Clinical trial NCT04534114
Conditions: End Stage Renal Disease Requiring Hemodialysis
Keywords: End stage renal disease (ESRD) Hemodialysis (HD) Thrombotic Events
Sponsor: Bayer
Start date: 2020-09-04; Completion date: 2022-05-12
Enrollment: 307 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients whose kidneys are no longer able to work as they should and require treatment to filter wastes from the blood (hemodialysis) are at high risk for blood clots that form in blood vessels (thrombosis) blocking blood flow that causes heart attacks, strokes, and other life-threatening conditions. BAY2976217 is under clinical development for prevention of thrombosis. The goal of the study is to learn more about the safety of BAY2976217, how it is tolerated and the way the body absorbs, distributes and gets rid of the study dug given as multiple doses in participants with renal impairment who require hemodialysis.

Detailed description:

Arms: arm 1: Participants received subcutaneous treatment with matching placebo. arm 2: Participants received subcutaneous treatment with 40 mg BAY2976217. arm 3: Participants received subcutaneous treatment with 80 mg BAY2976217. arm 4: Participants received subcutaneous treatment with 120 mg BAY2976217.
Interventions: intervention 1: Fesomersen sodium (BAY2976217) intervention 2: Placebo
Intervention descriptions: intervention 1: Study intervention will be injected subcutaneously. intervention 2: Matching placebo to BAY2976217 will be injected subcutaneously.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal 
Disease Patients on Hemodialysis: A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled Study of the Safety, 
Pharmacokinetics, and Pharmacodynamics of Multiple Doses of 
BAY 2976217 
NCT Number: 
NCT04534114 
Document Date: 
07 JULY 2021 
 


CONFIDENTIAL
Clinical Study Protocol Global Amendment 2
No. BAY 2976217/21170
07 JUL 2021 
Page:  1 of 90
Title Page
Protocol Title: 
Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal Disease Patients on 
Hemodialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the 
Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of BAY 2976217
Protocol Number:
21170
Version Number
3.0
Amendment Number:
Global Amendment 2
Compound Number:
BAY 2976217
Study Phase:
2
Short Title: Ph 2 Safety, PK/PD of multiple doses of BAY 2976217 in ESRD
Acronym: RE-THINC ESRD
Sponsor Name:
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):
EudraCT: 2019-003927-39
IND number: 143093
Protocol Date: 
07 JUL 2021
Medical Monitor name and contact information will be provided separately. 
Name:
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
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.
PPD
PPD


CONFIDENTIAL
Clinical Study Protocol Global Amendment 2
No. BAY 2976217/21170
07 JUL 2021
Page:  2 of 90
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
07 JUL 2021
Amendment 1
29 SEP 2020
Original Protocol
09 MAR 2020
Amendment 2
This amendment is considered to be substantial, based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
Overall Rationale for the Amendment:
The rationale of this amendment is to implement the possibility of local laboratory safety 
assessments in case centrally provided laboratory kits are not available due to COVID-19-
related logistical reasons.
Further it is to update the requirements for discontinuation of study intervention and the rules 
for prohibited medications intake. Minor corrections and clarifications were also added.
Key changes
Section # 
and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 3 Objectives and 
Endpoints
Section 4.4. End of study 
definition
Wording of the secondary safety 
endpoint was moved down 
together with a secondary 
objective. 
Clarification for the analysis of the primary 
efficacy and safety outcomes. Wording was 
also updated to reflect changes that were 
carried out in a previous amendment on the 
analysis of TEAEs. Time windows for the 
analyses were also clarified, and end of study 
definition was updated to reflect the changes 
in the primary endpoints.
Section 1.3 Schedule of 
Activities (SoA)
Sentence requiring the 
procedures to be performed in 
the order they are indicated in the 
SoA was removed.
This previous requirement was removed to 
ease the study conduct at the sites.
Section 1.3 Schedule of 
Activities (SoA)
Measurement of Pre- & Post-HD 
weight, post-HD blood pressure, 
urea reduction ratio and Kt/V 
have been added to Visits FU2 
and FU3, URR or Kt/V also to V8
and FU1
Addition of missing components of the renal
replacement therapy procedure, and needed 
to assess successful dialysis procedure.
Section 3 Objectives and 
Endpoints
Section 9.4.6.1. 
Exploratory efficacy 
endpoints
Exploratory endpoints have been 
updated as follows to include 
VTE into the composite endpoint
Based on expert opinion, the exploratory 
efficacy outcomes death due to MI, stroke, 
PE and SE, non-fatal stroke, non-fatal MI, 
major amputation of vascular etiology, and 
acute limb ischemia needs to be merged with 
the exploratory efficacy outcome VTE 
because of similar clinical importance.
Section 5.4 Screen failures
Section 5.4 has been changed to 
allow rescreening once, with no 
conditions. 
The population under study has many 
comorbidities and may present transient 
laboratory abnormalities due to hemodialysis. 
Since screening period is short, by allowing 
rescreening, the investigator may choose to 
include a patient after clinical improvement or 
lab normalization.


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Section # 
and Name
Description of Change
Brief Rationale
Section 6.5 Concomitant 
Therapy
Section 7.1.1. Events 
Requiring Definitive 
Discontinuation of Study 
Intervention
Section 7.1.2 Temporary 
discontinuation
If a prohibited concomitant 
medication is indicated, study 
intervention will be temporarily 
interrupted. Study intervention is 
permanently discontinued only in 
cases where the study 
intervention is interrupted for >56 
days.
Participants make use of prohibited 
medication for a limited period to treat a 
specific condition. Once this has been 
resolved and the participant is no longer 
using the concomitant medication, the study 
intervention may be restarted. 
Section 7.1.1 Events 
Requiring Definitive 
Discontinuation of Study 
Intervention
Section 8.2.1.3 
Recommendations for 
Surgeries Including Kidney 
Transplant
If participant discontinues during 
the main treatment period, the 
participant should conduct Visit 
22 and then proceed to the 
follow-up period. 
If participant discontinues during 
the extended treatment period, 
the participant should conduct 
Visit 28, and then proceed to the 
follow-up period.
This change aims to minimize participant 
burden and, at the same time, secure 
participant safety and data acquisition as they 
will be followed for 20 weeks after the last 
dose. Full PK and PD sampling during follow 
up is important with view on interpretation of 
the data.
Section 8.2 Safety 
assessments
If the platelet value or liver 
enzyme tests are uninterpretable 
(e.g., due to clumping, hemolysis 
or quantity not sufficient) or 
missing, a local or central 
laboratory repeat blood specimen 
must may be re-drawn as soon 
as possible (ideally at the next 
dialysis session, however, within 
no more than 7 days).
Patients are being seen 3 times a week, 
therefore one week has been perceived as 
too long.
Section 8.2.1.4: AV access 
bleeding
AV access bleeding assessment 
may be done prior to 15 minutes 
if the bleeding has already 
stopped. 
Participant and site burden will be reduced 
without compromising the safety of the 
participant. 
Section 9.4. statistical 
analyses
The investigator, study staff, 
participants, blinded monitors, 
and members of the Sponsor's 
clinical operations team and data 
management team and CIAC will 
remain blinded throughout until 
the end of the study.
Due to the planned snapshot, Sponsor's 
clinical team will need to be unblinded.
Section 9.4.1.1 Planned 
Methods of Analysis
All analyses and tabulations will 
be performed using SAS@ 
Version 9.2 or higher or if 
applicable, other software
In case of a software update, also other 
softwares apart from SAS Version 9.2 or 
higher may be used for the analyses.
Section 9.4.1.5 Definition 
of Baseline
The section was rewritten to 
reflect the change in definition of 
baseline. Reference to SAP for 
further details was added. 
Baseline measurements are done at one 
timepoint only, and mean value will no longer 
be calculated
Section 9.4.1.6 On 
Treatment
Text was reorganized for better 
readability, and to not limit “on-
treatment“ to the main treatment 
period.
Text was reorganized for better readability, 
and to not limit "on-treatment“ to the main 
treatment period.
Section 10.2 Appendix 2: 
Clinical Laboratory tests
Local laboratory results are 
allowed if due to logistical 
reasons central laboratory kits 
are not available, or in the event 
that the central laboratory results 
are not available in time for either 
study intervention administration 
and/or response evaluation.
To enable the use of local laboratory for 
safety assessments, in case of shortage of 
central laboratory kits due to the COVID-19 
pandemic.


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Section # 
and Name
Description of Change
Brief Rationale
Section 10.3.2 Definition of 
SAE
Text in section f (other situations) 
was updated 
Text was updated to reflect the changes 
implemented in protocol template update.
Clarifications to the protocol
Section # 
and Name
Description of Change
Section 1.3 Schedule of Activities 
(SoA)
Informed consent form must be signed on V1 day, other assessments may 
be done at a later date.
Sentence “Post-HD weight is to be measured after hemodialysis” was 
removed as unnecessary.
Section 2.3.2 Benefit assessment
Text was revised for better readability.
Section 3 Objectives and 
Endpoints
Link to estimand components for primary endpoint was removed as 
unnecessary in this section.
Section 4.1 Overall design
1)Clarification that ASA is not the only allowed antiplatelet therapy, but is 
only allowed, at doses below 150mg/day.
2)The primary analysis will be performed to expedite management  review 
and Phase 3 dose selection.
“Management review” was removed as it is part of the Phase 3 dose 
selection process.
Section 6.5 Concomitant Therapy 
UFH or LMWH are also allowed to maintain patency of hemodialysis 
access
Section 7.1
Added a reference to section 7.1.1 to clarify the time participant will stay in 
the study in case the study intervention is withdrawn.
Section 7.1.1 Events Requiring 
Definitive Discontinuation of Study 
Intervention
The following paragraph was removed, as it does not belog to this section: 
If consent is withdrawn, or the participant signs-off dialysis without 
expected return of life-sustaining kidney function or without transferring to 
an alternative form of renal-replacement therapy, the Early Termination 
Visit will be conducted immediately (Section 7.2). See the SoA (Section 
1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.      
Section 7.3 Lost to Follow Up
The survival status will be recorded in the eCRF, if no survival status is 
known, the contact attempt will be recorded.
Section 8.1 Efficacy assessments
Section 8.3.6. Cardiovascular and 
Death Events
Clarification on how the adjudication process is triggered was added, as 
well as the location of further information on the adjudication process.
Section 8.2. Safety Assessments
Clinically significant changes in platelet count, ALT/AST are to be reported 
both as laboratory parameters as well as adverse events. 
Repeat samples for uninterpretable liver enzyme and platelet values 
samples may be done  locally or centrally, and should be done as soon as 
possible. Specific time limit has been removed.  
Section 8.2.1 Bleeding events
1) first paragraph: Clarification of text: bleeding event is an outcome, not 
an analysis, which is described in Section 9. 
2)Third paragraph: no central laboratory samples are needed in case of 
bleeding events
Section 8.2.1 Bleeding events
Bleeding events are not adjudicated by the investigator, and the section 
has been revised accordingly.
Section 8.2.1.2: remedial 
treatment for bleeding 
Clarification that remedial treatment for bleeding events is not considered 
rescue medication
Section 8.2.1.3: recommendations 
after surgeries 
Modifications were made to to reflect the changes made in amendment 2 
to the discontinuation and concomitant medication sections.
Section 8.2.1.4 AV access 
bleeding
A clarification was made that the AV access bleeding is assessed, at the 
end of the dialysis session. 
Section 8.2.5 Clinical Safety 
Laboratory Assessments
Duplicated information on safety laboratory samples for ALT/AST was 
deleted, as this information is already available in Section 8.2
Section 8.3.10 Adjudication 
Adjudication of an adverse event will only be carried out after 
randomization.


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Section # 
and Name
Description of Change
Section 9.4.2 Primary Endpoints
1)Text was reorganized for better readability and correctness
2)Treatment policy strategy was removed from the protocol as the time 
windows are described later in this Section.
3)Description of primary and secondary safety analyses was further 
clarified, including time windows for the analyses.
Section 9.4.3 Secondary
endpoints
Text was reorganized for better readability and consistency.
Section 9.4.6 Tertiary/exploratory 
endpoints
Text clarifying that further details on exploratory endpoints are described 
in the SAP was added.
Corrections of inconsistencies and minor corrections (editorial corrections not detailed):
Section # 
and Name
Description of Change
Section 1.1 Synopsis
A sentence was deleted that was not needed.
Section 1.3 Schedule of Activities 
(SoA)
Erroneous plus sign at visit window for V1 was corrected to a minus 
sign
Section 1.3 Schedule of Activities 
(SoA)
Erroneous ** at Screening (1 Week) was removed
Section 8.6.1 Secondary 
pharmacodynamic parameters
Section 8.6.2 Other 
pharmacodynamic parameters
Secondary and Other pharmacodynamic parameters were aligned with 
protocol section 3. 
Section 9.4.1.3 Inter-current event
Section 9.4.2 Primary endpoints
Unblinding to study intervention: the study will allow unblinding of the 
treatment assignment if the investigator deemed it necessary after
related to a bleeding event or AE   
Section 9.4.2 Primary endpoints
Intercurrent events were separated to different bullet points.
The order of primary safety endpoints was changed to reflect the 
improtance of each endpoint, with the most important now on top.
Throughout
The term combination of MB and CRNMB Bleeding has been changed 
to composite of MB and CRNMB Bleeding
Throughout
As vital signs comprise only post HD BP measurements, the term “vital 
signs“ has been replaced by post HD BP where appplicable.
Throughout
Observation period was deleted as observation period has been 
removed from the study in previous amendment.
Administrative changes
Section # 
and Name
Description of Change
Title page
Protocol version number was removed from the header and placed on the protocol title page
Throughout
Protocol version number was deleted from the header, and protocol date as added.


