below LLOQ are included in the calculation of mean values, these means will be marked.
Further details will be specified in the statistical analysis plan.
Pharmacokinetic and exposure-response analysis using population approaches (popPK and 
popPK/PD, e.g., by non-linear mixed effect modeling) will be reported under separate cover, 
if applicable.
PD variables
Results of the additional pharmacodynamics parameter will be displayed utilizing appropriate 
summary statistics and figures. The parameters will be described by the following summary 
statistics: arithmetic mean, standard deviation, median, minimum and maximum. These 
summary statistics will be presented by actual dose group for the original data as well as for 
the absolute and relative changes from baseline as ratio to baseline. In addition, for each 
participant the maximum and minimum relative change from baseline will be determined and 
presented by appropriate summary statistics and figure.
The exploratory PD marker results may be reported separately.
9.5
Interim Analyses
No formal interim analysis is planned.
The primary analysis will be performed after all participants have completed the main 
treatment period (primary completion). A full analysis will be performed after the last 
participant has completed the follow-up of 4 months (study completion).
Furthermore, the DMC will frequently review safety data to ensure the safety of the 
participants in the ongoing study. The required tables and listings will be created by an 
independent Statistical Analysis Center (SAC).
9.6
Data Monitoring Committee (DMC)
A DMC will frequently review safety data to ensure the safety of the participants in the 
ongoing study.
For details on DMC refer to Section 10.1.5.


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10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. Modifications to the study protocol will not be implemented by either the sponsor or 
the investigator without agreement by both parties. However, the investigator or the sponsor 
may implement a deviation from, or a change of the protocol to eliminate an immediate 
hazard(s) to the trial participants without prior IEC/IRB/sponsor approval/favorable opinion. 
As soon as possible, the implemented deviation or change, the reasons for it and if appropriate 
the proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
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:
1.
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
2.
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
3.
Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 


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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 (Code of Federal Regulations), 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
The signed informed consent is to remain in the Investigator Site File or, if locally required, in 
the participant’s note/file of the medical institution. 
Participants who are re-screened are required to sign a new ICF.
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 
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10.1.5
Committees Structure
Three independent committees will be established in order to ensure a high-standard study 
conduct according to GCP, aiming to achieve ultimate integrity, consistency, and high quality 
data, and most importantly ensure the safety of the participants enrolled in the study. The 
committees are:
Steering Committee (SC): 
The SC will advise on all scientific aspects of the study and it will ensure that study execution 
and management of the study are of the highest quality. The Steering committee will consist 
of: External key experts in the field of nephrology, cardiology and hematology and sponsor 
representatives. Further details can be found in the SC charter.
Data Monitoring Committee (DMC): 
The primary role of the DMC is to frequently review the safety data and ensure the safety of 
the participants in the ongoing study including unblinded data if deemed necessary. The DMC 
will consist of members who have recognized clinical expertise or expertise in biostatistics
and who are not members of the steering committee, or involved as investigators or otherwise 
in the trial. Further details can be found in the DMC charter.
Central Independent Adjudication Committee (CIAC):
The central independent adjudication committee is blinded to treatment allocation and dose 
cohort and will objectively assess the safety and efficacy outcomes of the study and may 
convene on an ad-hoc basis for timely assessment. Further details will be found in the CIAC 
charter.
10.1.6
Dissemination of Clinical Study Data
Result Summaries of Bayer's sponsored clinical trials 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 European 
Union (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 EU on or 
after January 01, 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (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. 


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
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. 
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 location list.
10.1.9
Study and Site Start and Closure
The study start date is the date on which the first clinical study site is opened for recruitment 
of participants.
The first act of recruitment is the First Patient First Visit for whole study.
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.


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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 subject and 
should assure appropriate subject therapy and/or follow-up
10.1.10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

In addition the sponsor recognizes the right of the investigator to publish the results 
upon completion of the study. However, the investigator, whilst free to utilize study 
data derived from his/her center for scientific purposes, must obtain written consent of 
the sponsor on the intended publication manuscript before its submission. To this end, 
the investigator must send a draft of the publication manuscript to the sponsor within a 
time period specified in the contract. The sponsor will review the manuscript promptly 
and will discuss its content with the investigator to reach a mutually agreeable final 
manuscript.
10.2
Appendix 2: Clinical Laboratory Tests
For details on the sampling scheme, please refer to Section 1.3 Schedule of Activities (SoA).

The tests detailed in Table 10–1 will be mostly performed by the central laboratory. 

Central laboratory results may not be available in time for necessary medical 
decisions. Therefore, local laboratory tests are performed according to usual patient 
care schemes at the site, per decision of the investigator/treating physicians. If SAEs 
are triggered by local laboratory results the respective findings must be documented in 
the eCRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.


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
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing

Biomarkers (for details see Section 8.8) 
Pharmacodynamic and pharmacokinetic parameters as well as safety laboratory parameters 
will be analyzed by central laboratories. The names and the addresses of the central laboratory 
service providers can be found in the documentation supplied by the vendor (laboratory 
manual).
During the screening visit, only local laboratory samples will be assessed to check the 
eligibility of the patient. 
At least all parameters listed in Table 10–1 under screening tests at local laboratory must be 
assessed at the screening visit and entered in the eCRF to check the patient’s eligibility for the 
study.


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Table 10–1: Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Central laboratory 
Hematology
Hemoglobin
Hematocrit
Red blood cell (RBC) count (MCV, MCH, MCHC, %reticulocytes)
Platelet count
White blood cell (WBC) count with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Clinical chemistry
Alanine aminotransferase (ALT)
Albumin
Alkaline phosphatase
Amylase
Aspartate aminotransferase (AST)
Bicarbonate
Bilirubin, total and direct
Blood urea nitrogen (BUN)
Calcium
Chloride
Cholesterol [high density lipoprotein (HDL), low density lipoprotein 
(LDL), total]
Creatinine
Creatine kinase (CK)
Glucose
Gamma glutamyl transpeptidase (GGT)
high-sensitivity C-reactive protein (hs-CRP)
Highly sensitive serum beta human chorionic gonadotropin (βhCG)
Iron saturation and ferritin
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Parathyroid hormone (PTH)
Phosphorus
Potassium
Serum glutamic-oxaloacetic transaminase (SGOT)
Serum glutamic-pyruvic transaminase (SGPT)
Sodium
Total protein
Triglycerides
Troponin
Uric acid
Coagulation parameters should not be reviewed by blinded staff.
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT), seconds and INR (International normalized 
ratio)
D-Dimer


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Laboratory 
Assessments
Parameters
Local laboratory
Screening Tests
Highly sensitive serum beta human chorionic gonadotropin (βhCG) 
pregnancy test (as needed for women of childbearing potential)
All study-required laboratory assessments for eligibility will be performed 
by a local laboratory:
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Bilirubin (direct, total)
Alanine aminotransferase (ALT)
Hemoglobin
Platelet count
The results of each test must be entered into the electronic case report 
form.
NOTES:
Please note that if screening parameters are available as part of routine medical practice, these 
are not required to be repeated as long as they were measured within 14 days of screening and 
meet the thresholds defined in the in-/exclusion criteria.
Abbreviations: MCH = mean corpuscular/cellular hemoglobin, MCHC = mean corpuscular/cellular hemoglobin 
concentration, MCV = mean corpuscular/cell volume
Investigators must document their review of each laboratory safety report.
Coagulation parameters that could unblind the study will not be reported to investigative sites 
or other blinded personnel if not medically required.
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, 
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) whether or 
not 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 


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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 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.


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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 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 eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to sponsor in lieu of completion of the AE/SAE eCRF page.


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
There may be instances when copies of medical records for certain cases are 
requested by sponsor and CIAC. 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 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.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

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’s PV. 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 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 sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the CIAC with a copy of any post-mortem 
findings including histopathology. 

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the sponsor’s PV within 24 
hours of receipt of the information.


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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 sponsor will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the sponsor’s medical monitor by telephone.

Contacts for SAE reporting can be found in Investigator Site File.
SAE Reporting to Sponsor via Paper CRF

Email transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor.

In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Investigator Site File.
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.


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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., mullerian 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.
3. 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 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:
Women of childbearing potential with their partner must agree to use a highly effective 
contraception method from signing informed consent until approx. 150 days (due to long half-
life with only monthly administration) after last study intervention.
If engaged in sexual activity with child-bearing potential partner, male participants with their 
female partner must use highly effective contraception from signing informed consent until 
approx. 150 days (due to long half-life with only monthly administration) after last study 
intervention. 
Highly effective contraception methods are for example: 

History of surgical sterilization (male participant or female partner)

Female partner uses hormonal contraception or intrauterine contraception/device

Sexual abstinence
Male participants with partners that are pregnant must use condoms as contraception to ensure 
that the fetus does not get in contact with sperm fluid in case it may contain osocimab. Also 
male participants with female partners who are breast feeding must use condoms.


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Collection of Pregnancy Information:
Male participants with partners who become pregnant 

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention, after 
up to the last follow-up visit (5 months after the last intervention is given).

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female participants who become pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 

Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.


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10.5
Appendix 5: Genetics
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study. See Section 8.8 for details.
Details on sample handling will be provided separately.
10.6
Appendix 6: Country-specific Requirements 
China:

Study participating sites in China are excluded from all PD and biomarker sampling 
and analyses.
Germany:

The exclusion of participants, who are committed to an institution by virtue of an 
order issued either by the judicial or the administrative authorities.


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10.7
Appendix 7: Abbreviations and Definitions
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ASA
Acetylsalicylic acid
ASO
Antisense oligonucleotide
AST
Aspartate aminotransferase
AV
Arteriovenous
AXIA
Activated Factor XIa activity
BUN
Blood urea nitrogen
BW
Body weight
βhCG
Beta human chorionic gonadotropin
CAD
Coronary artery disease
CFR
Code of Federal Regulations
CIAC
Central Independent Adjudication Committee
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine kinase
CKD
Chronic kidney disease
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CRNMB
Clinically relevant non-major bleeding
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Cardiovascular
CYP
Cytochrome P450
DMC
Data Monitoring Committee
e.g.
exempli gratia, for example 
ECG
Electrocardiogram
eCRF
Electronic case report form
ED
Early discontinuation
ELISA
Enzyme-linked immunosorbent assay
EOET
End of extension treatment period
EOMT
End of main treatment period
ESRD
End-stage renal disease
EU
European Union
EudraCT
European Clinical Trials Database
FEIBA
Factor eight inhibitor bypass activity
FFP
Fresh frozen plasma
FPFV
First patient first visit
FSH
Follicle stimulating hormone
FVIIa
Factor VIIa
FVIII
Factor VIII
FXI
Factor XI
FXIa
Factor XIa


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FXII
Factor XII
GCP
Good Clinical Practice
GGT
Gamma glutamyl transpeptidase
Hb
Hemoglobin
HDL
High density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HRT
Hormonal replacement therapy
hs-CRP
high-sensitivity C-reactive protein
i.e.
id est, that is
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IgG1
Immunoglobulin G1
IMP
Investigational medical product
IND
Investigational new drug
INN
International non-proprietary name
INR
International normalized ratio
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Hemostasis
iv
Intravenous(ly)
IWRS
Interactive web response system
LD
Loading dose
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LLOQ
Lower limit of quantification
LMWH
Low molecular weight heparin
LTFU
Lost to follow-up
MACE
Major adverse cardiovascular event
MB
Major bleeding
MCH
Mean corpuscular/cellular hemoglobin
MCHC
Mean corpuscular/cellular hemoglobin concentration
MCV
Mean corpuscular/cell volume
MD
Maintenance/ monthly dose
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic resonance imaging
NA
Not applicable
NAB
Neutralizing antibodies
NYHA
New York Heart Association
PAD
Peripheral artery disease
PCC
Prothrombin complex concentrate
PD
Pharmacodynamic(s)
PE
Pulmonary embolism
PID
Participant identification code
PK
Pharmacokinetic(s)
popPK
Population PK