CONFIDENTIAL
Clinical Study Protocol Global Amendment 2
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Page:  6 of 90
Table of Contents
Title Page................................................................................................................................... 1
Protocol Amendment Summary of Changes Table............................................................... 2
Table of Contents ..................................................................................................................... 6
Table of Tables ......................................................................................................................... 9
Table of Figures........................................................................................................................ 9
1.
Protocol Summary .......................................................................................................... 10
1.1
Synopsis......................................................................................................................... 10
1.2
Schema........................................................................................................................... 15
1.3
Schedule of Activities (SoA) ......................................................................................... 16
2.
Introduction..................................................................................................................... 20
2.1
Study Rationale.............................................................................................................. 20
2.2
Background.................................................................................................................... 20
2.2.1
Unmet Need for Reducing Cardiovascular Morbidity and Mortality in ESRD ......... 20
2.2.2
Factor XI..................................................................................................................... 21
2.2.3
BAY 2976217............................................................................................................. 21
2.2.3.1
Preclinical Data with BAY 2306001 (ISIS 416858) and BAY 2976217 (ION 
957943).................................................................................................................... 22
2.2.3.2
Clinical Data with BAY 2306001........................................................................... 23
2.2.3.3
Clinical Data with BAY 2976217 (ION 957943) ................................................... 24
2.3
Benefit/Risk Assessment ............................................................................................... 24
2.3.1
Risk Assessment......................................................................................................... 26
2.3.2
Benefit Assessment .................................................................................................... 27
2.3.3
Overall Benefit: Risk Conclusion............................................................................... 27
3.
Objectives and Endpoints............................................................................................... 27
4.
Study Design .................................................................................................................... 29
4.1
Overall Design ............................................................................................................... 29
4.2
Scientific Rationale for Study Design ........................................................................... 30
4.3
Justification for Dose..................................................................................................... 31
4.4
End of Study Definition................................................................................................. 32
5.
Study Population............................................................................................................. 32
5.1
Inclusion Criteria ........................................................................................................... 32
5.2
Exclusion Criteria .......................................................................................................... 33
5.3
Lifestyle Considerations ................................................................................................ 34
5.4
Screen Failures............................................................................................................... 34
6.
Study Intervention .......................................................................................................... 35
6.1
Study Intervention(s) Administered............................................................................... 35
6.2
Preparation/Handling/Storage/Accountability............................................................... 36
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 36
6.4
Study Intervention Compliance ..................................................................................... 37
6.5
Concomitant Therapy .................................................................................................... 37
6.6
Dose Modification ......................................................................................................... 38
6.7
Intervention after the End of the Study.......................................................................... 38


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 38
7.1
Discontinuation of Study intervention........................................................................... 38
7.1.1
Events Requiring Definitive Discontinuation of Study Intervention ......................... 39
7.1.2
Temporary Discontinuation........................................................................................ 39
7.1.3
Rechallenge ................................................................................................................ 40
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 40
7.3
Lost to Follow Up.......................................................................................................... 40
8.
Study Assessments and Procedures............................................................................... 41
8.1
Efficacy Assessments .................................................................................................... 41
8.2
Safety Assessments........................................................................................................ 42
8.2.1
Bleeding events .......................................................................................................... 43
8.2.1.1
Stopping Rules for Bleeding Events ....................................................................... 44
8.2.1.2
Remedial Treatment for Bleeding........................................................................... 44
8.2.1.3
Recommendations for Surgeries Including Kidney Transplant.............................. 45
8.2.1.4
AV access bleeding................................................................................................. 47
8.2.2
Physical Examinations................................................................................................ 47
8.2.3
Vital Signs .................................................................................................................. 47
8.2.4
Electrocardiograms..................................................................................................... 48
8.2.5
Clinical Safety Laboratory Assessments .................................................................... 48
8.2.6
Dialysis information ................................................................................................... 48
8.2.6.1
Renal Replacement Therapy Baseline Information ................................................ 48
8.2.6.2
Dialysis Prescription Changes................................................................................. 49
8.2.7
Medical History.......................................................................................................... 49
8.3
Adverse Events and Serious Adverse Events ................................................................ 49
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 49
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 50
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 50
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 50
8.3.5
Pregnancy ................................................................................................................... 51
8.3.6
Cardiovascular and Death Events............................................................................... 51
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs....................................................................................................................... 52
8.3.8
Adverse Events of Special Interest............................................................................. 52
8.3.8.1
Thrombocytopenia .................................................................................................. 52
8.3.8.2
Elevation of Hepatic Enzymes ................................................................................ 54
8.3.9
Injection-related events............................................................................................... 55
8.3.10
AEs requiring submission of an adjudication package to the CIAC.......................... 55
8.4
Treatment of Overdose .................................................................................................. 55
8.5
Pharmacokinetics........................................................................................................... 56
8.5.1
Sampling time for PK, PD and immunogenicity........................................................ 57
8.5.1.1
PK, PD and immunogenicity sampling (all participants)........................................ 58
8.5.1.2
PK, PD and immunogenicity sampling, participants from the alternative PK&PD 
sampling group starting on a non-dialysis day........................................................ 58
8.6
Pharmacodynamics ........................................................................................................ 59
8.6.1
Secondary pharmacodynamic parameters:................................................................. 59
8.6.2
Other Pharmacodynamic parameters:......................................................................... 59
8.7
Genetics ......................................................................................................................... 60


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8.8
Biomarkers..................................................................................................................... 60
8.9
Immunogenicity Assessments........................................................................................ 61
8.10
Health Economics.......................................................................................................... 61
9.
Statistical Considerations ............................................................................................... 62
9.1
Statistical Hypotheses.................................................................................................... 62
9.2
Sample Size Determination ........................................................................................... 62
9.3
Populations for Analyses ............................................................................................... 63
9.4
Statistical Analyses........................................................................................................ 63
9.4.1
General considerations ............................................................................................... 64
9.4.1.1
Planned Methods of Analysis.................................................................................. 64
9.4.1.2
Incomplete or Missing Data.................................................................................... 64
9.4.1.3
Inter-current event................................................................................................... 64
9.4.1.4
Demographic and Baseline characteristics.............................................................. 64
9.4.1.5
Definition of Baseline ............................................................................................. 65
9.4.1.6
On treatment............................................................................................................ 65
9.4.2
Primary endpoint(s).................................................................................................... 65
9.4.3
Secondary endpoints................................................................................................... 66
9.4.4
Pharmacokinetic endpoints......................................................................................... 67
9.4.5
Pharmacodynamic endpoints...................................................................................... 67
9.4.6
Tertiary/exploratory endpoints ................................................................................... 67
9.4.6.1
Exploratory efficacy endpoints ............................................................................... 67
9.4.6.2
Other pre-specified safety endpoints....................................................................... 67
9.4.6.3
Pre-specified PD endpoints..................................................................................... 68
9.4.7
Other analyses ............................................................................................................ 68
9.5
Interim Analyses............................................................................................................ 68
9.6
Data Monitoring Committee (DMC) ............................................................................. 68
10. Supporting Documentation and Operational Considerations .................................... 69
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 69
10.1.1
Regulatory and Ethical Considerations ...................................................................... 69
10.1.2
Financial Disclosure ................................................................................................... 69
10.1.3
Informed Consent Process.......................................................................................... 69
10.1.4
Data Protection ........................................................................................................... 70
10.1.5
Committees Structure ................................................................................................. 70
10.1.6
Dissemination of Clinical Study Data ........................................................................ 71
10.1.7
Data Quality Assurance.............................................................................................. 71
10.1.8
Source Documents...................................................................................................... 72
10.1.9
Study and Site Start and Closure................................................................................ 72
10.1.10 Publication Policy....................................................................................................... 72
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 73
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 74
10.3.1
Definition of AE......................................................................................................... 74
10.3.2
Definition of SAE....................................................................................................... 75
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 76
10.3.4
Reporting of SAEs...................................................................................................... 78
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 79
10.5
Appendix 5: Country-specific Requirements ................................................................ 81
10.6
Appendix 6: Protocol Amendment History ................................................................... 81


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10.6.1
Amendment 1: (29 SEP 2020).................................................................................... 81
10.7
Appendix 7: Abbreviations............................................................................................ 85
11. References ........................................................................................................................ 87
Table of Tables
Table 1–1: Schedule of Activities, Visit V1 to Visit V13........................................................ 16
Table 1–2: Schedule of activities, Visit V14 to visit V22........................................................ 18
Table 1–3: Schedule of Activities, extended treatment visits and Visit FU1 to FU4 .............. 19
Table 2–1: Risk Assessment for the study Intervention BAY 2976217 .................................. 26
Table 3–1: Objectives and Endpoints....................................................................................... 27
Table 6–1: Study interventions administered........................................................................... 35
Table 8–1: Overview PK/PD and immunogenicity, sampling................................................. 57
Table 9–1: Confidence Interval for proportion of participants with composite of MB and 
CRNMB Bleeding................................................................................................. 62
Table 10–1: Protocol-Required Safety and Routine Laboratory Assessments ........................ 73
Table of Figures
Figure 1–1: Study design.......................................................................................................... 11


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1.
Protocol Summary
1.1
Synopsis
Study 21170 is a Phase 2 trial designed to evaluate the safety, pharmacokinetics and 
pharmacodynamics of BAY 2976217 in a population of patients with ESRD on HD treatment.
The investigational agent, BAY 2976217 is a ligand conjugated antisense oligonucleotide 
(LICA) targeting coagulation factor XI synthesis. BAY 2976217 is ligand-conjugated to 
GalNAc
 
It is designed to inhibit synthesis of FXI in the liver with 
low circulating blood levels of the drug and the potential for reduced systemic effects.
The participant population for this trial, ESRD patients on HD, are at high risk for both 
arterial and venous thrombosis and thromboembolism. However, treatment with
antithrombotics in order to reduce the thrombosis risk has been complicated by increased risk 
of bleeding in this participant population. The study intervention BAY 2976217 is expected to
reduce thrombotic events with minimal bleeding complications, a profile which may be ideal 
in this participant population. The action and tolerability of BAY 2976217 is supported by 
pre-clinical studies and Phase 1 human trials. The effects of targeting FXI have been 
evaluated with the unconjugated FXI ASO (BAY 2306001), that shares the same nucleotide 
sequence with BAY 2976217 and has an identical mechanism of action, in ESRD patients on 
HD in two Phase 2 placebo-controlled studies that enrolled 256 participants. Dose-dependent 
decreases in circulating FXI antigen and FXI activity were observed, there was no increase in 
clinically significant bleeding over placebo, and clotting of the dialysis circuit was reduced in 
a dose-dependent manner.
Study 21170 is a parallel group treatment study design with 3 dose cohorts that is participant 
and investigator blinded to assignment to active treatment versus placebo, in ESRD patients 
who are on HD ≥ 3 months, and are receiving hemodialysis for a minimum of 9 hours per 
week. Participants receiving therapeutic anticoagulation or antiplatelet other than 
ASA ≤150 mg/day are excluded. Approximately 288 randomized participants (to achieve an 
estimated 240 evaluable participants) with ESRD on HD are randomly assigned in a 3:1 
fashion to receive SC treatment with one of 3 dose levels of BAY 2976217 or matching 
placebo. Following a 1-week screening, participants will be treated for 24 weeks, with the 
final 4 weeks of the main treatment period as an evaluation period for certain PD and safety 
parameters. To collect additional long-term safety information, participants will continue to 
be treated as randomized in the extended treatment period, with up to 24 weeks of additional 
treatment with study intervention. Once the overall treatment period is complete, participants 
will have a 16-week post-treatment follow-up period.  
As this is a Phase 2 safety trial, the primary endpoint is the incidence of major bleeding and 
clinically relevant non-major bleeding as assessed by a CIAC. Additional study endpoints 
include the incidence and frequency of TEAEs, AESIs, changes in vital signs and laboratory 
findings, trough levels of BAY 2976217, maximum change in FXI activity levels during the 
main treatment period and coagulation parameters and clotting in the dialysis filters and 
circuit.
CCI


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The study is graphically illustrated in Figure 1–1.
Figure 1–1: Study design
Protocol Title: Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal Disease 
Patients on Hemodialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of BAY 2976217
Short Title: Ph 2 Safety, PK/PD of multiple doses of BAY 2976217 in ESRD
Rationale:
Patients with ESRD on hemodialysis are at a high risk for arterial and venous 
thromboembolic complications. However, because of the documented high risk for bleeding, 
no antithrombotic regimen has ever been evaluated in this group in a large clinical trial
setting. 
Patients with congenital deficiency of FXI and agents used to inhibit or decrease production 
of FXI have shown promise in reducing thrombotic events without increasing clinically 
significant bleeding, making it an attractive candidate for use in the ESRD patient on HD. An 
unconjugated FXI ASO (BAY 2306001) was studied in clinical trials. Pre-operative reduction 
of the synthesis of FXI levels by the unconjugated FXI ASO in patients who had elective 
primary unilateral total knee arthroplasty was highly effective for prevention of venous 
thrombosis and was not associated with increased peri-operative or subsequent bleeding. Two 
Phase 2 studies were conducted in ESRD patients, that showed that the reduction of the 
synthesis of FXI levels by the ASO was associated with less clotting of the dialysis circuit 
without an increase in bleeding risk.  
However, the unconjugated FXI ASO requires higher doses with relatively high injection 
volumes, and a long loading phase to achieve adequate liver delivery to reduce FXI levels, 
and was associated with certain adverse events such as thrombocytopenia and injection site 
reactions. Therefore, the GalNAc-conjugated FXI ASO BAY 2976217 was developed  
Animal studies as well as a Phase 1 human trial of BAY 2976217 have confirmed significant 
dose-dependent reduction in FXI activity with lower doses of the drug, and no evidence of 
injection site reactions or platelet effects. 
rogression to a Phase 2 trial in ESRD patients on HD is reasonable as 
there is a high unmet medical need to reduce thrombotic events without increasing bleeding in 
this population. As there is currently no accepted alternative therapy proven to reduce 
thrombotic events in this population, the use of low-dose ASA is recommended and widely 
accepted (1).
C
CI
CCI


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Objectives and Endpoints:
Objectives
Estimands/Endpoints
Primary

To evaluate the safety of 
BAY 2976217as compared to 
placebo
Primary Endpoint

The incidence of composite of major bleeding 
and clinically-relevant non-major bleeding during 
the main treatment period and within the on-
treatment time window, as assessed by blinded 
CIAC
Secondary

To evaluate the safety of BAY 
2976217as compared to 
placebo

The incidence of composite of major bleeding 
and clinically-relevant non-major bleeding during 
the main and extended treatment periods and 
within the on-treatment time window, as 
assessed by blinded CIAC

Incidence and severity of TEAEs during
o
the main treatment period and within the 
on-treatment time window
o
the main and extended treatment 
periods and within the on-treatment time 
window
o
the main and extended treatment 
periods and until 20 weeks after the last 
study intervention dose

To evaluate the PK and PD of 
BAY 2976217
Pharmacokinetic Endpoints

Trough concentrations for 3 dose levels of 
BAY 2976217
Pharmacodynamic Endpoints

Maximum change in FXI antigen levels during 
the main treatment period

Maximum change in FXI activity levels during 
the main treatment period
Overall Design
This is a multicenter, double-blind, randomized, parallel group treatment study with 3 dose
cohorts tested against placebo, in ESRD patients who are on HD (including hemodiafiltration) 
≥ 3 months, and are receiving hemodialysis for a minimum of 9 hours per week. Participants 
receiving therapeutic anticoagulation or antiplatelet other than ASA ≤ 150 mg/day are 
excluded. Approximately 288 participants will be randomized in this study. Participants will 
be stratified at randomization for use of ASA (yes/no) and CV risk factors (stratum 1 / stratum 
2), and will then be randomized to 1 of 3 dose cohorts in a 1:1:1 ratio (Cohort A [40 mg], 
Cohort B [80 mg], and Cohort C [120 mg]). Within each cohort participants will be 
randomized to receive either BAY 2976217 or matching placebo (administered at equivalent 
dose volumes) in a 3:1 ratio. Sponsor, participants and investigators are blinded with respect 
to active treatment versus matching placebo, but not blinded to dose cohort. With an assumed 
attrition rate of approximately 15% during the main treatment period, approximately 288
randomized participants would allow for an estimated 240 participants. All standard of care 


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hemodialysis therapies as prescribed by their providers, including use of heparins to maintain 
dialysis circuit patency, will be continued.  
Use of ASA will remain at the discretion of the investigator. However, all efforts should be 
made during the treatment period to avoid change in ASA use or dose, unless clinically 
indicated. Additionally, participants will be stratified based on the presence of selected CV 
risk factors. The investigator will evaluate the presence or absence of the following at the time 
of randomization:
(i)
age >65 years, 
(ii)
history of DM type I or II,
(iii)
history of MI, 
(iv)
history of stroke or TIA, 
(v)
history of CHF, 
(vi)
history of PAD,
(vii)
history of Afib
Stratum 1- zero or one risk factor, except the presence of DM or Afib; 
Stratum 2- either DM or Afib alone, or two or more risk factors.
All cohorts will consist of up to 1-week screening period and a 24-week main treatment 
period, the last 4 weeks of which are an evaluation period, an up to 24-week extended 
treatment period, followed by a 16-week post-treatment follow-up period.
The data and outcomes collected in the study will be analyzed by 4 groups: Pooled placebo 
group (from Cohorts A, B and C), 40 mg dose group (BAY 2976217 from Cohort A), 80 mg 
dose group (BAY 2976217 from Cohort B), and 120 mg dose group (BAY 2976217 from 
Cohort C). All suspected bleeding, cardiovascular and thrombosis events will be assessed by 
CIAC blinded to treatment allocation. An independent DMC will monitor the participant’s 
safety and give recommendations to the Steering Committee (see below).
Selected clinical sites will participate in the alternative PK&PD Sampling group. A target 
population of approximately 24-40 participants distributed among the three cohorts is sought 
for this group. Whereas all other participants will receive their first dose of study intervention
on a dialysis day, participants in the alternative PK&PD Sampling group will receive their 
first dose of study intervention on a non-dialysis day, preceding a scheduled dialysis day.
Intervention Model: Parallel
Primary Purpose: Treatment
Number of Arms: 3 Dose cohorts
Blinding: Participant, Investigator, Outcomes Assessor
Number of Participants: Approximately 288 randomized
Assuming 15% screen failure rate, approximately 340 participants will be screened to achieve 
an estimated total of 288 randomized participants, 96 per each cohort group and an estimated
80 participants per cohort after an assumed attrition rate of approximately 15%. Additional 
participants may be enrolled based on recommendations from the Steering Committee and/or 
DMC (e.g.- based on actual retention of participants, or other scientific or safety reasons).


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Intervention Groups and Duration:
Within each dose cohort, participants will be randomized in a 3:1 ratio to receive SC 
treatment with either BAY 2976217 or placebo. All standard of care hemodialysis therapies as 
prescribed by their providers, including use of heparins to maintain dialysis circuit patency,
will be continued.

Cohort A: 40 mg BAY 2976217 or placebo SC (3:1) n~96

Cohort B: 80 mg BAY 2976217 or placebo SC (3:1) n~96

Cohort C: 120 mg BAY 2976217 or placebo SC (3:1) n~96
Study intervention will be administered once every 4 weeks as described in the SoA, unless 
there is a need for dose interruption (Section 7.1). All cohorts will consist of 1-week screening 
period and a 24-week main treatment period, the last 4 weeks of which are an evaluation 
period for certain PD and safety parameters. To collect additional long-term safety 
information, participants will continue to be treated as randomized in the extended treatment 
period, with up to 24 weeks of additional treatment with study intervention. A participant is 
considered to be on treatment until 4 weeks after their last dose, whether they discontinue 
treatment early, complete only the main treatment period, or complete part or all the extended 
treatment period. Once the overall treatment period is completed, participants will have a 16-
week post-treatment follow-up period, for a total of up to 65 weeks of participation.
All participants who are in the extended treatment period will need to stop treatment when the 
last participant enrolled into the study has completed the 24-week main treatment period 
(Visit 22). Participants in the extended treatment period will complete Visit 28 four weeks 
after their last dose, and move to the 16-week post-treatment follow-up period. The sponsor 
reserves the discretion to halt further dosing in the extended treatment period earlier in 
anticipation of the last participant completing the main treatment period.
Data Monitoring Committee:
Yes
An independent DMC will monitor the participant’s safety and give recommendations to the 
Steering Committee.
The DMC will review unblinded data from the study on regular basis, as outlined in the DMC 
Charter. At any time, if there is an unexpected safety finding(s) in cohort C (the 120 mg dose 
cohort), the DMC may elect to modify the cohort to either a 100 mg dose level or 80 mg dose 
level. If recommended by the DMC, the change will be implemented by administrative letter 
and will not require a protocol amendment. All ongoing participants in cohort C will have 
their dosing modified to 100 mg or 80 mg once monthly and all new participants in cohort C 
will initiate dosing at 100 mg or 80 mg once monthly.
All suspected bleeding, cardiovascular and thrombosis events will be assessed by CIAC 
blinded to treatment allocation.


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1.2
Schema
EoT = end of treatment, N = number of subjects, S = screening, R = randomization, T = treatment, FU = follow-up, 
V = visit
* As per amendment 1, Visits 2, 3 and 4 are not performed (i.e. they are applicable only for patients enrolled 
before amendment 1).


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1.3
Schedule of Activities (SoA)

PK and PD sampling are to be performed at timepoints indicated in Section 8.5.

In addition to the study procedures described in this section, on dialysis days HD is to be started between 15 minutes before to 15 minutes
after study intervention administration.
Visit 1 procedures should preferably be done on one day; however, if not possible, some procedures can be also done over more than one day. 
Signing informed consent will be recorded as the V1 date, other procedures from V1 may be done on a later date, as long as all results are timely 
available for assessing eligibility prior to V5. It should be ensured that reports of the lab tests required for eligibility are available at 
randomization.
Table 1–1: Schedule of Activities, Visit V1 to Visit V13
Screening (1 week)
Main treatment period 
(24 weeks)
Comments
Visit Number
V1
V2**
V3**
V4**
V5
V6
V7
V8
V9
V10
V11
V12
V13 * At sites participating in the alternative PK & PD 
sampling group. Study Days marked with an asterisk 
are as listed in the table + 1 day (e.g.- V7 is Week 2, 
Study Day 9).
** Not performed as of amendment 1
Week
-1
1
1
2
3
4
5
7
9
11
Day
-7
1
2
8*
15*
22*
29*
43*
57*
71*
Window (days)
-6
0
0
+5
+5
+5
+5
+5
+5
+5
Informed Consent and PID
●
See Section 6.3
Inclusion/Exclusion Criteria / 
Eligibility Check
●
●
On V5 eligibility should be confirmed, including check 
of laboratory test results from the screening visits.
Medical History
●
Height
●
Randomization
●
See Section 6.3
Pre- & Post-HD Weight
●
●
●
●
●
See Section 8.2.2
Vital signs (post-HD BP)
●
●
●
●
●
See Section 8.2.3 for further details
ECG (12-lead)
●
●
●
See Section 8.2.4 for further details
Chemistry/Liver Panel
●
●
●
●
●
●
●
●
●
●
See Section 10.2 and Section 8.3.8 for further 
information
Hematology Panel
●
●
●
●
●
●
●
●
●
●
Blood sample for genetic 
testing
●
Study sites in China are excluded from 
pharmacogenetic and BM sample collection.


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Table 1–1: Schedule of Activities, Visit V1 to Visit V13
Screening (1 week)
Main treatment period 
(24 weeks)
Comments
Visit Number
V1
V2**
V3**
V4**
V5
V6
V7
V8
V9
V10
V11
V12
V13 * At sites participating in the alternative PK & PD 
sampling group. Study Days marked with an asterisk 
are as listed in the table + 1 day (e.g.- V7 is Week 2, 
Study Day 9).
** Not performed as of amendment 1
Week
-1
1
1
2
3
4
5
7
9
11
Day
-7
1
2
8*
15*
22*
29*
43*
57*
71*
Window (days)
-6
0
0
+5
+5
+5
+5
+5
+5
+5
Biomarker blood sample 
(FVIII, FIX, FXII, vWF 
antigen, vWF activity)
●
See Section 8.8
Immunogenicity blood 
Sampling
●
●
●
See Section 8.5 for details on sampling times
Biomarker blood sample 
(other BM)
●
●
●
See Section 8.8
PK blood sampling
●
●
●
●
●
●
●
●
●
See Section 8.5 for details on PK/PD sampling.
PD blood sampling
●
●
●
●
●
●
●
●
●
●
●
●
●
Serum Pregnancy test 
(WOCBP only)
●
●
●
●
●
●
●
See Section 8.3.5.
Urea reduction ratio or Kt/V 
(local)
●
●
●
●
●
Local URR or Kt/V results obtained in the previous 
month to the study visit will be accepted. 
Study intervention 
administration
●
●
●
See Section 6.1 for further details.
Dialysate effluent
●
●
See Section 8.5 for details on dialysate sampling
Clotting Score & AV access 
bleeding severity
●
●
●
●
●
●
●
●
See Section 8.6 for further details
Adverse events and 
outcome events
●
●
●
●
●
●
●
●
●
●
●
●
●
See Section 8.3; certain events will also require 
submission of an adjudication package to CIAC as 
described in Sections 8.1 and 8.2
AESI
●
●
●
●
●
●
●
●
●
See Section 8.3.8
Dialysis prescription
●
●
●
●
●
Concomitant medications
●
●
●
●
●
●
●
●
●
●
●
●
●
AESI = adverse events of special interest, AV = Arterio venous, BM = Biomarker, BP = Blood pressure, CIAC = Central Independent Adjudication Committee, ECG = 
Electrocardiogram, HD = Hemodialysis, KtV = Value used to quantify hemodialysis and peritoneal dialysis treatment adequacy, PID = participant identification code, FVIII 
= Coagulation Factor VIII, FIX = Coagulation factor IX, FXII = Coagulation factor XII, PK = Pharmacokinetics, PD = Pharmacodynamics(s), URR = Urea reduction ratio, 
vWF = Von Willebrand factor, WOCBP = Women of childbearing potential.