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PRIND
Prolonged reversible ischemic neurological deficit
PT
Prothrombin time
PTH
Parathyroid hormone
pts
Participants
PV
Pharmacovigilance
QC
Quality control
q.i.d
Quater in die, four times a day
R
Randomization
RBC
Red blood cell
RCTs
Randomized clinical trials
RND
Randomization
RRR
Relative risk reduction
RRT
Renal replacement therapy
SAC
Statistical Analysis Center
SAE
Serious adverse event
SAS
Statistical Analysis Software
sc
Subcutaneous(ly)
SC
Steering Committee
SE
Systemic embolism
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
Schedule of activities
SOP
Standard operating procedure
SQCS
Semi-quantitative clotting score
SUSAR
Suspected unexpected serious adverse reactions
TAT
Thrombin-antithrombin complex
TE
Thromboembolic
TF
Tissue factor
TKA
Total knee arthroplasty
UFH
Unfractionated heparin
ULN
Upper limit of normal
URR
Urea reduction ratio
V
Visit
VTE
Venous thromboembolism
vWF
Von Willebrand factor
WBC
White blood cell (count)
WHO
World Health Organization
WOCBP
Woman of childbearing potential
%CV
Percent coefficient of variation
Month
equals 30 days ± 3 days when referring to monthly dosing
Hemodialysis
the term hemodialysis includes hemodiafiltration
Outcome Assessor
the term Outcome Assessor includes CIAC and DMC


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11.
References
1.
WHO. World Health Organization Cardiovascular diseases (CVDs) Fact Sheet 
(available from: httpp://www.who.int/mediacentre/factsheets/fs317/en/. 2018.
2.
United States Renal Data System. 2015 USRDS annual data report: Epidemiology of 
Kidney Disease in the United States. National Institutes of Health, National Institute 
of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, . 2015.
3.
Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, et al. Effect of 
dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med. 
2002;347(25):2010-9.
4.
Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in 
chronic renal disease. Am J Kidney Dis. 1998;32(5 Suppl 3):S112-9.
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Bhatti NK, Karimi Galougahi K, Paz Y, Nazif T, Moses JW, Leon MB, et al. 
Diagnosis and Management of Cardiovascular Disease in Advanced and End-Stage 
Renal Disease. J Am Heart Assoc. 2016;5(8):e003648.
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O'Hare AM, Bacchetti P, Segal M, Hsu CY, Johansen KL, Dialysis M, et al. Factors 
associated with future amputation among patients undergoing hemodialysis: results 
from the Dialysis Morbidity and Mortality Study Waves 3 and 4. Am J Kidney Dis. 
2003;41(1):162-70.
7.
O'Hare AM, Glidden DV, Fox CS, Hsu CY. High prevalence of peripheral arterial 
disease in persons with renal insufficiency: results from the National Health and 
Nutrition Examination Survey 1999-2000. Circulation. 2004;109(3):320-3.
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Reinecke H, Brand E, Mesters R, Schabitz WR, Fisher M, Pavenstadt H, et al. 
Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc 
Nephrol. 2009;20(4):705-11.
9.
Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. 
Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 
2017;377(14):1319-30.
10.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.
11.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. 
Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 
2011;365(11):981-92.
12.
Kaw D, Malhotra D. Platelet dysfunction and end-stage renal disease. Semin Dial. 
2006;19(4):317-22.
13.
Palmer SC, Sciancalepore M, Strippoli GF. Trial quality in nephrology: how are we 
measuring up? Am J Kidney Dis. 2011;58(3):335-7.
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Schumacher WA, Luettgen JM, Quan ML, Seiffert DA. Inhibition of factor XIa as a 
new approach to anticoagulation. Arterioscler Thromb Vasc Biol. 2010;30(3):388-92.
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Von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, BN B. Thrombin-mediated 
activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-
dependent inhibition of fibrinolysis. J Clin Invest. 1997;99(10):2323-7.
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Bouma BN, Meijers JC. Role of blood coagulation factor XI in downregulation of 
fibrinolysis. Curr Opin Hematol. 2000;7(5):266-72.
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Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. Reduced 
incidence of ischemic stroke in patients with severe factor XI deficiency. Blood. 
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Cushman M, O'Meara ES, Folsom AR, Heckbert SR. Coagulation factors IX through 
XIII and the risk of future venous thrombosis: the Longitudinal Investigation of 
Thromboembolism Etiology. Blood. 2009;114(14):2878-83.
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Preis M, Hirsch J, Kotler A, Zoabi A, Stein N, Rennert G, et al. Factor XI deficiency 
is associated with lower risk for cardiovascular and venous thromboembolism events. 
Blood. 2017;129(9):1210-5.
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Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, et al. Factor XI 
antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 
2015;372(3):232-40.
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Schaefer M, Buchmueller A, Dittmer F, Strassburger J, Wilmen A. Allosteric 
Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody 
Targeting the Activated Form of Coagulation Factor XI. J Mol Biol. 
2019;431(24):4817-33.
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Weitz JI, Bauersachs R, Becker B, Berkowitz SD, Freitas MCS, Lassen MR, et al. 
Effect of Osocimab in Preventing Venous Thromboembolism Among Patients 
Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial. JAMA. 
2020;323(2):130-9.
23.
Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of 
therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493-507.
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Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of 
Anticoagulation. Definition of clinically relevant non-major bleeding in studies of 
anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical 
patients: communication from the SSC of the ISTH. J Thromb Haemost. 
2015;13(11):2119-26.
25.
Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. Evidence-based 
Treatment Recommendations for Uremic Bleeding. Nat Clin Pract Nephrol. 
2007;3(3):138-53.
26.
Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb 
Hemost. 2013;39(6):621-31.
27.
Berliner S, Horowitz I, Martinowitz U, Brenner B, Seligsohn U. Dental surgery in 
patients with severe factor XI deficiency without plasma replacement. Blood Coagul 
Fibrinolysis. 1992;3(4):465-8.
28.
O'Connell NM, Riddell AF, Pascoe G, Perry DJ, Lee CA. Recombinant factor VIIa to 
prevent surgical bleeding in factor XI deficiency. Haemophilia. 2008;14(4):775-81.
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Riddell A, Abdul-Kadir R, Pollard D, Tuddenham E, Gomez K. Monitoring low dose 
recombinant factor VIIa therapy in patients with severe factor XI deficiency 
undergoing surgery. Thromb Haemost. 2011;106(3):521-7.
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Livnat T, Tamarin I, Mor Y, Winckler H, Horowitz Z, Korianski Y, et al. 
Recombinant activated factor VII and tranexamic acid are haemostatically effective 
during major surgery in factor XI-deficient patients with inhibitor antibodies. Thromb 
Haemost. 2009;102(3):487-92.
31.
Ring J, Beyer K, Biedermann T, Bircher A, Duda D, Fischer J, et al. Guideline for 
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SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A randomized, double-blind, parallel group, placebo-controlled, 
multi-center study to assess the safety and tolerability of monthly 
subcutaneous administrations of a low and high dose cohort of 
osocimab to ESRD patients on regular hemodialysis 
NCT Number: 
NCT04523220 
Document Date: 
23-Jun-2022 
 


Statistical Analysis Plan
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Page: 1 of 36
Title page
A randomized, double-blind, parallel group, placebo-controlled, multi-
center study to assess the safety and tolerability of monthly subcutaneous
administrations of a low and high dose cohort of osocimab to ESRD
patients on regular hemodialysis
Osocimab in ESRD Phase 2b study
Bayer study drug
BAY 1213790 / Osocimab
[Study purpose:]
Dose finding
Clinical study 
phase:
IIb
Date:
23 JUN 2022
Study No.:
20115
Version:
4.0
Author:
 
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD
PPD


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Table of Contents
Title page................................................................................................................................... 1
Table of Figures........................................................................................................................ 3
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 4
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 6
3.1
Randomization and Blinding ........................................................................................... 8
4.
General Statistical Considerations .................................................................................. 9
4.1
General Principles............................................................................................................ 9
4.2
Handling of Dropouts ...................................................................................................... 9
4.3
Handling of Missing Data.............................................................................................. 10
4.4
Interim Analyses and Data Monitoring ......................................................................... 11
4.5
Data Rules...................................................................................................................... 11
4.5.1
Laboratory measurements........................................................................................... 12
4.6
Blind Review ................................................................................................................. 12
5.
Analysis Sets .................................................................................................................... 12
6.
Statistical Methodology .................................................................................................. 13
6.1
Population characteristics .............................................................................................. 14
6.1.1
Demography and baseline characteristics................................................................... 14
6.1.2
Medical history........................................................................................................... 14
6.1.3
Prior and Concomitant Medication............................................................................. 14
6.1.4
Renal Replacement Therapy Baseline Information.................................................... 15
6.2
Efficacy.......................................................................................................................... 15
6.2.1
Main efficacy analysis................................................................................................ 15
6.2.2
Supplementary Analyses ............................................................................................ 15
6.2.3
Other efficacy analyses............................................................................................... 16
6.2.4
Subgroup analysis....................................................................................................... 17
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 17
6.4
Safety ............................................................................................................................. 19
6.4.1
Primary safety variables ............................................................................................. 19
6.4.2
Supplementary Safety Analysis.................................................................................. 22
6.4.3
Other safety analyses .................................................................................................. 22
6.4.4
Subgroup analysis....................................................................................................... 24
6.4.5
Adverse events............................................................................................................ 25
6.4.6
Vital signs................................................................................................................... 26
6.4.7
Laboratory parameter ................................................................................................. 26
6.4.8
Hemodialysis data ...................................................................................................... 26
6.4.9
Pregnancies................................................................................................................. 27
6.5
Data affected by the regional crisis................................................................................ 27
7.
Document history and changes in the planned statistical analysis............................. 27
7.1
Version 1.0..................................................................................................................... 27


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7.2
Version 2.0..................................................................................................................... 27
7.3
Version 3.0..................................................................................................................... 28
7.4
Version 4.0..................................................................................................................... 28
8.
References ........................................................................................................................ 29
9.
Appendix.......................................................................................................................... 29
9.1
Determination of sample size......................................................................................... 29
9.2
Randomization Methodology ........................................................................................ 30
9.3
Treatment Assignment Probabilities.............................................................................. 31
Table of Figures
Figure 3–1: Study design review................................................................................................ 8
Abbreviations
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AP
Asia Pacific
aPTT
activated Partial Thromboplastin Time
ASA
Acetylsalicylic acid
AST
Aspartate aminotransferase
ATC 
Anatomical Therapeutic Chemical
AV
Arteriovenous
BMI
Body mass index
CARURS
Covariate Adaptive Randomization User Requirements Specification
CI
Confidence interval
CIAC
Central Independent Adjudication Committee
CIF
Cumulative incidence function
CRF
Case report form
CRNMB
Clinically relevant non-major bleeding
cs
cause specific 
CSR
Clinical Study Report
CV
Cardiovascular
DMC
Data monitoring committee
eCRF
Electronic case report form
EOMT
End of main treatment phase
EOET
End of extension treatment phase
ESRD
End Stage Renal Disease
FAS
Full Analysis Set
F1.2
Prothrombin fragment 1.2
GCP
Good Clinical Practice
HEOR
Health Economics and Outcome Research
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonization
ISTH
International Society on Thrombosis and Haemostasis
IwRS
Interactive web response system
LD
Loading dose
LMWH
Low molecular weight heparin
LOS
Listing only set


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LTFU
Lost to follow-up
MACE
Major adverse cardiovascular event
MD
Maintenance/ monthly dose
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial Infarction
NAB
Neutralizing Antibody
N/A
Not applicable
PD
Pharmacodynamic(s)
PE
Pulmonary embolism
PK
Pharmacokinetic(s)
PPS
Per-protocol set
PT
Preferred term
RBC
Red blood cell
RHR
Relative hazard reduction
RRR
Relative risk reduction
SAC
Statistical Analysis Center
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SE
Systemic embolism
SOC
System organ class
SQCS
Semi-quantitative clotting score
TAT
Thrombin-antithrombin complex
TE
Thromboembolic
UFH
Unfractionated heparin
VTE
Venous thromboembolism
WBC
White blood cell
1.
Introduction
Osocimab is a novel long-acting anticoagulant targeting the activated form of FXI with the 
potential to exhibit lower risk of bleeding events than currently available anticoagulants.
It is well known that ESRD patients on dialysis are at high risk for cardiovascular diseases. 
By targeting FXI, osocimab has the potential to provide an efficacious treatment for the 
prevention of thromboembolic events like MI, stroke, and cardiovascular death with a 
favorable risk profile for unwanted bleeding. This Phase 2b trial will assess the safety and 
characterize the PK/PD profile of two different dose cohorts of osocimab given 
subcutaneously once a month to subjects with ESRD.
Further information can be found in the clinical study protocol.
2.
Study Objectives
Objectives and endpoints are listed in the table below:


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Objectives
Endpoints
Primary

To clinically assess the safety and 
tolerability of different doses of osocimab 
administered subcutaneously once a month 
during main treatment period as compared 
to placebo

Composite of major and clinically relevant 
non-major bleeding events (in alignment with 
the ISTH guidelines) as assessed by blinded 
central independent adjudication committee 
(CIAC)

Composite of moderate and severe AEs and 
SAEs
Secondary

To assess the change of key PD parameter 
from baseline

aPTT, FXIa activity at trough levels after 6 
months
Tertiary/Exploratory

To clinically assess the efficacy of osocimab 
during main treatment period 

To evaluate the anticoagulant effect of 
osocimab on the extracorporeal blood circuit 
by the assessment of a semi-quantitative 
clotting score (SQCS) 

To evaluate the impact of osocimab on the 
AV access for subjects with fistulas or grafts

To assess key PK parameter

To explore additional PK/PD parameters, 
biomarkers, and biomarker 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

Composite endpoint consisting of: vascular 
death [due to MI, stroke, PE, and SE], non-
fatal stroke, non-fatal MI, major amputation 
of vascular etiology, acute limb ischemia,
symptomatic VTE and systemic embolism as 
assessed by blinded central independent 
adjudication committee (CIAC)

Incidence of thrombosis of the arterio-
venous grafts or fistulas 

Semi-quantitative clotting score 

AV access bleeding score

Osocimab trough levels

Various biomarkers and biomarker genetics 
may be explored (e.g. diagnostic, safety, 
population PK, PD, monitoring, or potentially 
predictive biomarkers)
Abbreviations: AE = adverse event, aPTT = activated partial thromboplastin time, AV = arteriovenous, 
CIAC = Central Independent Adjudication Committee, ISTH = International Society on Thrombosis 
and Hemostasis, MI = myocardial infarction, PD = pharmacodynamic(s), PE = pulmonary 
embolism, PK = pharmacokinetic(s), SAEs = serious adverse events, SE = systemic embolism, 
SQCS = semi-quantitative clotting score, VTE = venous thromboembolism
The primary objective is to assess the safety under an osocimab concentration which is 
expected to be maintained during a chronic treatment. Thus, the attributes constituting the 
primary estimand are the following:
Population: The population consists of ESRD patients, further defined by the in- and 
exclusion criteria, who received assigned treatment at least once.


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Variable:

Time from first dose of assigned treatment to treatment emergent major and clinically
relevant non-major bleeding events (in alignment with ISTH guidelines) up until 30 
days after the last administration of assigned treatment

Time from first dose of assigned treatment to moderate or severe AEs and SAEs up 
until 30 days after the last administration of assigned treatment
Treatment: Low/high-dose osocimab or matching placebo on top of standard of care
Intercurrent events: Of interest is the response to treatment while the subject is

alive (intercurrent event “death”) and

exposed to assigned treatment ( intercurrent event “premature discontinuation of
treatment”. Rationale: The primary objective is to assess the safety under an osocimab 
concentration which is expected to be maintained during a chronic treatment.),
i.e. both intercurrent events are handled using the same strategy “while alive” or “while on
treatment”.
Changes in the background therapy etc. will be handled following the treatment policy 
strategy. Other potential intercurrent events are not anticipated. 
Population-level summary: (Cause-specific) hazard ratios comparing each of the osocimab 
dose groups with the placebo group as estimated from cause-specific Cox proportional 
hazards models.
Of note, based on the current expert assessment of the COVID-19 Public Health Emergency, 
it was to be expected that a low number of patients will suffer from (symptomatic) COVID-
19. In addition, as ESRD patients visit dialysis centers on a regular basis anyway, no increase 
in missing data is to be expected. This is why no intercurrent event linked to the COVID-19 
Public Health Emergency was accounted for. However, any premature discontinuation will be 
summarized, and selected analyses will be repeated by (symptomatic) COVID-19 (Yes/No).
Also, if occurred, number of missed visits related to the COVID-19 pandemic will be 
summarized.
3.
Study Design
Study 20115 is a covariate-adaptive randomization, double-blind, parallel group, placebo
controlled, multi-center study to assess the safety and tolerability of monthly administrations 
of a low and high dose cohort of osocimab given subcutaneously in ESRD patients on 
hemodialysis. Here the term hemodialysis includes hemodiafiltration. The overall study 
design is depicted in the figure below.
Approximately 600 subjects (up to 750) from approximately 150 sites are planned to be 
randomized and will receive either osocimab (200 subjects on each dose arm), or placebo 
(200 subjects, i.e. 100 subjects receiving low dose volume placebo and 100 subjects receiving 
high dose volume placebo).
The following regions are planned to be included: North America, Europe, Asia Pacific.
The planned study will consist of:

Screening period (visit 1): up to 14 days


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
Randomization (visit 2): 1 day

Pre-treatment period (from visit 2 until visit 4): 7 days

Main treatment period (from visit 5 until EOMT visit): 6 months

Extension treatment period (from visit 19 until EOET visit): up to 12 months

Follow-up period (from visit 32 until visit 35): 4 months after end of treatment
(EOMT or EOET)
Informed consent form will be obtained at the beginning of the screening period. During the 
screening period, subject’s eligibility evaluations will be performed. Subjects will be 
randomized either to osocimab or to placebo using a covariate-adaptive randomization 
technique (minimization methods) (for details see Section 6.3).
During the pre-treatment period, which will serve as a baseline period, a series of 3 
hemodialysis sessions will be performed. Unfractionated or low molecular weight heparin 
(UFH/LMWH) is allowed as anticoagulation for maintenance of hemodialysis treatment 
during the whole study duration.
The study intervention will be administered subcutaneously abdominal with one single
loading dose at visit 5 and monthly maintenance doses from visit 8 onwards until the end of
the extension treatment period with an overall maximum of 18 months of treatment. The main
treatment period consists of 6 months of treatment as this time frame is deemed to be the
minimum clinically relevant treatment time to assess osocimab as chronic life-time treatment
in an appropriate manner and in preparation for Phase 3.
Study intervention will be administered during the extension treatment period for up to a
maximum of 12 months or until the last subject randomized to the study has performed the
EOMT visit (whichever comes first).
The treatment period (main or extension) will end with the study assessments performed 30
days after the last study intervention administration.
The follow-up period is an observational period of 4 months, i.e. ends approximately 5
months after the administration of the last dose of osocimab.
All suspected bleeding and cardiovascular (CV) or thromboembolic (TE) events occurring
after signing informed consent (randomized subjects only) will be adjudicated by the CIAC in 
a blinded fashion; blinded to treatment allocation and dose cohort (details are described in the 
CIAC charter).
The procedures followed by the CIAC are detailed in the CIAC charter. Detailed instructions
regarding documentation, reporting and transferal of adjudication dossiers will be provided in
a study specific guidance document.
A DMC will frequently review safety data to ensure the safety of the subjects in the ongoing 
study. Further details can be found in the DMC charter.
Details of study procedures and their timing are summarized in the clinical study protocol.


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Figure 3–1: Study design review
Abbreviations: EOET = end of extension treatment phase, EOMT = end of main treatment 
phase, LD = loading dose, MD = maintenance/ monthly dose, pts = participants, R = 
randomization, V = visit
The Follow-up ends 5 months after last study intervention and 4 months after EOMT or 
EOET.
3.1
Randomization and Blinding
Subjects will be randomized between osocimab low dose and placebo low dose and osocimab 
high dose and placebo high dose in a ratio of 2:1:2:1. Covariate-adaptive randomization 
techniques, or better the Pocock and Simon Minimization with Biased-coin Assignment 
methodology (Pocock, SJ, R Simon. ‘Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial’, Biometrics, 31, pp 103–115, 1975) will be 
utilized to perform subject randomization for this study.
In brief, each subject’s randomization is performed by calculating the imbalance that will 
exist by assigning each treatment group in turn – by considering the previous treatment 
assignments to pre-specified balancing factor levels corresponding to the subject being 
randomized, and summing the individual factor level imbalances to determine which 
treatment(s) have minimal imbalance. The treatment assignment for this subject is then 
performed in a non-deterministic manner, by assigning probabilities of treatment assignment 
to each of the treatment arms based on the calculated treatment imbalances.
More detailed information can be found in sections 9.2, 9.3 and in the Covariate Adaptive 
Randomization User Requirements Specification (CARURS) as provided by the IwRS 
provider ALMAC Clinical Technologies. 
The following baseline covariates will be taken into account:

Region (categorical) 

Age (<50yrs/>=50-<60yrs/>=60-<65yrs/>=65-<70yrs/>=70-<80yrs/>=80yrs) 

Prior major adverse cardiovascular event (MACE) (Yes/No)

Dialysis access via catheter (Yes/No)

Low-dose ASA use (Yes/No) 


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
Diabetes (Yes/No) 

Atrial fibrillation (Yes/No) 
The first five covariates will have twice the factor weight then the latter two.
Sponsor, subjects, and investigators are being blinded with respect to active treatment versus 
placebo, but not blinded to dose cohort (low or high dose). In order to reduce any risk which 
could be associated with the open-label nature of the dose cohort, the final SAP will be 
available before first patient first visit. No ad hoc interim analyses comparing the treatment 
effect of the two dose cohorts will be performed. Aggregation of treatment-specific interim 
results will only be performed for safety measures in the context of DMC meetings.
The CIAC will remain blinded to the subject’s treatment allocation and dose cohort 
throughout the course of the study. The DMC is unblinded.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA) or other software if applicable. All variables will 
be analyzed by descriptive statistical methods. The number of data available and missing data, 
mean, standard deviation, minimum, quartiles, median, and maximum will be calculated for 
metric data. Frequency tables will be generated for categorical data.
In general, subjects receiving placebo in either the low dose or the high dose cohort will be 
analyzed in a pooled manner. This group will be referred to as placebo group. The group of 
subjects receiving osocimab in the high dose cohort (or low dose cohort) will be referred to as 
high dose (or low dose) osocimab group.
4.2
Handling of Dropouts
A subject 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. The subject will be permanently discontinued both from the study intervention 
and from the study at that time. If a subject permanently discontinues/withdraws from the 
study and is unwilling or unable to attend regular study visits at the study site, all possible 
efforts should be made to obtain information on the health status of the subject.
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. The following actions must be taken if a 
subject fails to return to the clinic for a required study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study.