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Table 1–2: Schedule of activities, Visit V14 to visit V22
Main treatment period (24 weeks)
Comments
Evaluation Period * At sites participating in the alternative PK & PD sampling group, days marked with an 
asterisk are as listed in the table + 1 day (e.g.- V7 is Week 2, Study Day 9)
** these time points (Study Weeks and Study Days) are based on completion of either the 
main treatment period or the extended treatment period. 
The early termination visit will be conducted when a study participant has terminated the 
study (see Section 7.2)
Visit Number
V14 V15 V16 V17 V18 V19 V20 V21 V22
Week
13
15
17
19
21
22
23
24
25
Day
85* 99* 113*127*141*148*155*162* 169*
Window
+5
+5
+5
+5
+5
+5
+5
+5
+5
Pre- & Post-HD weight
●
●
●
●
See Section 8.2.2
post-HD BP
●
●
●
●
See Section 8.2.3 for further details
ECG (12-lead) 
●
●
Chemistry/liver panel
●
●
●
●
●
●
●
●
●
See Section 10.2 for further details
Hematology panel
●
●
●
●
●
●
●
●
●
See Section 10.2 for further details
Immunogenicity blood sampling
●
●
See Section 8.5 for details on immunogenicity sampling times
Biomarker blood sample (other BM)
●
●
●
●
See Section 8.8
PK blood sampling
●
●
●
●
●
●
●
See Section 8.5 for details on PK/PD sampling.
PD blood sampling
●
●
●
●
●
●
●
Serum pregnancy test (WOCBP only)
●
●
●
●
Urea Reduction Ratio or Kt/V (local)
●
●
●
●
Study intervention administration 
●
●
●
●***
See Section 6.1 for further details.
***Dosing of study intervention will occur at V22 in all participants except those who will 
not participate in the Extension Treatment Period
Clotting Score & AV access bleeding 
severity
●
●
●
●
●
●
●
See Section 8.6 for further details
Adverse events and outcome events
●
●
●
●
●
●
●
●
●
See Section 8.3; certain events will also require submission of an adjudication package 
to CIAC as described in Sections 8.1 and 8.2
AESI
●
●
●
●
●
●
●
●
●
See Section 8.3.8
Dialysis prescription
●
●
●
●
Concomitant medications
●
●
●
●
●
●
●
●
●
AESI = adverse events of special interest, AV = Arterio venous, BM = Biomarker, CIAC = Central Independent Adjudication Committee, ECG = Electrocardiogram, HD = 
Hemodialysis, PK = Pharmacokinetics, PD = pharmacodynamics(s), WOCBP = Women of childbearing potential.


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Table 1–3: Schedule of Activities, extended treatment visits and Visit FU1 to FU4
Extended treatment 
period 
(24 weeks)
Follow-up period
(16 weeks)
Early
Termination
Comments
* At sites participating in the alternative PK & PD sampling group, days 
marked with an asterisk are as listed in the table +1 day (e.g.V7 is Day 9)
** these time points (Study Weeks and Study Days) are based on 
completion of either the main treatment period or the extended treatment 
period. FU1-FU4 Should take place every 4 weeks (+5 days). The early 
termination visit will be conducted when a study participant has terminated 
the study (see Section 7.2)
Visit Number
V23 V24 V25 V26 V27 V28
FU1
FU2
FU3
FU4
Week
29
33
37
41
45
49 29-53** 33-57** 37-61** 41-65**
Day
197* 225*253*281*309* 337*
Window (days)
+5
+5
+5
+5
+5
+5
n/a
Pre- & Post-HD weight
●
●
●
●
●
●
●
●
●
●
●
See Section 8.2.2
ECG (12-lead) 
●
●
●
See Section 8.2.4
Chemistry/liver panel
●
●
●
●
●
●
●
●
●
●
●
See Section 10.2, Section 8.2.5 and Section 8.3.8. 
Platelet count and ALT/AST are to be measured every 2 weeks during 
extended treatment period, local lab monitoring, unscheduled visits can 
occur between the scheduled visits.
Hematology panel
●
●
●
●
●
●
●
●
●
●
●
Immunogenicity blood 
sampling
●
●
●
●
●
See Section 8.5 for details on immunogenicity sampling times
PK blood sampling
●
●
●
●
●
●
●
●
●
See Section 8.5 for details on PK/PD sampling.
PD blood sampling
●
●
●
●
●
●
●
●
●
Serum pregnancy test 
(WOCBP only)
●
●
●
●
●
●
Urea reduction ratio or
Kt/V(local)
●
●
●
●
●
●
●
●
●
●
●
Study intervention 
administration
●
●
●
●
●
See Section 6.1 for further details.
Post-HD blood pressure 
●
●
●
●
●
●
●
●
●
●
●
See Section 8.2.3 for further details
Clotting Score & AV 
access bleeding severity 
●
●
●
●
●
●
●
●
●
●
●
See Section 8.6 for further details
Adverse Events and 
outcome events
●
●
●
●
●
●
●
●
●
●
●
See Section 8.3; certain events will also require submission of an 
adjudication package to CIAC as described in Sections 8.1 and 8.2.
AESI
●
●
●
●
●
●
●
●
●
●
●
See Section 8.3.8
Dialysis Prescription
●
●
●
●
●
●
●
●
●
●
●
Concomitant Medications
●
●
●
●
●
●
●
●
●
●
●
AESI = Adverse events of special interest, ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, AV = Arterio venous, BM = Biomarker, CIAC = Central 
Independent Adjudication Committee, ECG = Electrocardiogram, FU = Follow-up, HD = Hemodialysis, PK = Pharmacokinetics, PD = pharmacodynamics(s), WOCBP = 
Women of childbearing potential.


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2.
Introduction
BAY 2976217 is a novel long-acting ligand conjugated antisense oligonucleotide (LICA) 
targeting the hepatic synthesis of FXI with the potential to exhibit an antithrombotic effect 
with lower risk of bleeding events than currently available antithrombotics. 
2.1
Study Rationale
Patients with ESRD on hemodialysis are at a high risk for arterial and venous 
thromboembolic complications. However, because of the documented high risk for bleeding, 
no antithrombotic regimen has ever been evaluated in this group in a large clinical trial
setting. Pre-operative reduction of the synthesis of FXI levels by unconjugated FXI ASO in 
patients who had elective primary unilateral total knee arthroplasty was highly effective for 
prevention of venous thrombosis and was not associated with increased peri-operative or 
subsequent bleeding. 
In ESRD patients, the reduction of the synthesis of FXI levels by the ASO was associated 
with less clotting of the dialysis circuit without an increase in bleeding risk. The unconjugated 
FXI ASO requires higher doses and a long loading phase to achieve adequate liver delivery 
and reduced FXI levels; therefore, the GalNAc-conjugated FXI ASO was developed,  
 Treatment with GalNAc-conjugated FXI ASO in 
patients with ESRD has a potential to prevent thromboembolic complications such as MI, 
stroke, peripheral arterial events, and cardiovascular death without increasing risk of clinically 
significant bleeding. This Phase 2 trial will assess the safety and characterize the PK/PD 
profile of three different doses of BAY 2976217 given SC once a month to participants with 
ESRD on HD.
2.2
Background
2.2.1
Unmet Need for Reducing Cardiovascular Morbidity and Mortality in 
ESRD
ESRD is associated with high CV comorbidity including CAD and PAD each associated with 
high mortality. Dialysis is associated with a prothrombotic state driven by inflammation, 
uremia-induced endothelial dysfunction and contact between blood and the dialysis circuit
(2). Compared to the general population, patients receiving dialysis are at higher risk of 
thrombotic events including stroke (4-10x higher in dialysis patients)(3), MI (CAD 
prevalence in dialysis patients is 5-10x higher) (4), and amputations, limb-ischemia and 
chronic skin ulcers related to PAD (PAD prevalence is as high as 40%) (5). Only 40% of 
patients receiving HD are alive five years after onset (6), and the mortality rate for those 
initiating dialysis is 15x higher than in matched controls from the general population (7). This 
high mortality is largely driven by CV causes (7).
Therapies directed at both traditional and non-traditional CV risk factors have not been 
studied in dialysis patients (8, 9), or have failed to demonstrate a benefit in clinical trials (10-
14). The use of currently available antithrombotics is uncertain, and clinicians are faced with 
the challenging task of assessing the risk of atherothrombosis or thromboembolism against a 
high risk for bleeding in their patients. Lower dose (≤150mg daily) ASA use is widely 
accepted as the mainstay preventative therapy (1, 15). Atrial fibrillation, one important risk 
factor for stroke, is present in 15%–40% of hemodialysis patients (16), which is a much 
higher rate than the 1% prevalence in the general adult population (17). Dialysis patients with 
C
CI


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AFib treated with oral anticoagulation experience bleeding 10x more frequently than AFib
patients with normal kidney function (18). In dialysis AFib patients’ risk of hemorrhagic 
stroke with anticoagulation is 1.4 to 2.7x higher (19-22). In non-AFib dialysis patients, 
bleeding risk is increased 2-20x with anticoagulation versus without (23). These unique 
benefit-risk considerations (unproven benefit of antithrombotics for preventing CV events 
versus bleeding risk) often leave patients with inadequate protection from their CV risk. 
Given the multi-fold higher rates of CAD, PAD, stroke and AFib in patients with ESRD on 
hemodialysis coupled with an increased risk of bleeding versus the general population, there 
is a very high unmet need for therapies proven to address CV disease burden in these patients 
without increasing bleeding risk. Targeting FXI with GalNAc-conjugated FXI ASO 
(BAY2976217) may address this unmet need to reduce CV morbidity and mortality without 
increasing the risk of clinically significant bleeding (24).
2.2.2
Factor XI
FXI is a new antithrombotic target with the potential for a lower risk of bleeding than 
currently available antithrombotics. The identification of FXI as a safer target is supported by 
epidemiological data in patients with congenital deficiency of FXI, studies in FXI deficient 
mice, studies with FXI knockdown or inhibition, and animal bleeding models (25).
The formation and stability of clots are enhanced by FXI in vitro (26). Furthermore, FXI 
amplifies thrombin generation when coagulation is initiated by low levels of tissue factor 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 therapeutic target comes from epidemiological 
data. Observational studies in patients with congenital FXI deficiency suggest that these 
patients are at a reduced risk of ischemic stroke, myocardial infarction, and venous 
thromboembolism compared with those with normal FXI levels (27-29). Additionally, 
spontaneous bleeding is rare in FXI deficiency, and a variable bleeding risk exists after 
surgery or trauma, with greatest bleeding risk localized to areas of high fibrinolytic activity 
(30); in a recent study there was no association between FXI coagulant activity level and 
bleeding severity (31).
2.2.3
BAY 2976217
The investigational agent, BAY 2976217 is a ligand conjugated antisense oligonucleotide
(LICA) targeting FXI synthesis in the liver. BAY 2976217 is ligand-conjugated to 
triantennary GalNAc
 
 Delivery is targeted to the hepatocyte, leading 
to 
 efficient inhibition of FXI synthesis, thereby reducing potential for dose-dependent 
effects.
BAY 2976217 is a member of a class of molecules, 2ʹ-MOE modified ASOs, that primarily 
differ from each other in their antisense nucleotide sequence that determines their specificity 
and binding to their respective mRNA target. The sponsor’s collaboration partner for BAY 
2976217 (Ionis) has studied multiple 2ʹ-MOE modified ASOs in clinical trials. At the time of 
this protocol finalization, approximately 6,500 subjects have been treated systemically (dosed 
intravenously and/or SC) with unconjugated 2ʹ-MOE-modified ASOs at doses of 15 mg to 
1200 mg, and for durations that range from short-term (e.g., single dose) to durations that 
CCI
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exceed 4 years. Three publications that summarize the analyses of the Ionis integrated safety 
database include results from >2,600 subjects treated with 16 unconjugated 2‘-MOE ASOs 
systemically in 52 completed clinical trials (32-34). Key safety findings include the potential 
for renal dysfunction and thrombocytopenia with unconjugated 2’-MOE ASOs.
More recently, conjugation of GalNAc to 2’-MOE ASOs has been shown to increase 
productive delivery of ASOs to the liver resulting in substantial increases in potency for 
hepatocyte expressed target RNAs such as FXI (35). At the time of this protocol finalization, 
fifteen 2’-MOE ASOs conjugated with a GalNAc moiety are in development and 10 have 
completed at least a 4-week clinical trial in healthy volunteers. In total, >1100 subjects have 
been exposed to GalNAc-conjugated ASO’s and ~400 subjects for at least 6 months up to 1 
year. An integrated analysis of the safety database in healthy volunteers showed increased 
potency of up to 30-fold over their paired unconjugated ASO; no clinically relevant changes 
in chemistry, hematology (including in platelet counts), urinalysis, vital sign measurements, 
or ECG parameters; no changes in heart rate, blood pressure, ECG or respiration function 
were reported; and the most commonly reported TEAEs that were considered related to ASO 
administration were injection site reactions and headache (35). BAY 2976217 is GalNAc
conjugated and the increase in potency of BAY 2976217 relative to the unconjugated ASO 
was compared between Phase 1 trial results (see below). 
 