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
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record.

Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
In both cases, when the subject permanently discontinues/withdraws from the study or the 
subject is lost to follow-up, he/she is considered a dropout. The number of dropouts for any 
reason, as well as the reasons for dropout, will be displayed by treatment arm. Baseline 
characteristics will be displayed by dropout (yes/no). All data collected until the dropout will 
be analysed. Of note, subjects who drop out because they suffer from COVID-19 will be 
displayed here with the corresponding reason.
In rare instances, it may be necessary for a subject to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
subject will remain in the study to be evaluated until the end of the follow-up period. If a 
subject permanently discontinues study intervention and is unwilling or unable to attend 
regular study visits at the study site, all possible efforts should be made to obtain information 
on the health status of the subject. The reason for discontinuation of study intervention must 
be recorded in the eCRF and source documentation.
The number of subjects who permanently discontinue (definitive discontinuation) study 
intervention and the reason for discontinuation will be displayed by treatment arm. Baseline 
characteristics will be displayed by permanently discontinue study intervention (yes/no). All 
data collected until the discontinuation will be analysed according to the treatment emergent 
definition.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF). 
General rules
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data:

Efficacy and Safety clinical variables, adverse events
For cases where start month and year are reported but day is missing, impute the 
maximum of (date of randomization + 1 week, first date of study intervention, 
01.month.year). For cases where only start year is reported, impute the maximum of 
(date of randomization + 1 week, first date of study intervention, 01.01.year), but not 
later than death date if the patient died.

PD variables
No imputation will be done for pharmacodynamic parameters.

Study intervention start date
If the start date and time is missing it will be imputed with the randomization date + 1 


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week and time. If start date and time is recorded as earlier than randomization and 
cannot be clarified, date and time of randomization will be used for the statistical 
analysis.

Study intervention stop date
If the stop day is missing, but the stop month and stop year are available then the stop 
date will be imputed as minimum of (15.month.year and last study visit date in main 
treatment or extension treatment period and death date).
If the stop day and month are missing then the stop date will be imputed as minimum 
of (the last study visit date before the post treatment follow-up period and death date).
4.4
Interim Analyses and Data Monitoring
No formal interim analysis is planned.
The primary analysis will be performed after all subjects have completed the main treatment 
period (primary completion). 
A full analysis will be performed after the last subject has completed the follow-up of 4 
months (study completion). Of note, the full analysis, or better the evaluation of the data 
collected after the main treatment period will be considered open-label due to the unblinding 
caused by the primary analysis.
Furthermore, the DMC will frequently review safety data to ensure the safety of the subjects 
in the ongoing study. The required tables and listings will be created by an independent 
Statistical Analysis Center (SAC). Only the open session of the DMC meetings may be 
attended by representatives of the Sponsor. Overall treatment data presented here may include 
enrollment data, adverse event data, baseline characteristics, update on study status or any 
potential issues, outcome data. More details can be found in the Data Monitoring Committee 
Charter.
4.5
Data Rules
The pre-treatment period serves as baseline period and takes place before first study 
intervention was given. If there is more than one measurement, the mean of the respective 
measures will serve as baseline.
Baseline for PD will be visit 5 data prior to dosing.
The primary analysis will be based on all respective events that occurred during the scheduled 
main treatment period. 
Additional analyses may be based on all respective events that occurred during the overall 
study period, consisting of both the main treatment and extension treatment period.
In addition, further analyses may be based on all events occurring during the full study period 
consisting of the main treatment, extension treatment and post-treatment follow-up period.
These time scopes are summarized in the table below.
An event is considered treatment emergent if it occurred between start of treatment and not 
later than 30 days after last administration of study intervention.


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An event is considered as full study treatment emergent if it occurred between first study 
intervention and not later than 5 months after last administration of study intervention. 
Additional analysis may be performed post-hoc. 
Time scope definition:
Overall study period
Main treatment phase + extension treatment phase 
Full study period
Main treatment phase, extension treatment phase + follow up
4.5.1
Laboratory measurements
Numeric laboratory measurements outside the calibration range, marked by “<x” (<LLOQ) or 
“>x” (>ULOQ) will be replaced by LLOQ/2 or ULOQ, respectively, in the statistical analysis.
For the analysis of PD, means and standard deviation will only be calculated if at least 2/3 of 
the individual data were measured and were within the calibration range.
Laboratory records without a RAVE Datapage ID (corresponding record in the electronic case 
report form is missing) will be excluded from the analysis.
4.6
Blind Review
There will be two data assessment lists. The first one will occur after primary completion and 
the second one will occur after end of study. The results of both data lists will be documented 
in separate lists of important deviations, validity findings and assignment to analysis set(s).
Any changes to the statistical analysis prompted by the results of the review of study data will 
be documented in an amendment and, if applicable, in a supplement to this SAP.
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis sets. Pharmacodynamic values to be 
excluded from statistical analysis will be documented in the list of pharmacodynamic values 
to be flagged as invalid.
5.
Analysis Sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis set(s) (see section 4.6).
The following populations are defined:


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Population
Description
Enrolled
All subjects who sign the ICF
Full Analysis Set
All subjects randomly assigned to study intervention.
Safety Analysis Set
All subjects randomly assigned to study intervention and who 
took at least 1 dose of study intervention. Subjects will be 
analyzed according to the intervention they actually received.
Pharmacokinetic analysis set
All osocimab-treated subjects with at least 1 PK sample in 
accordance with the PK sampling schedule (Section 1.3 and 
Section 8.5 of the study protocol) and without deviation from 
the protocol that would interfere with the evaluation of the PK 
data will be included in the PK analysis.
Pharmacodynamic analysis set
All subjects with at least 1 PD sample in accordance with the 
PD sampling schedule and without deviation from the protocol 
that would interfere with the evaluation of the PD data will be 
included in the PD analysis.
Listing only set
All subjects who signed ICF but are not randomized.
In accordance with the “population” attribute of the primary estimand, the primary analysis 
set is the safety analysis set.
Supplementary analyses of the efficacy variables will be performed on the full analysis set.
6.
Statistical Methodology
In general, the evaluations will be conducted on each osocimab group and on the placebo 
group. 
In addition, the primary safety and efficacy variables will be analysed descriptively for the 
following groups:

each osocimab group, placebo high dose group, placebo low dose group,

pooled osocimab group, pooled placebo group.
For the primary analysis and all analyses conducted at primary completion which will occur 
once the last patient completed the end of main treatment phase visit, only the main treatment 
period will be considered. The partial data of a subject’s extended treatment period up until 
primary completion may be presented in separate tables. 
At full study completion, also the extension treatment and follow-up period will be 
considered.
Incidence rates and cumulative incidences will be calculated only for endpoints with at least 3 
events in at least one treatment arm. Hazard ratios (cause specific and subdistribution) will be 
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6.1
Population characteristics
6.1.1
Demography and baseline characteristics 
Demographic and baseline data will be evaluated descriptively for the SAF as well as for the 
FAS, by treatment groups and overall. No statistical tests will be performed to compare these 
characteristics across treatment groups.
Descriptive statistics (such as mean, standard deviation, median, quartiles (inter quartile 
range), minimum and maximum) will be provided for continuous variables such as 

Age at Screening

Year of birth

Body weight

Body height

Calculated BMI

Hemoglobin level

Platelet count

Dialysis vintage (time since start of chronic dialysis)

aPTT
Counts and (appropriate) percentages will be provided for categorical variables such as

Sex (male/female)

Race (American Indian or Alaska Native, Asian, Black or African American,
Multiple, Native Hawaiian or Other Pacific Islander, Not Reported, White)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported)

Low dose ASA use (yes/no)

Dialysis access via catheter (yes/no)

Diabetes mellitus (yes/no)

Atrial Fibrillation (AF) (yes/no)

Prior CV events (Stroke, TIA, MI, DVT, PE) (yes/no)

Hemodiafiltration (yes/no)
Reasons for exclusion from analysis populations will be summarized.
6.1.2
Medical history
Medical history data will be evaluated by frequency tables, showing the number and 
percentage of subjects with medical history findings (i.e. previous diagnoses, diseases or 
surgeries) that started before signing of the informed consent and that are considered relevant 
to the study using MedDRA Primary System Organ Class / Preferred Term.
6.1.3
Prior and Concomitant Medication
The dictionary used for coding concomitant medications is the World Health Organization 
Drug Registration and Listing. Frequency tables displaying frequency of subjects for each 
drug category summarized by Anatomical Therapeutic Chemical (ATC) and coded terms will 


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be used to summarize the number and percentage of subjects with prior and concomitant 
medications. The following time windows will be used:

Prior medication: medication stopped prior to randomization

Concomitant medication present in pre-treatment, main treatment, extension period, 
follow-up period, overall study period, full study period ( i.e administered at least one 
dose within the respective period)

Concomitant medication started in pre-treatment, main treatment, extension period, 
follow-up period, overall study period, full study period
Frequency tables of subjects taking prohibited concomitant medications (see study protocol 
section 6.5) are considered as well as by categories: anticoagulants, antiplatelets (incl. ASA), 
thrombolytic medication.
6.1.4
Renal Replacement Therapy Baseline Information
Information of the renal replacement therapy at baseline will be evaluated similar to the other 
baseline characteristics. In this context the use of unfractionated heparins and LMWH for 
dialysis maintenance at baseline will be descriptively summarized by treatment groups and 
overall. 
6.2
Efficacy
6.2.1
Main efficacy analysis
Two main efficacy variables will be considered. The first is the composite endpoint consisting 
of the following components:

Death due to MI, ischemic stroke, pulmonary embolism (PE),non-CNS systemic 
embolism (SE) and undetermined - presumed cardiovascular death

Stroke (ischemic stroke or undetermined type)

MI

Major amputation of vascular etiology

Acute limb ischemia

Symptomatic VTE

Systemic embolism
The second variable is the thrombosis of the arteriovenous fistulas or grafts.
The analysis for both main efficacy variables is a descriptive time to first event analysis 
which will be conducted separately for the osocimab low and high dose group similar to the 
primary safety analysis (i.e. only treatment emergent efficacy events which occurred during 
the main treatment period will be considered), see section 6.4.1. Thus, the descriptive analysis 
focuses on estimating the efficacy under constant osocimab concentration during chronic 
treatment.
6.2.2
Supplementary Analyses
Efficacy Analysis for the overall study period and full study period in SAF


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Treatment emergent efficacy events occurring in the overall study period (main and extension 
treatment period) and the full study period (main, extension and follow-up period) will be 
analysed similarly as the main efficacy analysis.
Efficacy Analysis in FAS
All efficacy events of the main efficacy variables occuring from randomization until the 
respective periods (main treatment period, overall treatment period and full study period) will 
be considered. Similar statistical methods will be applied as for the main efficacy analyses, 
but the intercurrent event “premature discontinuation of treatment” will be handled following 
the treatment policy strategy.
6.2.3
Other efficacy analyses 
Efficacy Analysis by Component
The main efficacy analysis will be repeated for all single components of the main efficacy 
variable (MI, stroke (ischemic and undetermined type), major amputation of vascular 
etiology, acute limb ischemia, symptomatic VTE, systemic embolism).
Analysis of Death Events
The main efficacy analysis will be repeated for all-cause death and for vascular death (Death 
due to MI, ischemic stroke, pulmonary embolism (PE) and non-CNS systemic embolism 
(SE)).  In addition, frequencies of other reasons (including COVID-19 related) will be 
displayed by the categories as adjudicated by the CIAC. 
Pre-Treatment Efficacy Summary
All efficacy events that started after randomization and before first dose of study intervention 
will be summarized by presenting counts and percentages of subjects by treatment group.
SQCS Analysis
The effect of osocimab on the clotting in the dialysis circuit will be assessed by the SQCS.
Clotting scores will be assigned as follows:

“0” clean filter and no visible clots in the drip chamber/air trap

“1” traces of coagulation in the filter and/or in the drip chamber/air trap

“2” intermediate state between “1” and “3”

“3” fully clotted extracorporeal system resulting in an interruption of the hemodialysis 
session
Adequate anticoagulation is defined by a SQCS of less or equal “1”.
The mean difference of SQCS values during main treatment period and baseline between each 
of the osocimab groups and the placebo group by visit will be displayed together with the 
corresponding 90% (and 95%) confidence intervals applying ANOVA with treatment group 
as factor. This will also be repeated for the overall study period. The distribution of SQCS 
between each of the osocimab groups and the placebo group by visit will be compared using 


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the Wilcoxon Rank sum test. Change in SQCS scores from baseline per visit will be also 
calculated. Baseline will be the median of all pre-treatment values.
Percentage of subjects with adequate anticoagulation (SQCS "0" or "1") by visit will be 
presented.
Additionally, a table will be created showing SQCS categories over time per visit, at pre-
treatment all values will be shown. This will be done for the full study period. Figures will be 
provided.
6.2.4
Subgroup analysis
The time to event analysis for the efficacy variables will be repeated by the following 
subgroups:

Age group 1 (<60 years, 60-75, >75years)

Age group 2 (<50yrs/>=50-<60yrs/>=60-<65yrs/>=65-<70yrs/>=70-<80yrs/>=80yrs) 

Sex (male, female)

Patients with AF (Yes/No)

Patients with diabetes mellitus (Yes/No)

Patients with prior CV events (Stroke, TIA, MI, DVT, PE) (Yes/No)

Patients with prior MACE (Yes/No)

Patients with ASA / non-ASA

History of (symptomatic) COVID-19 (Yes/No)

Symptomatic COVID-19 during the study (Yes/No)
Forest plots showing incidences and hazard ratios will be provided for the comparison of high 
dose osocimab and placebo and for low dose osocimab versus placebo.
6.3
Pharmacokinetics/pharmacodynamics
There might be some inaccuracies in the actual sampling times compared to planned sampling 
times due to the fact, that the study procedures orientate on the dialysis schedule rather than 
specifiying exact days for the study procedures. These deviations can be relevant for the 
interpretation of pharmacokinetic and pharmacodynamic data. Accepted time windows were 
prespecified in the guidance document for PD validity for study #20115 and will be 
referenced in the final blind review report. Accepted time windows for the assessment of 
pharmacokinetic concentrations will be handled analoguously.
All valid results will be included in the listings and graphical displays of individual data, 
which are displayed using actual times. Measurements taken outside the predefined time 
windows will be flagged by the pharmacokinetic and pharmacodynamic experts to be 
excluded from the calculation of summary statistics (with respect to planned times) in order to 
avoid biased results.
For the primary completion analyses all duplicates at the same visit will be excluded for the 
statistical analyses in section 14 by programming algorithm, and they will be listed only in 
section 16.2.


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For the final analyses all PK data and PD data (aPTT, FXIa activity, FXI activity) flagged as 
invalid will not be used for the analyses. Duplicates in other PD data at the same visit will be 
excluded for the statistical analyses in section 14 by programming algorithm, and they will be 
listed only in section 16.2. 
PK variables
Osocimab concentrations will be summarized by visit, separated according to actual dose 
cohort. Descriptive statistics of plasma concentrations [geometric mean and percent 
coefficient of variation (%CV), arithmetic mean and %CV, median and range] will be 
presented by treatment group and time in tabular form. Means at any time will only be 
calculated if at least 2/3 of the individual data were measured and were above the lower limit 
of quantification (LLOQ). For the calculation of the mean value, a data point below LLOQ 
will be substituted by one half of this limit. In tables showing mean values, where values 
below LLOQ are included in the calculation of mean values, these means will be marked. Box 
plots for osocimab trough levels will be provided by treatment. 
For all treatments where at least one subject with at least one confirmed ADA formation is 
included, the individual concentrations of osocimab in plasma will be displayed including 
supplemental information about the ADA titer. Individual subjects with confirmed ADA 
formation will be indicated by different colors and symbols. Filled symbols will indicate 
neutralizing characteristics.
Pharmacokinetic and exposure-response analysis using population approaches (popPK and 
popPK/PD, e.g., by non-linear mixed effect modeling) will be reported under separate cover, 
if applicable.
Bioanalysis and population PK (popPK) evaluation might be started prior to database lock: if 
this is applicable, appropriate measures will be taken to maintain blinding of the study team.
PD variables
All PD analyses will be conducted in the pharmacodynamic analysis set.
The activated partial thromboplastin time (aPTT) and FXIa activity at trough levels after 6 
months will be analyzed as ratio to baseline by providing the mean and median, together with 
the standard deviation and quantiles, respectively.
Results of the additional pharmacodynamics parameters will be displayed utilizing 
appropriate summary statistics and figures. The parameters will be described by the following 
summary statistics: arithmetic mean, standard deviation, median, minimum, and maximum. 
These summary statistics will be presented by actual dose group for the original data as well 
as for the absolute and relative changes from baseline as ratio to baseline. In addition, for each 
subject the maximum and minimum relative change from baseline will be determined and 
presented by appropriate summary statistics and figure.
In addition, a scatter plot of the following pairs of parameters by time point is provided to 
evaluate the correlation, the first parameter on the y-axis and the second parameter on the x-
axis:
Parameter on y-axis
Parameter on x-axis
aPTT
FXIa activity (AXIA assay)


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aPTT
FXI activity (clotting assay)
aPTT
FXI concentration
aPTT
Plasma concentration of osocimab
FXIa activity (AXIA assay)
FXI activity (clotting assay)
FXIa activity (AXIA assay)
FXI concentration
FXIa activity (AXIA assay)
Plasma concentration of osocimab
FXI activity (clotting assay)
FXI concentration
FXI activity (clotting assay)
Plasma concentration of osocimab
FXI concentration
Plasma concentration of osocimab
D-dimer
aPTT
D-dimer
FXIa activity (AXIA assay
D-dimer
FXI activity (clotting assay)
D-dimer
Plasma concentration of osocimab
TAT
aPTT
TAT
FXIa activity (AXIA assay)
TAT
FXI activity (clotting assay)
TAT
FXI concentration
TAT
Plasma concentration of osocimab
F1.2
aPTT
F1.2
FXIa activity (AXIA assay)
F1.2
FXI activity (clotting assay)
F1.2
FXI concentration
F1.2
Plasma concentration of osocimab
These plots will be repeated using a semi-logarithmic scale.
It is important to present the PD tables and figures in the following order:

aPTT, 

FXIa activity (AXIA), 

FXI activity (clotting assay), 

FXI concentration, 

D-dimer, 

TAT, 

F1.2
The scatterplots will be sorted by the parameter on the y-axis.
The exploratory PD marker results may be reported separately.
6.4
Safety
6.4.1
Primary safety variables
The composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) 
events, as assessed by CIAC, and the composite of moderate and severe AEs and SAEs will 


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be the primary safety endpoints in this study. Only events that started after the first dose of 
study treatment and during the main treatment period are considered for the primary analysis.
For the primary safety analysis descriptive time to first primary safety event (both treatment 
emergent AEs and composite of treatment emergent major and CRNMB events [in alignment 
with ISTH guidelines]) analyses will be performed. 
According to the description of the primary estimand, the following events will be considered 
as competing events for the respective safety endpoint:

death 

premature end of exposure to assigned treatment (last administration of assigned 
treatment plus 30 days).
For the primary analysis, the time to event for a subject will be censored at the date of the 
EOMT visit or after no further data collection happened for a subject (e.g. lost to follow-up). 
According to the study protocol (section 7.1.1) one maintenance dose can be missed. If a 
subject misses a maintenance dose, has a so called administration gap, that lasts longer than 
30 days, the subject is not considered at risk for treatment-emergent events during this time
until the next dose. When the subject then takes a maintenance dose again, he/she is at risk 
again. Accordingly there will be additional analyses, where the time not under exposure 
between two doses will be ignored and events during that time will not be counted. The time 
under risk will be calculated by removing time between the interrupted dose + 30 days and the 
next dose and the time more than 30 days after permanent discontinuation to study drug and if 
occurred the 1st event per patient will be counted. For the primary analysis in this data scope, 
the time to event for a subject will be censored at the date of the EOMT visit or after no 
further data collection happened for a subject (e.g. lost to follow-up).
The cumulative incidence function for the event-of-interest as well as the associated 
competing event(s) together with the corresponding confidence interval will be estimated for 
each treatment arm using Aalen-Johansen estimators. 
The competing event for the primary safety endpoint is death and premature discontinuation 
of exposure to assigned treatment.
The cumulative incidence, i.e. the probability of having a specific event E at or before a 
timepoint t, ( ≤, 
 = 1), will be estimated for time-to-event endpoints by Aalen-
Johansen estimators with the competing event.
The difference of the Aalen-Johansen estimators between high dose osocimab and placebo 
and low dose osocimab and placebo will be presented with a 90% confidence interval. 
As the Aalen-Johansen estimator is approximately normal distributed (Aalen, Borgan and 
Gjessing 2008), the difference of Aalen-Johansen estimators is approximately normal 
distributed. Thus, the two-sided 90% confidence interval is obtained via:
(
 () −
()) ± . !"#(
()) + "#(
())   % ,
with 
()/
 () the Aalen-Johansen estimator for treatment TRT/ control 
CON at study day, . the 90% quantile of the standard normal distribution and 
"#(
()) ' "#(
()) the estimated variance of the Aalen-Johansen 