2.2.3.1
Preclinical Data with BAY 2306001 (ISIS 416858) and BAY 2976217
(ION 957943)
Proof-of-concept studies have been conducted with both GalNAc-conjugated and
unconjugated mouse-specific FXI ASOs in mouse models of thrombosis. Twice weekly 
administration of FXI ASOs for 3 weeks reduced hepatic levels of FXI mRNA and plasma 
levels of FXI protein in a dose-dependent manner. The administration of FXI ASOs to date 
has not caused an increase in bleeding risk. FXI ASOs evaluated in vivo using the FeCl3
inferior vena cava thrombosis model demonstrated an antithrombotic effect with GalNAc-
conjugation increasing potency as compared to unconjugated ASO. 
In an arterial model, FXI ASO treatment reduced platelet and fibrin accumulation and 
completely prevented occlusion of mouse mesenteric arteries after FeCl3 injury. The 
antithrombotic effect was comparable to clopidogrel (Plavix, 12.5 mg/kg). Furthermore, FXI 
ASOs have been shown to be pharmacologically active in the cynomolgus monkey and 
decrease the hepatic FXI mRNA expression and plasma FXI protein activity levels. (36).
FXI ASOs previously demonstrated antithrombotic activities with efficacy comparable to
warfarin or enoxaparin. Warfarin and enoxaparin both have exhibited bleeding issues which
have not been observed by inhibiting FXI with ASO. After withdrawal of ASO treatment 
there was no rebound increase (above baseline) in FXI levels. The anticoagulant effect of FXI 
antisense therapy has been shown to be effectively and rapidly reversed by plasma-derived 
FXI concentrate (37).
These results support the concept that the potent inhibition of FXI through antisense therapy 
may serve as a new and effective strategy for the treatment and prevention of 
thromboembolism with improved specificity and safety as compared to currently available 
drugs. Details for the preclinical programs for BAY 2306001 and BAY 2976217 can be found 
in the Investigator’s Brochure.
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2.2.3.2
Clinical Data with BAY 2306001
BAY 2306001, an unconjugated 2ʹ-MOE ASO that has the same base sequence as 
BAY 2976217 and can be considered to have the same mechanism of action, has been 
evaluated in approximately 558 subjects in two Phase 1 studies and three Phase 2 studies. The 
details for each study can be found in the Investigator’s Brochure.  
A Phase 2, open-label multi-center study (ISIS 416858-CS3) was conducted comparing
BAY 2306001 at 100, 200, and 300 mg with enoxaparin for the prophylaxis of VTE in 
patients undergoing total knee arthroplasty. This study showed a 7-fold reduction in VTE 
after SC administration of BAY 2306001 compared to the standard of care treatment with 
enoxaparin. The reduction in VTE in ISIS 416858-CS3 was not associated with an increase in 
clinically significant bleeding events (38). BAY 2306001 has also been evaluated at 200 and 
300 mg SC in a Phase 2, randomized, double- blind and placebo-controlled study in patients 
with ESRD on hemodialysis (ISIS 416858-CS4).
Plasma PK in patients with ESRD on hemodialysis was studied in the PK cohort of 
ISIS 416858-CS4. The mean concentration of BAY 2306001 in plasma over 24 hours 
following the SC dose administration on Day 1 (300 mg administered 10 minutes after 
completion of the 4-hour dialysis) and on Day 29 (300 mg administered immediately prior to 
the start of dialysis) were very similar and there were no differences between the two 
treatment days for either Cmax or AUC values including the partial AUC values (AUC0-3hr or 
AUC0-4hr), suggesting that hemodialysis had no effect on the PK of BAY 2306001 in ESRD 
patients.
Furthermore, dialysate samples were collected to determine concentrations of BAY 2306001 
and representative metabolites in dialysate as well as dialysis clearance of BAY 2306001, if 
detected in the dialysate. Samples were collected prior to dialysis (baseline, C0min) and at the 
beginning (within first 5 minutes), during (approximately 30 minutes after start of dialysis), 
and toward the end of dialysis (last 15 minutes of dialysis) on Day 29 from the PK cohort and 
Day 78 from Cohorts A and B. Concentrations of BAY 2306001 and its 10mer metabolites 
were below the LLOQ (< 2.50 nM) at all the time points examined. The lack of diffusion 
across the dialysis membrane of BAY 2306001 is consistent with the earlier observation on 
hemodialysis having no effect on the PK of BAY 2306001. Only the 3ʹ-5mer metabolite was 
quantifiable at the beginning (within first 5 minutes) and 30 minutes after start of dialysis, 
suggesting that dialysis of shortmer metabolites was a rapid process.
There were sustained dose-dependent reductions in FXI. A reduction in dialysis circuit 
clotting was demonstrated by BAY 2306001 treatment with no increase in clinically-
significant bleeding when compared to placebo (39). 
A larger 213-patient Phase 2 multicenter, double-blind, randomized, stratified, placebo-
controlled study was conducted in ESRD patients receiving hemodialysis (ISIS 416858-CS5). 
The results of ISIS 416858-CS5 after 26 weeks of treatment with BAY 2306001 are generally 
consistent with the smaller 12-week study ISIS 416858-CS4 in ESRD patients of HD.
There were sustained dose-dependent decreases in FXI, as well as in reduced clotting scores 
of the dialysis circuit. BAY 2306001 demonstrated a good safety profile and was well-
tolerated up to 26 weeks of treatment at 200 mg, 250 mg and 300 mg doses. There were dose-
dependent decreases in platelet counts, 2 cases of severe thrombocytopenia were observed 
with BAY 2306001 treatment. Platelet function assessments indicated BAY 2306001 did not 
increase platelet activation and had negligible effects on platelet reactivity. There was no 


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increase in MB or CRNMB over placebo. Minor bleeds did not appear to be correlated with 
FXI levels.
The results of the BAY 2306001 clinical development program support FXI as a therapeutic 
target for prevention of thrombotic events in ESRD patients on hemodialysis.
2.2.3.3
Clinical Data with BAY 2976217 (ION 957943)
ION-957943-CS1 was a double-blind, placebo-controlled, dose-escalation Phase 1 study to 
assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and 
multiple doses of BAY 2976217 administered SC to healthy volunteers.
Following SC administration, BAY 2976217 was absorbed rapidly into the systemic 
circulation with median tmax values ranging from 1.5 to 3.5 hours across all evaluated cohorts. 
After reaching peak concentrations, mean plasma concentrations of BAY 2976217 declined in 
a multiphasic fashion with time with an initial, relatively fast disposition phase that dominated 
plasma clearance followed by a slower elimination phase. The rapid disposition-dominated 
phase resulted in plasma concentrations at 24 hours post dosing being lower by several 
magnitudes compared to Cmax whereas the elimination phase is characterized by an apparent 
terminal elimination half-life of approximately 2 to 3 weeks. Overall, pharmacokinetic
parameters appear to increase in proportional with dose over a dose range of 10 mg to 120 
mg.
2.3
Benefit/Risk Assessment
Due to the much higher bleeding risk of ESRD patients and the unproven benefits of currently 
available antithrombotic therapy in these patients, most hemodialysis patients are not 
adequately treated for the prevention of thromboembolic events. The mainstay of thrombosis 
prevention is low dose ASA, and is recommended based mostly on small studies in ESRD 
patients on HD treated with ASA to prevent arterio-venous access thrombosis (1).
Epidemiologic data in FXI deficient patients, and preclinical and clinical data generated so far 
with various compounds inhibiting FXI as part of the intrinsic coagulation pathway, support 
the hypotheses that targeting FXI may be ideal for the reduction of the thromboembolic risk 
without increasing the risk for bleeding in general, as well as in the ESRD patients on HD.
BAY 2976217 is ligand-conjugated to GalNAc oligonucleotide targeting FXI synthesis. This 
Phase 2b study will be the first study investigating BAY 2976217 in ESRD patients on HD.
However, 256 ESRD patients on HD were studied with the parent unconjugated ASO 
(BAY 2306001) that works by the same antisense mechanism, using the same antisense 
ribonucleic acid sequence to inhibit hepatic production of FXI. BAY 2306001 reduced 
circulating FXI levels, FXI activity and dialysis circuit clotting in a dose-dependent manner 
without an increase in clinically significant bleeding over placebo.
Preclinical data suggest that this compound provides antithrombotic properties without 
increasing the risk for bleeding. BAY 2976217 may cause transient and reversible 
prolongations of aPTT, which is known effect due to reduction in FXI activity.
Clinical safety and efficacy are yet to be established for BAY 2976217. However, clinical 
data from parent unconjugated ASO (BAY 2306001) is directly relevant to the development 
of BAY 2976217 because the 2 compounds share the same RNA sequence as well as same 
overall structure, except the addition of the GalNAc sidechain and linker to BAY 2976217. 
BAY 2306001 has already shown a positive proof of concept in patients undergoing TKA 
with less VTE after surgery than with enoxaparin at higher doses of ASO, and in patients with 


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ESRD on hemodialysis with dose-dependent reduction in dialysis circuit clotting. In both 
settings, these favorable findings did not come with an increase in clinically significant 
bleeding over enoxaparin in TKA or placebo in ESRD patients. Clinical data of 
BAY 2976217 in healthy volunteers demonstrated dose dependent reduction of FXI activity 
and concentration after SC administration, which may lead to prevention of thromboembolic 
events.
Assuming that results from relevant animal models, human congenital FXI deficiency, and 
other compounds with similar mode of action can be translated into ESRD patients, 
BAY 2976217 is a promising drug candidate with the potential to prevent thromboembolic 
events with a low risk of bleeding. The current development program plans to enroll ESRD 
patients, with an anticipated pivotal trial composite exploratory efficacy endpoint of 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. The use of BAY 2976217 aims to 
achieve a 25% clinically relevant risk reduction of the composite endpoint. This would 
translate to an absolute risk reduction of >3%.
Potential risks such as bleeding, thrombocytopenia or increase in hepatic enzymes will be 
closely monitored to minimize risks to participants. In addition to routine measures in the 
conduct of a clinical trial, carefully chosen, specific in- and exclusion criteria, dose of study 
medication, and additional measure have been selected to manage the key risks identified for 
BAY 2976217. The elimination half-life of BAY 2976217 in plasma is approximately 2 to 3
weeks, however, plasma clearance is biphasic with a rapid decrease after tmax in plasma 
concentration due to uptake in hepatocytes. Due to the prolonged pharmacodynamic effect of 
the compound, participants will be kept under observation for approximately 5 months after 
the last administration of BAY 297217 (the first 4 weeks after the last dose is considered on-
treatment, and may include an evaluation period upon completing the main treatment period 
or upon discontinuing study intervention early during the main treatment period, and 16-
weeks for a post-treatment follow-up period for safety).
In order to ensure the safety of the participants during the study conduct, an independent data 
monitoring committee will monitor the safety of all participants.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of BAY 2976217 can be found in the Investigator’s Brochure.