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estimator for osocimab (treatment, TRT) and placebo (control, CON) at study day, estimated 
with the Aalen method.
Rates
Cause-specific incidence rates will be calculated for each treatment arm with an 90% 
confidence interval.
The exposure-adjusted incidence rate will be expressed a “subjects with an event – per 100 
participant years”. For that the following formula is used:
()*+, =
#./0/1'2 3/ℎ ' 565'
∑ /85 9'5. .585' (/' 2)/(100 ∗365.25)
The 90% confidence interval for the exposure-adjusted IR will be computed as
()*+, ∗ @#(0.05; 25)
25
; ()*+, ∗ @#(0.95; 25)
25
 % ,
with @#(C; 25) the q quantile of a chi square distribution with 2e degrees of freedoms and e 
the number of participants with an event. (Nelson 1982)
With respect to the cause-specific hazards for the respective safety variable, each of the 
osocimab groups will be compared to the placebo group using two-sided log-rank tests at a 
type I error rate of α=10%. Due to the explorative nature of these analyses, no multiplicity 
adjustment will be done.
Cause-specific hazard ratios, cause-specific relative hazard reduction (csRHR; csRHR = 100 
× [1 – cause-specific hazard ratio]%), and corresponding 2-sided 90% and 95% confidence 
intervals, comparing the hazards for the event-of-interest in each of the osocimab groups with 
the placebo group will be estimated based on two separate cause-specific Cox proportional 
hazards models. Censoring will be assumed independent of the randomized group assignment.  
To complete the analysis, cause-specific HRs will be estimated for (each of) the competing 
events.
For the analysis of the primary endpoint in this study, the cause-specific hazard function hk(t) 
is the chance that an individual experiences an event of the primary safety outcome in the next 
instant in time, given that the individual has not had such an event or a competing event up to 
time t. For example, for the comparison of the osocimab high dose group with the placebo 
group, the corresponding cause-specific Cox proportional hazards model can be described by 
the following equation:
Hk(t,xi) = h0,k(t) exp(βk xi),
where 
hk(.)
cause-specific hazard function for primary safety outcome, as a function of time and 
subject’s covariates
h0,k(.)
unspecified underlying baseline hazard function for primary safety outcome; hazard 
of an individual with xi = 0
t
time (in days) relative to the date of first administration


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xi
treatment group of subject i
(0 corresponds to “placebo group” and
1 corresponds to “osocimab high dose group”)
βk
unknown parameter (to be estimated); cause-specific hazard ratio = exp(βk)
k 
type of event
Probability
As a supportive analysis, the cumulative incidence functions for the respective event-of-
interest will be compared using the Fine and Grays subdistribution hazards model as well as 
using the Gray’s test.
6.4.2
Supplementary Safety Analysis
The primary safety analyses will be repeated for the overall treatment period for the safety
analysis set. Here, all events which occurred during the main and extension treatment period 
will be taken into account. Therefore, a subject will be censored after a primary safety event 
occurred, or after the date of the EOET visit, or 30 days after study drug discontinuation or 
after no further data collection happened for a subject (e.g. lost to follow-up).
6.4.3
Other safety analyses 
All Bleedings Analysis
The primary safety analyses will be repeated for all bleedings (defined as the composite of 
MB, CRNMB and minor bleedings) and its components for the safety analysis set. 
Bleeding analysis by ISTH category
The descriptive primary safety analysis will be repeated for all major bleedings and their
respective ISTH categorization. 
BARC Bleedings Analysis
The descriptive primary safety analyses will be repeated for bleeding types 1 to 5, including 
any sub types, according to the BARC Bleeding Criteria. These are defined as follows:

Type 0:
o
No bleeding

Type 1:
o
Bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a health-
care professional; may include episodes leading to self-discontinuation of 
medical therapy by the patient without consulting a health-care professional.

Type 2:
o
Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging 


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alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one 
of the following criteria:

requiring nonsurgical, medical intervention by a health-care 
professional,

leading to hospitalization or increased level of care, or

prompting evaluation

Type 3:
o
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
o
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
o
Type 3c:

Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal),

Subcategories confirmed by autopsy or imaging or lumbar puncture,

Intraocular bleed compromising vision.

Type 4:
o
CABG-related bleeding,
o
Perioperative intracranial bleeding within 48 h,
o
Reoperation after closure of sternotomy for the purpose of controlling bleeding
o
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h 
period,
o
Chest tube output more than or equal to 2L within a 24-h period

Type 5:
o
Fatal bleeding
o
Type 5a:

Probable fatal bleeding; no autopsy or imaging confirmation but 
clinically suspicious


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o
Type 5b:

Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation
Bleeding Characteristics Summary
The characteristics of all bleedings will be summarized by presenting counts and percentages 
of events with a certain attribute separated by treatment group. 
Pre-Treatment Safety Summary
All safety events that started after randomization and before first dose of study intervention 
will be summarized by presenting counts and percentages of subjects with efficacy event 
before start of treatment separated by treatment group.
AV Access Bleeding Score Analysis
Severity of bleeding at the dialysis access will be assessed approx. 15 minutes after removal 
of the dialysis needle(s) from the AV access according to the following categories 
(exploratory bleeding score):

“0” no access bleeding

“1” slow oozing

“2” overt bleeding
The mean difference of AV access bleeding score during main treatment period and baseline 
between each of the osocimab groups and the placebo group by visit will be displayed with 
the corresponding 90% (and 95%) confidence intervals applying ANOVA with treatment 
group as factor. The distribution of AV access bleeding score between each of the osocimab 
groups and the placebo group by visit will be compared using the Wilcoxon Rank sum test. 
Change in AV accesss bleeding scores from baseline per visit will be also calculated. Baseline 
will be the median of all pre-treatment values.
Additionally, a table will be created showing AV access bleeding categories over time per 
visit, at pre-treatment all values will be shown. Change from baseline per visit will be 
calculated. This will be done for the full study period. Figures will be provided.
Furthermore, the difference of the proportion of hemodialysis sessions with no AV access 
bleeding during main treatment period and baseline between each of the osocimab groups and 
the placebo group will be summarized with the corresponding 90% (and 95%) confidence 
intervals based on the score method as described by Newcombe (1998).
6.4.4
Subgroup analysis
The time to event analysis for the safety variable (composite of major bleeding (MB) and 
clinically relevant non-major bleeding (CRNMB) events, as assessed by CIAC) will be 
repeated by the following subgroups:

Age group 1 (<60 years, 60-75, >75years)

Age group 2 (<50yrs/>=50-<60yrs/>=60-<65yrs/>=65-<70yrs/>=70-<80yrs/>=80yrs) 

Sex (male, female)


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
Patients with AF (Yes/No)

Patients with diabetes mellitus

Patients with prior CV events (Stroke, TIA, MI, DVT, PE) (Yes/No)

Patients with prior MACE

Patients with ASA / non-ASA

History of (symptomatic) COVID-19 (Yes/No)

Symptomatic COVID-19 during the study (Yes/No)
Forest plots showing incidences and hazard ratios will be provided for the comparison of high 
dose osocimab and placebo and low dose osocimab and placebo, respectively.
6.4.5
Adverse events
The investigator has to record on the respective CRF pages all adverse events (AEs) occurring 
in the period between the signing of the informed consent and the end of the post-treatment 
follow-up period. 
The original terms used by investigators to report AEs via the CRFs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  All reported adverse events during 
the main treatment period will be summarized by means of AE tables based on the treatment-
emergent approach (see section 4.5).
All AE/SAE/AESI tables will also be provided for the following timeframe named “Full 
study TE AEs (SAE/AESI)”: AEs occurred after first intake of study intervention up to 5 
months after last intake.
If an AESI will be reported, this will always be done separated for the two categories listed 
below.
For each AE, the number and percentage of subjects who experienced at least 1 occurrence of 
the given event will be tabulated according to the affected primary system organ class (SOC) 
and preferred term (PT) by treatment arm. A total column will be included in all safety 
summaries.  
Frequency tables, showing an overall summary of number of subjects with AEs, serious 
adverse events (SAEs) and adverse events of special interest (AESIs) separated by the two 
categories will be given, and will include the following information.

if the AE (/ SAE/AESI) occurred with causal relationship to study drug ,

if the AE (/SAE/AESI) occurred with causal relationship to study procedures

reasonable causal relationship to ESRD 

reasonable causal relationship to hemodialysis procedure

maximum intensity for any AE 

maximum intensity for any study-drug related AE,

AE related deaths.

AE resulting in permanent discontinuation of study drug 
The two categories of AESI are:


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
Decrease in platelets below 75 x 109/L or > 50 % decrease in platelet count from 
baseline

Hypersensitivity (i.e. any allergic reactions of ≥CTCAE criteria 2 [Common 
Terminology Criteria for Adverse Events] or anaphylaxis)
A similar table showing overall summary information of AEs (/SAE/AESI) during screening 
will be given. 
Additionally, frequency tables summarizing infection site events will be provided for the 
SAF. 
Injection site event is defined as any AE at the injection site presenting as Injection site 
erythema, Injection site swelling, Injection site pruritus, or Injection site pain that started on 
the day of injection.
In addition, frequency tables will summarize the number of subjects with any event occurring 
during pre-treatment period.
For the full analysis set the event which occurred during the extension treatment period and 
during the post treatment follow-up period will be considered.
6.4.6
Vital signs
Vital signs will be displayed by means of descriptive statistics and change from baseline by 
visit and treatment group.
6.4.7
Laboratory parameter 
Only centrally analyzed blood samples will be considered for analysis.
Central laboratory parameters will be displayed by means of descriptive statistics and change 
from baseline by visit and treatment group. High/low abnormalities by laboratory parameter 
will be presented. This includes various hematology (white blood cell count (WBC), red 
blood cell count (RBC), …), clinical chemistry (aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), …) and urinalysis (color, appearance, specific gravity, …) 
parameters.
All duplicates at the same visit will be excluded from the statistical analyses in section 14 by 
programming algorithm, and they will be listed only in section 16.2.
6.4.8
Hemodialysis data
Hemodialysis data like heparin dose and Kt/V will be displayed by means of descriptive 
statistics and change from baseline by visit.
Furthermore, the difference of the proportion of hemodialysis sessions with adequate 
anticoagulation during main treatment period and baseline between each of the osocimab 
groups and the placebo group will be summarized with the corresponding 90% (and 95%)
confidence intervals based on a proportion test.
Additionally a table will be created showing all heparin values over time per visit, at pre-
treatment all values will be shown. Change from baseline per visit will be calculated. Baseline 
in this case will be the mean of all pre-treatment values. This will be done for the full study 
period. 


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Any changes to the dialysis prescription and compliance will be summarized by visit and 
treatment group.
6.4.9
Pregnancies
Any pregnancy occurring in a study subject (or in partners of study subjects) during the 
subject’s participation in this study will be displayed.
6.5
Data affected by the regional crisis
Data ‘affected’ by the war in the Ukraine will be assessed during the final Blind Review 
Meeting and will be documented in the Blind Review Report. As the war started after the 
primary analysis was completed, it is expected that only data in the post study intervention 
period will be affected, the impact of the war is considered to be minor/not substantial on the 
statistical analysis and on interpretation on the study results.
Any missing or invalid (not confirmed) data due to the war is considered as not related to the 
outcomes of the study i.e. the missingness is likely noninformative. The EMA guidance 
“Points to consider on the impact of the war in Ukraine on methodological aspects of ongoing 
clinical trials” released by the Biostatistics Working Party will be taken into account.
7.
Document history and changes in the planned statistical analysis
7.1
Version 1.0
Version 1.0 of the SAP was finalized on 26 JUL 2020.
7.2
Version 2.0
Version 2.0 of the SAP was finalized on 26 OCT 2021 with the following edits and additions:
Section 2: 

Add the following sentence “Changes in the background therapy etc. will be handled 
following the treatment policy strategy. Other potential intercurrent events are not 
anticipated.”