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2.3.1
Risk Assessment
Risk assessment for BAY 2976217 is described in Table 2–1.
Table 2–1: Risk Assessment for the study Intervention BAY 2976217
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Hemorrhage
Risk factor associated with ESRD 
due to uremia-induced endothelial 
and platelet dysfunction
Increased bleeding risk due to 
routinely administered anticoagulant 
and antiplatelet agents to reduce risk 
of thromboembolic events and for 
dialysis maintenance
No clinically significant bleeding (MB, 
CRNMB) observed so far in healthy 
volunteers with BAY 2976217
Specific in-and exclusion criteria
Reporting as primary safety 
outcome 
Regular hematological laboratory 
assessment (see Section 1.3)
Guidance on remedial measure 
and surgical prophylaxis including 
factor replacement
DMC will periodically review all 
bleeding events 
CIAC will adjudicate bleeding 
events
Thrombocytopenia
Like in other unconjugated ASOs, 
BAY 2306001 was associated with 
dose dependent platelet reductions in 
ESRD patients on HD, however, 
severe thrombocytopenia was a rare 
event; platelet reductions were not 
observed in healthy volunteers with 
BAY 2976217
Specific in-and exclusion criteria
Regular safety laboratory 
assessment (see Section 1.3)
Regular hematological laboratory 
assessment (see Section 1.3)
Reporting as adverse event of 
special interest, as well as 
instructions on following 
monitoring, evaluation, stopping 
rules and remedial treatment (see 
Section 8.3.8)
Elevation of hepatic 
enzymes
Based on toxicology findings in mice 
with BAY 297217, minimal to mild 
individual hepatocellular necrosis 
was observed and correlated with 
increased hepatic enzymes: also 
increased liver weights were 
observed
In preclinical studies with monkeys 
and in the Phase 1 study with healthy 
volunteers no clinically relevant 
changes in liver chemistry were seen
Specific in- and exclusion criteria
Regular liver laboratory 
assessment (see Section 1.3 and 
Section10.2)
Reporting as adverse event of 
special interest, as well as 
guidance on the monitoring, 
evaluation, and stopping rules 
(see Section 8.3.8)


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2.3.2
Benefit Assessment
The potential benefit of receiving study intervention is a reduced risk for thromboembolic 
events in patients with ESRD. Furthermore, this study will contribute to develop of 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
Currently available preclinical and clinical data regarding the key risks do not indicate an 
unfavorable risk profile for BAY 2976217. Considering the measures taken to minimize risk 
to participants in this study, the overall risk is projected to be acceptable in the context of the 
anticipated benefit.
3.
Objectives and Endpoints
Objectives and endpoints are listed in Table 3–1.
Table 3–1: Objectives and Endpoints
Objectives
Estimands/Endpoints
Primary

To evaluate the safety of 
BAY 2976217as compared to 
placebo
Primary Endpoint

The incidence of composite of major bleeding 
and clinically-relevant non-major bleeding during 
the main treatment period and within the on-
treatment time window, as assessed by blinded 
CIAC
Estimand components for primary endpoint are defined 
in section 9.4.2
Secondary

To evaluate the safety of BAY 
2976217as compared to 
placebo

The incidence of composite of major bleeding 
and clinically-relevant non-major bleeding during 
the main and extended treatment periods and 
within the on-treatment time window, as 
assessed by blinded CIAC

Incidence and severity of TEAEs during
o
the main treatment period and within the 
on-treatment time window
o
the main and extended treatment 
periods and within the on-treatment time 
window
o
the main and extended treatment 
periods and until 20 weeks after the last 
study intervention dose

To evaluate the PK and PD of 
BAY 2976217
Pharmacokinetic Endpoints

Trough concentrations for 3 dose levels of 
BAY 2976217
Pharmacodynamic Endpoints

Maximum change in FXI antigen levels during 
the main treatment period


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Table 3–1: Objectives and Endpoints
Objectives
Estimands/Endpoints

Maximum change in FXI activity levels during 
the main treatment period
Exploratory

To evaluate the effect of 
BAY 2976217 on 
thromboembolic events as 
compared to placebo
Exploratory Efficacy Endpoints 

Incidence of composite and event types of death 
due to MI, stroke, PE and SE, and non-fatal 
stroke, non-fatal MI, VTE, major amputation of 
vascular etiology, and acute limb ischemia as 
assessed by the blinded CIAC

Incidence of thrombosis of the arterio-venous 
grafts or fistulas, assessed by the blinded CIAC 

To further evaluate the safety 
profile of BAY 2976217 as 
compared to placebo
Other pre-specified Safety Endpoints

Incidence and severity of AESIs: hepatic 
enzyme elevation, thrombocytopenia

Changes in blood pressure and, laboratory 
assessments

Incidence and severity of bleeding of the arterio-
venous grafts or fistulas

To further evaluate the 
pharmacodynamics of BAY 
2976217 as compared to 
placebo
Other Pre-specified Pharmacodynamic Endpoints

Maximum change in PT, INR and aPTT 
during the main treatment period

Extent and frequency of clotting on the 
dialysis filters & circuit

Changes in d-dimer

TAT and F1.2
Other pre-specified

To further investigate 
BAY 2976217 (e.g. mode-of-
action-related effects, safety)
and to further investigate 
pathomechanisms deemed 
relevant to cardiovascular and 
renal diseases and associated 
health problems

To evaluate potential 
associations between 
genotypic information and 
clinical efficacy and / or 
pharmacodynamics effects

Various biomarkers (e.g. diagnostic, safety, 
pharmacodynamic, monitoring, or potentially 
predictive biomarkers)
AESI = Adverse event of special interest, aPTT = Activated partial thromboplastin time, CIAC = 
Central Independent Adjudication Committee, F1.2 = Prothrombin fragment 1 + 2, FXI = 
Coagulation factor XI, INR = International normalized ratio, MI = Myocardial infarction, PD = 
Pharmacodynamics(s), PE = Pulmonary embolism, PK = Pharmacokinetics, SE = Systemic 
embolism, TAT = Thrombin-antithrombin complex, TEAEs = Treatment-emergent adverse 
event(s); VTE = Venous thromboembolism


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4.
Study Design
4.1
Overall Design
This is a Phase 2 multicenter, double-blind, randomized, placebo-controlled study in ESRD 
patients who are stable on HD (including hemodiafiltration) ≥ 3 months for a minimum of 9 
hours per week. Patients receiving therapeutic anticoagulation or antiplatelet therapy (other 
than ASA ≤150 mg/day) are excluded. Approximately 288 participants will be randomized.
Participants will be allocated at randomization to 1 of 3 dose cohorts in a 1:1:1 ratio (Cohort 
A [40 mg], Cohort B [80 mg], and Cohort C [120 mg]), and within each cohort to receive SC
treatment with either BAY 2976217 or matching placebo in a 3:1 ratio. Sponsor, participants 
and investigators are blinded with respect to active treatment versus matching placebo, but 
assignment to dose cohort will be known. The CIAC will be blinded to dose cohort allocation 
and treatment assignment. With an assumed attrition rate of 15% during the main treatment 
period, 288 randomized participants would allow for an estimated 240 evaluable participants.
All standard of care hemodialysis therapies as prescribed by their providers, including use of 
heparins to maintain dialysis circuit patency, will be continued.

Cohort A: 40 mg BAY 2976217 or placebo SC (3:1) n~96

Cohort B: 80 mg BAY 2976217 or placebo SC (3:1) n~96

Cohort C: 120 mg BAY 2976217 or placebo SC (3:1) n~96
Participants will be stratified at randomization for use of ASA (yes/no). Use of ASA will 
remain at the discretion of the investigator. However, all efforts should be made during the 
treatment period to avoid change in ASA use or dose, unless clinically indicated. 
Additionally, participants will also be stratified based on the presence of selected CV risk 
factors. The investigator will evaluate the presence or absence of the following at the time of 
randomization:
(i)
age >65 years, 
(ii)
history of DM type I or II,
(iii)
history of MI, 
(iv)
history of stroke or TIA, 
(v)
history of CHF, 
(vi)
history of PAD,
(vii)
history of Afib.
Strata 1- zero or one risk factor, except the presence of DM or Afib; 
Strata 2- either DM or Afib alone, or two or more risk factors.
All cohorts will consist of 1-week screening period and a 24-week main treatment period, the 
last 4 weeks of which are an evaluation period for certain PD and safety parameters. To 
collect additional long-term safety information, participants will continue to be treated as 
randomized in the extended treatment period, with up to 24 weeks of additional treatment
with study intervention. A participant is considered to be on treatment until 4 weeks after their 
last dose, whether they discontinue treatment early, complete only the main treatment period, 
or complete part or all of the extended treatment period. Once the overall treatment period is 
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All participants who are in the extended treatment period will need to stop further treatment 
no later than when the last participant enrolled into the study has completed the 24-week main 
treatment period (Visit 22). Participants in the extended treatment period will complete Visit 
28 four weeks after their last dose, and move to the 16-week post-treatment follow-up period. 
The sponsor reserves the discretion to halt further dosing in the extended treatment period 
earlier in anticipation of the least participant completing the main treatment period.
The data and outcomes collected in the study will be analyzed by 4 groups: 

Pooled Placebo Group (from Cohorts A, B and C), 

40 mg Dose Group (BAY 2976217 from Cohort A), 

80 mg Dose Group (BAY 2976217 from Cohort B), and 

120 mg Dose Group (BAY 2976217 from Cohort C). 
All suspected bleeding, cardiovascular and thromboembolic events occurring after 
randomization will be assessed by CIAC blinded to treatment allocation. An independent 
DMC will monitor the participant’s safety and give recommendations to the Steering 
Committee.
The DMC will review unblinded data from the study on regular basis, as outlined in the DMC 
Charter. At any time, if there is an unexpected finding(s) in Cohort C (the 120 mg dose 
cohort), the DMC may elect to modify the Cohort C to a 100 mg or 80 mg dose level. If 
recommended by the DMC, the change will be implemented by administrative letter and will 
not require a protocol amendment. All ongoing participants will have their dosing modified to 
100 mg or 80 mg once monthly and all new participants will be initiate dosing at 100 mg or 
80 mg once monthly.
There will be an alternative PK&PD sampling group at selected sites. A target population of 
approximately 24 to 40 participants distributed among the three cohorts is sought for this 
group. Whereas all other participants will receive their first dose of study intervention on a 
dialysis day, participants in the alternative PK&PD sampling group will receive their first 
dose of study intervention on a non-dialysis day, preceding a scheduled dialysis day (Section 
8.5.1.2).
Central lab results for PD parameters including coagulation parameters will not be provided to 
the sites, as these are potentially unblinding. Investigators will also avoid local testing of 
coagulation parameters, as these may be unblinding, unless clinically indicated.
The primary analysis will be performed to expedite Phase 3 dose selection. 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 16-weeks post treatment follow-up period (study completion).
4.2
Scientific Rationale for Study Design
Patients with ESRD on hemodialysis are at a high risk for arterial and venous 
thromboembolic complications. However, because of the documented high risk for bleeding, 
no antithrombotic regimen has ever been evaluated in this group in a large clinical trial 
setting. 


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Patients with congenital deficiency of FXI are at decreased risk of thrombotic events, without 
spontaneous bleeding. Investigational compounds used to inhibit or decrease production of 
FXI have also shown promise in reducing thrombotic events without increasing clinically 
significant bleeding, making it an attractive candidate for use in the ESRD patient on HD. An 
unconjugated FXI ASO (BAY 2306001) was studied in clinical trials. Pre-operative reduction 
of the synthesis of FXI levels by the unconjugated FXI ASO in patients who had elective 
primary unilateral total knee arthroplasty was highly effective for prevention of venous 
thrombosis and was not associated with increased peri-operative or subsequent bleeding. Two 
Phase 2 studies were conducted in ESRD patients, that showed that the reduction of the 
synthesis of FXI levels by the ASO was associated with less clotting of the dialysis circuit 
without an increase in clinically significant bleeding.  
This previous experience with the unconjugated FXI ASO showed effective reduction in 
thrombotic events without increase in clinically significant bleeding. However, the 
unconjugated FXI ASO requires higher doses and relatively high injection volume, and a long 
loading phase to achieve adequate liver delivery and reduce FXI levels, and was associated 
with certain adverse events such as thrombocytopenia and injection site reactions. Therefore, 
the GalNAc-conjugated FXI ASO BAY 2976217 was developed, 
 
Animal studies as well as Phase 1 human trials of BAY 2976217 have confirmed significant 
dose-dependent reduction in FXI activity with lower circulating serum levels of the drug, and 
no evidence of injection site reactions or platelet effects. Progression to a Phase 2 trial in 
ESRD patients on HD is reasonable as there is a high unmet medical need to reduce 
thrombotic events without increasing bleeding in this population. As there is currently no 
accepted alternative therapy to reduce thrombotic events in this population except the use of 
low-dose ASA, the appropriate standard of care for the control arm of each cohort is placebo 
with or without low-dose ASA at the discretion of the investigator.
4.3
Justification for Dose
This study will investigate three dose levels (40 mg, 80 mg, and 120 mg BAY 2976217 given 
SC every 4 weeks). These doses were determined based on clinical data from the parent drug 
BAY 2306001 in healthy volunteers and in ESRD patients and clinical data from BAY 
2976217 in healthy volunteers. A population PK/PD model has been developed in order to 
bridge into the current Phase 2b study. The investigation of a range of less FXI suppression 
(approximately 50% remaining FXI activity) is justified by real life data from congenitally 
deficient patients. A large observation cohort including 10,193 adults in Israel demonstrating 
that FXI activity of 30-50% was associated with reduced CV event rates in a population with 
genetically lowered FXI levels when compared to the group of patients with >50% of FXI 
levels (27).
The investigation of a higher range of FXI suppression is justified by two publications 
describing a lower incidence of ischemic stroke and DVT in patients with FXI levels below 
15% (29, 40). Additionally, a Phase 2 study (ISIS 416858 -CS3) explored the role of FXI 
reduction in post-surgical VTE by comparing two doses of the unconjugated ASO BAY 
2306001 (200mg and 300 mg) to enoxaparin (38). The mean FXI activities around the time of 
knee surgery were 0.38 ± 0.01 U/mL and 0.20 ± 0.01 U/mL in patients given the 200 mg and 
300 mg BAY 2306001 regimens, respectively. VTE events occurred in 27% of patients 
receiving the 200 mg dose of FXI-ASO and in 4% of patients receiving the 300 mg dose of 
FXI-ASO, as compared with 30% of patients receiving enoxaparin. The authors concluded 
CCI