Change description of the COVID-19 problematic 
Section 6.1.1:

Add categories for demography and baseline characteristics
Section 6.1.3:

Describe the used time windows in more detail. 
Section 6.2.1:

Change “Death due to MI, stroke, pulmonary embolism (PE) and systemic embolism 
(SE)” to “Death due to MI, ischemic stroke, pulmonary embolism (PE) and systemic 
embolism (SE)”

Change “Non-fatal stroke” to “Non-fatal stroke (ischemic stroke or undetermined 
type)”


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Reordering of sections: former Section 6.2.4 is now section 6.2.2 and was renamed to 
Supplementary Analysis. Efficacy Analysis for the overall study period and full study period
in SAF was added. Sensitivity analyses (stratified analyses) were deleted.
Section 6.2.3:

Analyses of SQCS as categories and as scores were clarified.
Section 6.2.4: 

Forestplots are descried in more detail
Section 6.4.1:

The whole analysis is described in more detail regarding the estimand thematic (cause 
specific inciedence rates). Aalen-Johansen will be used instead of Kaplan-Meier. 
Reordering of sections: former Section 6.4.4 is now section 6.4.2 and was renamed to 
Supplementary Analysis. Sensitivity analysis (stratified analyses) were deleted
Section 6.4.3: Full Safety Analyses was added to this chapter and typo was deleted (Use SAF 
instead of FAS). 
Section 6.4.4:

Add name of safety variable

Forestplots are described in more detail.
7.3
Version 3.0
Version 3.0 of the SAP was finalized on 10 JUN 2022 with the following edits and additions:
Section 6.3: Procedure how to deal with the data issue of having duplicates was described in 
detail for the primary completion analysis and for the final analyses. 
Section 6.4.7: Procedure how to deal with the data issue of having duplicates was described in 
detail.
Section 6.5: Section was added relating to the handling of the data affected by the the war in 
Ukraine. Corresponding EMA guideline was added to the reference section.
7.4
Version 4.0
Version 4.0 of the SAP was finalized on 23 JUN 2022 with the following edits and additions:
Section 4.5.1: It is given that laboratory records without a RAVE Datapage ID (corresponding 
record in the electronic case report form is missing) will be excluded from the analysis.


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8.
References
Aalen O, Borgan O, Gjessing H. Survival and Event History Analysis, New York, 
Springer, 2008.
Biostatistics Working Party, EMA/214249/2022; Points to consider on the impact of 
the war in Ukraine on methodological aspects of ongoing clinical trials; 13 
April 2022.
Nelson W. Applied Life Data Analysis. New York: Wiley, 1982.
Newcombe RG. Interval estimation for the difference between independent 
proportions: comparison of eleven methods. Stat Med. 1998; 17:873-90.
9.
Appendix 
9.1
Determination of sample size
Assuming 25% screen failure proportion as based on historic operational experience, 
approximately 800 subjects will be screened to achieve an estimated total of approximately 
600 subjects randomly assigned to study intervention. Of those, 555 subjects are expected to 
complete the main treatment period assuming a true incidence rate of 15 subjects with LTFU 
(lost to follow-up) (including e.g., withdrawal of consent) per 100 patient-years across all 
groups.
As a subject will be evaluated once he was randomized and received at least one dose of study 
intervention, the number of evaluable and randomized subjects can be assumed to be similar.
In case that the observed overall incidence rate of subjects with LTFU after the 400th subjects
significantly higher than expected, the number of randomized participants may be increased 
(max. of 750 subjects) to ensure a sufficient number of subjects completing the main 
treatment period.
As all analyses will be performed in a descriptive manner, no statistically driven sample size 
calculation was performed.
The expected 90% confidence interval for the hazard ratio of the primary safety outcome is 
given by [0.57; 2.28], assuming

a true incidence rate of 10 subjects with a major or clinically relevant non-major 
bleeding event (in alignment with ISTH guidelines) per 100 patient-years in the 
placebo group (see below for definition)

a true hazard ratio of 1.0 (i.e. no change in relative risk) in both osocimab groups as 
compared to placebo

6 months of treatment with a true incidence rate of 15 subjects with LTFU per 100 
patient-years across all groups.
The corresponding expected 90% confidence interval for the hazard ratio of the primary 
efficacy outcome is given by [0.44; 1.53]. while additionally assuming 


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
a true incidence rate of 13 subjects with a main efficacy outcome per 100 patient-years 
in the placebo group. 

a true hazard ratio of 0.75 in both osocimab groups as compared to placebo
9.2
Randomization Methodology
STEP 1:
Taking each of the balancing (stratification) factors contained in Section 3.4 in turn (with 
associated factor weight), and only considering the factor level relevant to the current subject 
being randomized, the following is determined:

Determine the number of subjects currently assigned to each treatment arm: n_A, n_B, 
n_C, n_D.

Obtain the allocation ratios for each treatment arm: r_A, r_B, r_C, r_D.

Calculate the Treatment Imbalance value for each treatment arm (for that factor level):
o
To calculate the Ranges (as below), the IXRS actually calculates each pairwise 
imbalance (the range of each pair of values), and then determines which pair of 
values has the maximum pairwise imbalance – this is exactly equivalent to 
calculating the range over all applicable values.
o
Factor weights are applied as part of the Treatment imbalance calculations (where 
a higher factor weight value implies more ‘weight’ being given to that factor 
relative to other factor(s)).
o
Calculations also account for associated allocation ratios (for a fair comparison) by 
multiplying by all ‘opposite’ allocation ratios (where for A:B:C:D with 2:1:2:1 
ratio, values for Treatments=(A, B, C, D) will be multiplied by (x2, x4, x2, x4) 
respectively):
o
Imbalance_A: Max (
Range[r_B * r_C * r_D * (n_A+1),r_A * r_C * r_D * (n_B)],
Range[r_B * r_C * r_D * (n_A+1), r_A * r_B * r_D * (n_C)],
Range[r_B * r_C * r_D * (n_A+1), r_A * r_B * r_C * (n_D)],
Range[r_A * r_C * r_D * (n_B),
r_A * r_B * r_D * (n_C)],
Range[r_A * r_C * r_D * (n_B),
r_A * r_B * r_C * (n_D)],
Range[r_A * r_B * r_D * (n_C),
r_A * r_B * r_C * (n_D)] ) * <factor weight>
o
Imbalance_B: Max (
Range[r_B * r_C * r_D * (n_A),
r_A * r_C * r_D * (n_B+1)],
Range[r_B * r_C * r_D * (n_A),
r_A * r_B * r_D * (n_C)],
Range[r_B * r_C * r_D * (n_A),
r_A * r_B * r_C * (n_D)],
Range[r_A * r_C * r_D * (n_B+1), r_A * r_B * r_D * (n_C)],
Range[r_A * r_C * r_D * (n_B+1), r_A * r_B * r_C * (n_D)],
Range[r_A * r_B * r_D * (n_C),
r_A * r_B * r_C * (n_D)] ) * <factor weight>
o
Imbalance_C: Max (
Range[r_B * r_C * r_D * (n_A),
r_A * r_C * r_D * (n_B)],
Range[r_B * r_C * r_D * (n_A),
r_A * r_B * r_D * (n_C+1)],
Range[r_B * r_C * r_D * (n_A),
r_A * r_B * r_C * (n_D)],
Range[r_A * r_C * r_D * (n_B),
r_A * r_B * r_D * (n_C+1)],
Range[r_A * r_C * r_D * (n_B),
r_A * r_B * r_C * (n_D)],
Range[r_A * r_B * r_D * (n_C+1), r_A * r_B * r_C * (n_D)] ) * <factor weight>
o
Imbalance_D: Max (
Range[r_B * r_C * r_D  *(n_A),
r_A * r_C * r_D * (n_B)],
Range[r_B * r_C * r_D * (n_A),
r_A * r_B * r_D * (n_C)],
Range[r_B * r_C * r_D * (n_A),
r_A * r_B * r_C * (n_D+1)],
Range[r_A * r_C * r_D * (n_B),
r_A * r_B * r_D * (n_C)],
Range[r_A * r_C * r_D * (n_B),
r_A * r_B * r_C * (n_D+1)],
Range[r_A * r_B * r_D * (n_C),
r_A * r_B * r_C * (n_D+1)]
) * <factor weight>


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STEP 2:
Calculate the Total Imbalance value for each treatment arm by summing the calculated 
Treatment Imbalance values for that treatment arm over each of the factor levels.
STEP 3:
Determine the Minimum Imbalance value across the calculated Total Imbalance values for 
each treatment arm, and which of the treatment arm(s) have this Minimum Imbalance value.
STEP 4:
Based on Table 4.3 (below), assign a Treatment Assignment Probability to each treatment 
arm; the assigned probabilities are determined by the total number of treatment arms sharing 
the Minimum Imbalance value and each treatment Total Imbalance value.
The IXRS performs the Probabilistic Treatment Assignment by utilizing a Random Numbers 
List (generated by Almac – see Section 6) which contains generated random numbers 
between 0 and 1.  For each subject’s randomization, the next available random number from 
the Random Numbers List is allocated to the subject.  Based on the associated random 
number ranges in Table 4.3, the treatment assignment is made by determining the range 
within which the allocated random number for that subject lies.
9.3
Treatment Assignment Probabilities
Section 9.2 (Step 4) above describes how the IwRS allocates a random number to each subject 
to perform the probabilistic treatment assignment by comparing the allocated random number 
with the random number ranges associated with each of the treatment arms.
The IwRS utilizes the following rules when determining the random number ranges to be 
assigned to each treatment arm:

Treatment arms with Minimum Imbalance value are sorted alphabetically

Treatment arms with Total Imbalance value > Minimum Imbalance value are sorted 
by (a) lowest Total Imbalance value, and (b) alphabetically.
The table below outlines the Treatment Assignment Probabilities and the random number 
ranges for each treatment group (based on the defined Treatment Assignment Probabilities) 
that will be utilized for this study.
Treatment Assignment Probabilities and Associated Random Number Ranges
Treatment Assignment Probabilities
[associated random number range to be utilized by the IXRS]
Trt A
Trt B
Trt C
Trt D
Minimum Imbalance: 1 arm
Min. 
Imbala
nce = 
Trt A
Imbalance(Trt 
B) <= 
Imbalance(Trt 
C) <=
Imbalance(Trt 
D)
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.85001-0.88750]
p=0.07500
[0.88751-0.96250]
p=0.03750
[0.96251-0.99999]
Imbalance(Trt 
B) <= 
Imbalance(Trt 
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.85001-0.88750]
p=0.07500
[0.92501-0.99999]
p=0.03750
[0.88751-0.92500]


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D) <
Imbalance(Trt 
C)
Imbalance(Trt 
C) < 
Imbalance(Trt 
B) <=
Imbalance(Trt 
D)
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.92501-0.96250]
p=0.07500
[0.85001-0.92500]
p=0.03750
[0.96251-0.99999]
Imbalance(Trt 
C) <= 
Imbalance(Trt 
D) <
Imbalance(Trt 
B)
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.96251-0.99999]
p=0.07500
[0.85001-0.92500]
p=0.03750
[0.92501-0.96250]
Imbalance(Trt 
D) < 
Imbalance(Trt 
B) <=
Imbalance(Trt 
C)
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.88751-0.92500]
p=0.07500
[0.92501-0.99999]
p=0.03750
[0.85001-0.88750]
Imbalance(Trt 
D) < 
Imbalance(Trt 
C) <
Imbalance(Trt 
B)
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.96251-0.99999]
p=0.07500
[0.88751-0.96250]
p=0.03750
[0.85001-0.88750]
Min. 
Imbala
nce = 
Trt B
Imbalance(Trt 
A) <= 
Imbalance(Trt 
C) <=
Imbalance(Trt 
D)
p=0.06000
[0.85001-0.91000]
p=0.85000
[0.00001-0.85000]
p=0.06000
[0.91001-0.97000]
p=0.03000
[0.97001-0.99999]
Imbalance(Trt 
A) <= 
Imbalance(Trt 
D) <
Imbalance(Trt 
C)
p=0.06000
[0.85001-0.91000]
p=0.85000
[0.00001-0.85000]
p=0.06000
[0.94001-0.99999]
p=0.03000
[0.91001-0.94000]
Imbalance(Trt 
C) < 
Imbalance(Trt 
A) <=
Imbalance(Trt 
D)
p=0.06000
[0.91001-0.97000]
p=0.85000
[0.00001-0.85000]
p=0.06000
[0.85001-0.91000]
p=0.03000
[0.97001-0.99999]
Imbalance(Trt 
C) <= 
Imbalance(Trt 
D) <
Imbalance(Trt 
A)
p=0.06000
[0.94001-0.99999]
p=0.85000
[0.00001-0.85000]
p=0.06000
[0.85001-0.91000]
p=0.03000
[0.91001-0.94000]
Imbalance(Trt 
D) < 
Imbalance(Trt 
A) <=
Imbalance(Trt 
p=0.06000
[0.88001-0.94000]
p=0.85000
[0.00001-0.85000]
p=0.06000
[0.94001-0.99999]
p=0.03000
[0.85001-0.88000]


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C)
Imbalance(Trt 
D) < 
Imbalance(Trt 
C) <
Imbalance(Trt 
A)
p=0.06000
[0.94001-0.99999]
p=0.85000
[0.00001-0.85000]
p=0.06000
[0.88001-0.94000]
p=0.03000
[0.85001-0.88000]
Treatment Assignment Probabilities
[associated random number range to be utilized by the IXRS]
Trt A
Trt B
Trt C
Trt D
Minimum Imbalance: 1 arm (continued)
Min. 
Imbala
nce = 
Trt C
Imbalance(Trt 
A) <= 
Imbalance(Trt 
B) <=
Imbalance(Trt 
D)
p=0.07500
[0.85001-0.92500]
p=0.03750
[0.92501-0.96250]
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.96251-0.99999]
Imbalance(Trt 
A) <= 
Imbalance(Trt 
D) <
Imbalance(Trt 
B)
p=0.07500
[0.85001-0.92500]
p=0.03750
[0.96251-0.99999]
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.92501-0.96250]
Imbalance(Trt 
B) < 
Imbalance(Trt 
A) <=
Imbalance(Trt 
D)
p=0.07500
[0.88751-0.96250]
p=0.03750
[0.85001-0.88750]
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.96251-0.99999]
Imbalance(Trt 
B) <= 
Imbalance(Trt 
D) <
Imbalance(Trt 
A)
p=0.07500
[0.92501-0.99999]
p=0.03750
[0.85001-0.88750]
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.88751-0.92500]
Imbalance(Trt 
D) < 
Imbalance(Trt 
A) <=
Imbalance(Trt 
B)
p=0.07500
[0.88751-0.96250]
p=0.03750
[0.96251-0.99999]
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.85001-0.88750]
Imbalance(Trt 
D) < 
Imbalance(Trt 
B) <
Imbalance(Trt 
A)
p=0.07500
[0.92501-0.99999]
p=0.03750
[0.88751-0.92500]
p=0.85000
[0.00001-0.85000]
p=0.03750
[0.85001-0.88750]
Min. 
Imbala
nce = 
Trt D
Imbalance(Trt 
A) <= 
Imbalance(Trt 
B) <=
Imbalance(Trt 
C)
p=0.06000
[0.85001-0.91000]
p=0.03000
[0.91001-0.94000]
p=0.06000
[0.94001-0.99999]
p=0.85000
[0.00001-0.85000]
Imbalance(Trt 
A) <= 
Imbalance(Trt 
p=0.06000
[0.85001-0.91000]
p=0.03000
[0.97001-0.99999]
p=0.06000
[0.91001-0.97000]
p=0.85000
[0.00001-0.85000]


Statistical Analysis Plan
BAY 1213790 / 20115
Version 4.0
Page: 34 of 36
C) <
Imbalance(Trt 
B)
Imbalance(Trt 
B) < 
Imbalance(Trt 
A) <=
Imbalance(Trt 
C)
p=0.06000
[0.88001-0.94000]
p=0.03000
[0.85001-0.88000]
p=0.06000
[0.94001-0.99999]
p=0.85000
[0.00001-0.85000]
Imbalance(Trt 
B) <= 
Imbalance(Trt 
C) <
Imbalance(Trt 
A)
p=0.06000
[0.94001-0.99999]
p=0.03000
[0.85001-0.88000]
p=0.06000
[0.88001-0.94000]
p=0.85000
[0.00001-0.85000]
Imbalance(Trt 
C) < 
Imbalance(Trt 
A) <=
Imbalance(Trt 
B)
p=0.06000
[0.91001-0.97000]
p=0.03000
[0.97001-0.99999]
p=0.06000
[0.85001-0.91000]
p=0.85000
[0.00001-0.85000]
Imbalance(Trt 
C) < 
Imbalance(Trt 
B) <
Imbalance(Trt 
A)
p=0.06000
[0.94001-0.99999]
p=0.03000
[0.91001-0.94000]
p=0.06000
[0.85001-0.91000]
p=0.85000
[0.00001-0.85000]


Statistical Analysis Plan
BAY 1213790 / 20115
Version 4.0
Page: 35 of 36
Treatment Assignment Probabilities
[associated random number range to be utilized by the IXRS]
Trt A
Trt B
Trt C
Trt D
Minimum Imbalance: 2 arms
Min. 
Imbalan
ce = Trt 
A, Trt B
Imbalance(Trt 
C) <=
Imbalance(Trt 
D)
p=0.56667
[0.00001-
0.56667]
p=0.28333
[0.56668-
0.85000]
p=0.10000
[0.85001-0.95000]
p=0.05000
[0.95000-0.99999]
Imbalance(Trt 
D) <
Imbalance(Trt 
C)
p=0.56667
[0.00001-
0.56667]
p=0.28333
[0.56668-
0.85000]
p=0.10000
[0.90001-0.99999]
p=0.05000
[0.85001-0.90000]
Min. 
Imbalan
ce = Trt 
A, Trt C
Imbalance(Trt 
B) <=
Imbalance(Trt 
D)
p=0.42500
[0.00001-
0.42500]
p=0.07500
[0.85001-
0.92500]
p=0.42500
[0.42501-0.85000]
p=0.07500
[0.92501-0.99999]
Imbalance(Trt 
D) <
Imbalance(Trt 
B)
p=0.42500
[0.00001-
0.42500]
p=0.07500
[0.92501-
0.99999]
p=0.42500
[0.42501-0.85000]
p=0.07500
[0.85001-0.92500]
Min. 
Imbalan
ce = Trt 
A, Trt D
Imbalance(Trt 
B) <=
Imbalance(Trt 
C)
p=0.56667
[0.00001-
0.56667]
p=0.05000
[0.85001-
0.90000]
p=0.10000
[0.90001-0.99999]
p=0.28333
[0.56668-0.85000]
Imbalance(Trt 
C) <
Imbalance(Trt 
B)
p=0.56667
[0.00001-
0.56667]
p=0.05000
[0.95001-
0.99999]
p=0.10000
[0.85001-0.95000]
p=0.28333
[0.56668-0.85000]
Min. 
Imbalan
ce = Trt 
B, Trt C
Imbalance(Trt 
A) <=
Imbalance(Trt 
D)
p=0.10000
[0.85001-
0.95000]
p=0.28333
[0.00001-
0.28333]
p=0.56667
[0.28334-0.85000]
p=0.05000
[0.95000-0.99999]
Imbalance(Trt 
D) <
Imbalance(Trt 
A)
p=0.10000
[0.90001-
0.99999]
p=0.28333
[0.00001-
0.28333]
p=0.56667
[0.28334-0.85000]
p=0.05000
[0.85001-0.90000]
Min. 
Imbalan
ce = Trt 
B, Trt D
Imbalance(Trt 
A) <=
Imbalance(Trt 
C)
p=0.07500
[0.85001-
0.92500]
p=0.42500
[0.00001-
0.42500]
p=0.07500
[0.92501-0.99999]
p=0.42500
[0.42501-0.85000]
Imbalance(Trt 
C) <
Imbalance(Trt 
A)
p=0.07500
[0.92501-
0.99999]
p=0.42500
[0.00001-
0.42500]
p=0.07500
[0.85001-0.92500]
p=0.42500
[0.42501-0.85000]
Min. 
Imbalan
ce = Trt 
C, Trt D
Imbalance(Trt 
A) <=
Imbalance(Trt 
B)
p=0.10000
[0.85001-
0.95000]
p=0.05000
[0.95000-
0.99999]
p=0.56667
[0.00001-0.56667]
p=0.28333
[0.56668-0.85000]
Imbalance(Trt 
B) <
Imbalance(Trt 
A)
p=0.10000
[0.90001-
0.99999]
p=0.05000
[0.85001-
0.90000]
p=0.56667
[0.00001-0.56667]
p=0.28333
[0.56668-0.85000]
Min. Imbalance: 3 arms
Min. Imbalance = 
Trt A, Trt B, Trt C
p=0.34000
[0.00001-
p=0.17000
[0.34001-
p=0.34000
[0.51001-0.85000]
p=0.15000
[0.85001-0.99999]


Statistical Analysis Plan
BAY 1213790 / 20115
Version 4.0
Page: 36 of 36
0.34000]
0.51000]
Min. Imbalance = 
Trt A, Trt B, Trt D
p=0.425000
[0.00001-
0.42500]
p=0.21250
[0.42501-
0.63750]
p=0.15000
[0.85001-0.99999]
p=0.21250
[0.63751-0.85000]
Min. Imbalance = 
Trt A, Trt C, Trt D
p=0.34000
[0.00001-
0.34000]
p=0.15000
[0.85001-
0.99999]
p=0.34000
[0.34001-0.68000]
p=0.17000
[0.68001-0.85000]
Min. Imbalance = 
Trt B, Trt C, Trt D
p=0.15000
[0.85001-
0.99999]
p=0.21250
[0.00001-
0.21250]
p=0.425000
[0.21251-0.63750]
p=0.21250
[0.63751-0.85000]
Min. Imbalance: 4 arms
Min. Imbalance = 
Trt A, Trt B, Trt C, Trt D
p=0.33333
[0.00001-
0.33333]
p=0.16667
[0.33334-
0.50000]
p=0.33333
[0.50001-0.83333]
p=0.16667
[0.83334-0.99999]