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that the 200 mg regimen was noninferior, and the 300 mg regimen of FXI-ASO was superior 
to enoxaparin. These data would support the investigation of a higher FXI suppression level 
of approximate 20% remaining FXI activity.
Spontaneous bleeding, including clinically significant bleedings, do not show dependency on 
lower levels of FXI in the above cited publications and other published literature. In addition, 
no increase in number of clinically significant bleeding under treatment with the parent 
compound BAY 2306001 was seen in two studies with ESRD patients.
With a view on potential clinical efficacy and considering safety, reduced FXI levels of less 
than 15% to approximately 50% remaining activity are justified for the current study. The 
three doses of 40 mg, 80 mg, and 120 mg BAY 2976217 have been selected to optimally 
cover for this range.
A protocol-defined option for dose step-down for the 120 mg dose level (see section 4.1) is 
provided to the DMC. Also, the predicted steady-state FXI levels with 120 mg once monthly 
dosing are expected to be similar to those achieved with the 300 mg dose level in the TKA 
study (ISIS 416858-CS3) in which no increased clinically significant bleeding was observed.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all protocol 
defined visits/contacts.
The end of the study is defined as the date the last participant completes the last protocol-
defined visit/contact.
The primary completion date is the date when the last participant completes the main
treatment period (Visit 22) and the following ”on treatment” time window (28 days from the 
last intake of study intervention).
5.
Study Population
Subjects with ESRD on hemodialysis treatment (including hemodiafiltration) who meet all 
the inclusion criteria and none of the exclusion criteria will be eligible for enrollment in this 
study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1.
Participant must be at least 18 years of age at the time of signing the ICF.
Type of Participant and Disease Characteristics
2.
Participants with ESRD on HD for ≥3 months at the time of signing of the ICF, 
receiving dialysis at least 9 hours a week and stable in the view of the 
investigator.1
                                                
1 See section 5.4 for information on rescreening.  


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Sex
3.
Male 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.2.
Informed Consent
4.
Capable of giving signed ICF as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the ICF and in this 
protocol
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Prior/Concomitant Therapy
1.
Receiving antiplatelet therapy except daily ASA ≤ 150 mg/day
2.
Receiving anticoagulation in therapeutic doses, other than standard 
anticoagulation during the hemodialysis procedure.
Medical Conditions
3.
Known inherited bleeding disorder e.g. von-Willebrand disease or Hemophilia A, 
B or C
4.
Recent (<6 months before screening) clinically significant bleeding, or at high risk 
of bleeding (in the judgement of the investigator) 
5.
Recent (<3 months before screening) thromboembolic event, e.g. acute coronary 
syndrome, stroke, or VTE (except dialysis access thrombosis)
6.
Recent (<3 months before screening) major surgery or scheduled major surgery
during participation in the study
7.
Scheduled living donor renal transplant during study participation
8.
Known Hepatitis B or C
9.
Known HIV with recent documented detectable viral load (<3 months before 
screening)
10.
Persistent heart failure as classified by the New York Heart Association 
classification of 3 or higher
11.
Life expectancy less than 6 months
12.
Sustained uncontrolled hypertension (persistent measurements of diastolic blood 
pressure ≥100 mmHg, and/or systolic blood pressure ≥180 mmHg)
13.
Hepatic disease associated with either: coagulopathy leading to a clinically 
relevant bleeding risk, or ALT > 3x ULN, or total bilirubin >2x ULN with direct 
bilirubin > 20% of the total
                                                
2 See Section 10.4 for requirements on contraception


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14.
Hb < 9.0 g/dL at screening3
15.
Platelet count < 120,000 / mm3 at screening3
16.
Known hypersensitivity to the investigational drug or to inactive constituents of 
the study intervention
17.
Active malignancy requiring treatment during study participation (except non-
melanoma skin cancer, or cervical carcinoma in situ)
Prior/Concurrent Clinical Study Experience
18.
Participation in a study with an investigational medicinal product within 30 days 
or within 5 half-lives of the previous administered drug, whichever is longer, prior 
to the screening period
Note: Participants from previous BAY 2306001/ISIS 416858 and BAY 2976217 /
ION 957943 studies are eligible.
Other Exclusions
19.
Any other conditions, which, in the opinion of the investigator or Sponsor would 
make the subject unsuitable for inclusion
20.
Confirmed pregnancy
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria.
Individuals who do not meet the criteria for participation in this study (declared as screen 
failure) may be rescreened once.
The investigator should ensure that the resolution of a prior exclusionary circumstance or 
condition is fully resolved.
The investigator has to ensure that the repeated screening procedures do not expose the 
participant to an unjustifiable health risk. In addition, the participant must re-sign the ICF
during re-screening. Rescreened participants will be assigned a new participant number and 
all assessments for the study must be repeated. 
                                                
3 One re-assessment of hemoglobin and platelet levels is allowed during the screening period.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
Table 6–1: Study interventions administered
Arm Name
BAY 2976217
Placebo
Intervention Name
BAY 2976217
Placebo
Type 
Drug
Placebo
Dose Formulation
solution for injection
solution for injection
Unit Dose Strength(s)
100 mg/mL
not applicable
Dosage Level(s)
40 mg, 80 mg or 120 mg (or 
100 mg if dose reduction is 
recommended by DMC)
not applicable
Route of 
Administration
SC injection
SC injection
Use
Experimental
Placebo
Packaging and 
Labeling
Study intervention will be provided 
in 2 mL colorless vials.
Each vial will be labelled as 
required per country requirement.
Study intervention will be provided 
in 2 mL colorless vials. Each vial 
will be labelled as required per 
country requirement.
Current/Former 
Name(s) or Alias(es)
ION-957943
not applicable
DMC = Data Monitoring Committee, SC = Subcutaneous
BAY 2976217 is supplied in 2 mL clear, single-use injection glass vials as a solution. 
BAY 2976217 is a solution with a concentration of 100 mg/mL. The total content of the glass 
vial is approximately 1.05 mL, corresponding to 100 mg BAY 2976217. From the total 
1.05 mL, 0.8 mL (i.e. 80 mg) are extractable volume and 0.25 mL (i.e. 25 mg) are overfill.
Placebo to BAY 2976217 is supplied in 2 mL clear, single-use glass vials as a solution with a 
content of 1.05 mL (0.8 ml extractable volume). Further details can be found in the handling 
instruction provided separately.
Different doses will be achieved by administering a different volume. For dosage regimen and 
planned duration of intervention see Section 4.1.
Study intervention will be administered any time from 15 minutes before the start of dialysis
to 15 mins after the start of dialysis, when administered on a dialysis day.
Study intervention can be administered in the following SC injection areas:

Abdomen (upper right, upper left, lower right, lower left) 

Thigh 

Outer area of upper arm 
Note: Injection is not to be given within two inches (5cm) of any of the following: the 
umbilicus, the active reaction area of a previous injection, or in areas of the skin that are 
burned, reddened, inflamed, or swollen. Injections may be administered to a location that 
previously was involved in an injection site response provided that any symptoms have 
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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. 
6.3
Measures to Minimize Bias: Randomization and Blinding
After a participant has signed an ICF, the unique PID will be assigned via 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 7 for each participant.
All participants will be centrally assigned to randomized study intervention using 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 the IWRS will be 
provided to each site
Participants who meet the entry criteria will be randomized as described in Section 4.1
Participants will be stratified as described in Section 4.1
In order to be able to prepare and administer the correct volume of study intervention to be 
injected, sponsor, participants and investigators will be aware of dose cohort assignment, but 
blinded with respect to active treatment versus matching placebo. The CIAC will be blinded 
to cohort allocation and treatment assignment. DMC will have access to unblinded data as 
outlined in the DMC charter.
In order to maintain the blind, BAY 2976217 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 
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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.
Central lab results for PD parameters including coagulation parameters will not be provided to 
the sites or other blinded personnel, as these are potentially unblinding. Investigators will also 
avoid local testing of coagulation parameters, as these may be unblinding, unless clinically 
indicated.
Bioanalytics and pharmacometrics staff will be unblinded according to Bayer SOPs. 
Bioanalysis and 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 the unblinded data.
6.4
Study Intervention Compliance
Participants are dosed at the site, and they will receive study intervention directly from the 
investigator or other qualified and trained staff. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the 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
Prior medications that should be stopped at least 5 days prior to the first study intervention (if 
clinically appropriate) and are not allowed concomitantly with the study intervention are:

Antiplatelets except ASA ≤ 150 mg/day (e.g., clopidogrel, ticagrelor, prasugrel, 
dipyridamole, ASA >150 mg/day).
o
If a participant is taking low dose ASA (≤150mg/day) at randomization, the 
dosage should not be changed during the study, unless clinically indicated; if 
the dose is permanently increased >150 mg/day the participant should 
discontinue study intervention.
o
All efforts should be made during the treatment period to avoid change in ASA 
use, unless clinically indicated

Anticoagulant agents (e.g., VKAs such as phenprocoumon, warfarin-sodium, or 
DOAC oral anticoagulants such as rivaroxaban, apixaban, dabigatran, UFH, LMWH, 
etc.).

UFH or LMWH other than used during the hemodialysis session to prevent clotting of 
dialysis circuit or to maintain patency of hemodialysis access.
If a prohibited concomitant medication is indicated, study intervention will be temporarily
interrupted. 
In case study intervention is interrupted for >56 days, the participant will be discontinued 
from study intervention as described in Section 7.2.
In case study intervention is interrupted for ≤56 days, study intervention may be restarted as 
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of signing of the ICF or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Specifically, anticoagulants and antiplatelet agents taken within 30 days prior to Visit 1 even 
if taken before the ICF was signed should also be recorded in the eCRF.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.6
Dose Modification
See Section 4.1 for information on dose modification. No dose modifications are allowed 
except for the one described in section 4.1 (Cohort C), if recommended by the DMC.
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. Participants who completed or 
prematurely discontinued the study will discontinue study intervention and will switch to the 
most appropriate available treatment at the physician’s discretion.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for key outcome events, as described in 
Section 7.1.1, unless the participant withdraws from the study. See the SoA (Section 1.3) 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.
Abnormal liver function
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined in Section 8.3.8.2 or if 
the investigator believes that it is in best interest of the participant. 
Cardiac changes
If a clinically significant finding is identified in ECG (including, but not limited to changes 
from baseline in QT interval corrected using Bazett’s formula [QTcB] or Fridericia’s formula 
[QTcF]) after enrollment, the investigator or qualified designee will determine if the 
participant can continue in the study and if any change in participant management is needed. 
This review of the ECG printed at the time of collection must be documented. Any new 
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See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.1.1
Events Requiring Definitive Discontinuation of Study Intervention
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
8.2.1 and 8.3]) that in the judgment of the investigator necessitates permanent 
discontinuation of study intervention.

Requires surgery that in the judgment of the investigator necessitates permanent 
discontinuation of study intervention.

The participant develops laboratory test abnormalities that meet any of the stopping 
rules listed in Section 8.3.8.1.2 and 8.3.8.2.2.

The participant is no longer on maintenance hemodialysis (including 
hemodiafiltration) for a minimum of 9 hours per week, including a change in dialysis 
modality (e.g. peritoneal dialysis) or renal transplantation.

The participant moves their dialysis care to a different hemodialysis facility where the 
study team cannot continue to follow the participant.

The participant begins treatment with a disallowed concomitant medication and the 
study intervention is interrupted for >56 days, as described in Section 6.5. 
When a study participant discontinues the study intervention early:

During the main treatment period, the participant should conduct Visit 22 four weeks 
after the last dose of study intervention

During the extended treatment period, the participant will conduct Visit 28 four weeks 
after the last dose of study intervention

In both cases, the participant will then enter the 16-week follow-up period, giving a 
total of 20 weeks of follow-up from the last dose of study intervention.
If the participant moves their dialysis care to a different hemodialysis facility where the study 
team cannot follow the participant, all efforts should be made to conduct the evaluation and 
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. The reason for discontinuation of
study intervention must be recorded in the eCRF and source documentation.
7.1.2
Temporary Discontinuation 
The investigator may temporarily discontinue study intervention for an AE, bleeding event, 
temporary use of prohibited concomitant medication, for a surgery or other invasive 
procedure, or any other reason not listed as reasons for definitive discontinuation of study 
intervention (Section 7.1.1) or withdrawal from the study (Section 7.2). Examples of these are 


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(but not limited to): if any exclusion criterion applies during treatment, if a significant 
violation of the protocol occurs, as defined by the sponsor.
If the discontinuation remains necessary > 56 days from the last dose, the participant will be 
permanently discontinued from study intervention.
7.1.3
Rechallenge
Participants who permanently discontinue the study intervention must not be re-challenged
(i.e., must not restart study intervention). Participants who temporarily discontinue study 
intervention (for less than 57 days) (Section 7.1.2) may be rechallenged after careful 
assessment by the investigator of the potential risks.
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. If the participant withdraws consent, or the investigator withdraws the 
participant, the reason for withdrawal should be recorded on the eCRF.

Additional reasons for withdrawal from the study:
o
Death of participant, in which case only relevant eCRF pages will be 
completed (e.g.- AEs [including the cause of death] and concomitant 
medications up to death, vital status, etc).
o
The participant signs-off dialysis without expected return of life-sustaining 
kidney function or without transferring to an alternative form of renal-
replacement therapy, the reason for withdrawal of renal replacement therapy 
should be recorded on the eCRF.
o
If a stopping rule is met (see Sections 8.3.8.1.2, 8.2.1.1 and 8.3.8.2.2 ) during 
the screening period, the participant should be screen-failed.

At the time of discontinuing from the study, if possible, an early termination visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that 
need to be completed.

The participant will be permanently discontinued 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 is permanently discontinued/withdrawn from the study, the Early Termination 
Visit in the SoA will be conducted immediately. All study outcomes will be censored at Early 
Termination.
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
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
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
The investigator should make all efforts to determine the survival (vital status) of any 
participant who would otherwise be lost to follow-up during the treatment period or post-
treatment follow-up period, whether by direct contact or indirect contact with a reliable source 
(family-member, health-care provider, etc). The survival status will be recorded in the eCRF.
If no survival status is known, the contact attempt will be recorded.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA.

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. 
Unscheduled study visits will be documented in the eCRF. 
8.1
Efficacy Assessments 
The following efficacy outcomes will be assessed by the blinded CIAC in accordance with the 
pre-specified endpoint criteria in the adjudication charter:

Death due to MI, stroke, PE or SE

Non-fatal MI

Non-fatal stroke


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
Major amputation of vascular etiology 

Acute limb ischemia (new onset ischemia or worsening or pre-existing ischemia)

Venous thromboembolism

Thrombosis of the arterio-venous grafts or fistulas
All deaths and events suspected to be related to cardiovascular disease, or other arterial or 
venous thrombosis events (including arterio-venous access thrombosis), but not limited to 
these, will be reported as an AE or SAE as per adverse event reporting procedure in Section 
8.3. Additionally, the event will be triggered, within the eCRF, for adjudication by the CIAC. 
Details for the adjudication process are described in the adjudication charter. 
8.2
Safety Assessments 

Bleeding events, including minor bleeding such as injection site-related bleeding

AEs, including AEs of Special Interest, AEs leading to discontinuation of study 
intervention 

Vascular access bleeding: Assessment of the severity of bleeding at the dialysis access 
following the hemodialysis procedure (see Section 8.2.1.4 for details)

Injection site events (see section 8.3.9 for details)

Signs of hypersensitivity during and immediately after the administration of 
BAY 2976217 or placebo

Clinical laboratory data including (but not limited to):
o
CBC with differential count and platelets
o
Liver enzymes

Post HD blood pressure and ECG

Evaluation of concomitant medication

Changes in dialysis prescription and missed dialysis sessions
Laboratory assessments for safety will occur every 2 weeks during main treatment period. 
During extended treatment period, platelet count and ALT/AST should be measured every 2 
weeks, local lab monitoring at unscheduled visits can occur between the scheduled visits. 
Clinically significant changes in platelet count, ALT/AST are to be reported (as laboratory 
parameters as well as adverse events). All other laboratory assessments for safety will occur 
every 4 weeks at the scheduled visits, as described in the SoA.
If the platelet value or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis 
or quantity not sufficient) or missing, a local or central laboratory repeat blood specimen may
be re-drawn as soon as possible (preferably at the next dialysis session).
Incidence, severity and seriousness of AEs, and SAEs as well as the causal relationship 
between an AE/SAE and the administration of the study intervention and a causal relationship 
with ESRD and/or dialysis will be assessed throughout the study.
Planned time points for all safety assessments are provided in the SoA. Clinically significant 
abnormal findings will be reported as AEs in the eCRF.


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8.2.1
Bleeding events
The composite of MB and CRNMB as assessed by CIAC, is the primary endpoint in this 
study. 
Participants will be evaluated for occurrence of bleeding events continuously after signing 
consent up to end of the post-treatment follow-up for all cohorts. All bleeding events (other 
than the normal bleeding from arterio-venous graft or fistula post-dialysis) will be reported as 
AE or SAE per Section 8.3. Additionally, CIAC will have continuous access to data necessary 
for adjudication.
Bleeding events that are clinically significant will need to be monitored and treated 
immediately. Monitoring will include post HD blood pressure, labs (local CBC as needed), 
additional outpatient visits, overnight stays and laboratory tests may be needed for as long as 
necessary. Coagulation parameters are potentially unblinding, and local measurement should 
be avoided unless clinically indicated.
Bleeding after dialysis from arterio-venous graft or fistulas is expected and will only be 
reported as an AE or SAE and submitted to CIAC 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 week. 
The CIAC will classify bleeding events primarily based upon the ISTH definitions (41):
Major bleeding is defined as symptomatic bleeding and:

Fatal bleeding, and/or

Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intraarticular or pericardial, or intramuscular with compartment 
syndrome, and/or

Bleeding causing a fall in hemoglobin level of 20 g/L (2.0 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 bleeding is defined as 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 (i.e., not just a telephone or electronic communication) 
evaluation
Bleeding after dialysis from arterio-venous graft or fistulas is frequent, often requiring 
medical intervention. Medical interventions and face-to-face evaluations taken for post-
dialysis hemostasis of arterio-venous graft or fistula may be considered expected bleeding for 
the clinical circumstance by the investigator, and not reported as an AE/SAE and an 
adjudication package does not need to be sent to the CIAC. If events of post-dialysis bleeding 
are submitted to the CIAC that do not represent a change over the prior week for those 
participants, the events will be considered as expected bleeding for the clinical circumstance 
by the CIAC, and not adjudicated as CRNMB.  


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All other symptomatic bleeding episodes not meeting the criteria for CRNMB will be 
classified as minor bleeding.
8.2.1.1
Stopping Rules for Bleeding Events
If clinically significant bleeding occurs, careful assessment of the suitability of the participant
for continuation of dosing by the investigator will be made prior to resuming study 
intervention. In case the study intervention should be discontinued permanently, the 
participant should complete study visits as described in Section 7.1.1 including evaluation 
period and the post-treatment follow-up period.
8.2.1.2
Remedial Treatment for Bleeding
In general, the management of bleeding is at the discretion of the treating physician and 
should follow standard of care or applicable local guidelines, and should be tailored to the 
patient and their condition. Local prescribing information should be consulted for usage in 
ESRD for any drug administered. The following suggested approach is preliminary, based on 
currently available information and advice from external experts. As clinical experience 
accrues, these suggestions may be refined. 
If a participant has clinically significant bleeding event during the study, the following basic 
measures should be considered by the investigators to control bleeding:

Local measures for hemostasis - mechanical compression, interventional radiology, 
surgical intervention.

Hemodynamic resuscitation and volume management: fluid replacement & 
hemodynamic support, replacement blood products as appropriate, with careful 
volume management- packed red blood cells, platelet concentrate, FFP, 
cryoprecipitate or fibrinogen concentrate

If knowledge of treatment assignment will influence the choice of intervention during 
a bleeding event, the investigator may immediately obtain the participant’s treatment 
assignment by contacting IWRS; if unblinding is planned, aPTT, FXI levels and other 
standard coagulation tests may be measured locally.

Delay of the next injection of study intervention, or permanent discontinuation 
(Section 7.1).

Discontinue antiplatelet drugs and discontinue other concomitant medications that 
could exacerbate bleeding
Antifibrinolytics are often the first line therapy administered to congenital FXI deficient 
patients with bleeding (42). These agents are also used in patients without FXI deficiency
(e.g.- bleeding after trauma (43), post-partum bleeding (44)), and can be administered without 
unblinding the patient.

Tranexamic acid (consult prescribing information for use in reduced kidney function
(45))

Epsilon aminocaproic acid
If bleeding cannot be controlled by applying basic measures and antifibrinolytic therapy (if 
available), the investigator may consider administration of one of the following FXI 
replacement therapies, if available and used as part of local practice (according to the dosages 
advised in the package insert of the respective compound):


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
Fresh-frozen plasma (FFP)

Factor XI concentrate (Hemoleven®)
The dose of FFP or factor concentrate given should aim to increase Factor XI activity above 
0.3 U/mL. In a study of congenital FXI deficient patients, those with FXI > 0.2 U/mL had 
1/4 to 1/5th of the bleeding risk of those with FXI < 0.2 U/mL (42). Careful assessment of the 
participant’s volume status should be made when infusing factor replacement.
The investigator should recognize that the half-life of circulating Factor XI is approximately 
50 hours when considering the potential need for re-administration, particularly of FFP or FXI 
concentrate. Additionally, the time necessary to obtain a Factor XI concentration locally and 
to infuse FFP should be taken into consideration.
If uremic coagulopathy/platelet dysfunction is suspected, adjuvant measures may be 
considered (e.g.- desmopressin,  conjugated estrogens, etc) (46).
If bleeding cannot be controlled by these measures, administration of one of the following 
medications may be considered, if available and used as part of local practice (according to 
the dosages advised in the package insert of the respective compound). Due to risk of 
thrombosis, careful attention to dosing these procoagulants is needed. 

Recombinant Factor VIIa (NovoSeven®)

4-factor concentrate (prothrombin complex concentrate)
If a participant is unblinded, they may resume study treatment at the discretion of the 
investigator, but may be excluded from certain analyses.
8.2.1.3
Recommendations for Surgeries Including Kidney Transplant
Regarding management of bleeding risk in the surgical setting with FXI deficiency, there is 
clinical trial experience with BAY2306001. Patients undergoing total knee replacement in 
ISIS 416858-CS3 with the unconjugated FXI ASO (BAY 2306001), treated prior to surgery 
with 300 mg of the ASO, underwent their surgery with mean FXI levels of less than or equal 
to 0.2 U/mL (severe deficiency is < 0.3 U/mL) and a mean aPTT ratio of 1.4. Despite this, 
patients treated with ASO before their surgery had a rate of clinically significant bleeding of 
3%, less than half the rate observed in patients treated with enoxaparin (40 mg initiated the 
day of surgery and administered for 9 consecutive days), however, these differences were not 
statistically significant (38). 
BAY 2306001 was also studied in 213 ESRD patients on HD in ISIS 416858-CS5. Three 
kidney transplants occurred without prophylactic measures taken after dosing with BAY 
2306001, without bleeding or other complications. Values for FXI activity collected prior to 
surgery ranged from 0.42 to 0.74 U/mL (reference range 0.73 to 1.45 U/mL), and the aPTT 
28.5 to 39.4 sec (reference range 22.4 to 30.0 sec).
Spinal/epidural anesthesia should only be considered if the FXI levels are known, and within 
normal limits. Otherwise, only general or local anesthesia should be used.
In the event a participant requires an elective surgical or other invasive procedure and a delay
in the procedure until 20 weeks after the last dose of study intervention is not possible, the 
investigator should consider scheduling the surgery at the time of the next scheduled dose of 
study intervention (the end of a 28-day dose cycle) and the dose will be held until after 
surgery. In case of a surgery or other invasive procedure, participants may be temporarily or 


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permanently discontinued from further dosing of study intervention as outlined in Sections 
7.1.1 and 7.1.2.  
In the setting of an elective procedure that cannot be postponed until 20 weeks from the last 
dose of study intervention, or for an emergent procedure that is:

A major surgery (surgical procedure involving an organ within the cranium, chest, 
abdomen, or pelvic cavity) including kidney transplant

An extensive procedure in tissue with high fibrinolytic activity (e.g. gynecologic, 
urologic, or surgeries of the nasal and oral cavities)

or otherwise at high risk of perioperative bleeding, 

and 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 locally and the 
investigator may also monitor FXI levels locally.  
Careful post-operative assessment of the participant and his/her ongoing bleeding risk should 
be made by the investigator, before restarting study intervention. The investigator may 
consider restarting study intervention for minor procedures or surgeries at sites with low 
fibrinolytic activity (e.g. knee arthroplasty). Caution should be used when restarting study 
intervention after a major surgery or a surgery in an area of high fibrinolytic activity (e.g.,
gynecologic, urologic, or surgeries of the nasal and oral cavities). Participants who 
discontinue study intervention early due to a surgery will continue in the study as described in
Section 7.1.1.
If a participant is unblinded, he/she may resume treatment at the discretion of the investigator
but may be excluded from certain analyses.
There is an accepted approach to managing bleeding risk in surgical patients with congenital 
FXI deficiency that is likely relevant to acquired FXI deficiency with BAY 2976217
treatment (42). Firstly use of ASA should be discontinued 1 week before surgery; sites of 
surgery that include tissues with increased fibrinolytic activity are expected to bleed more 
than sites with low fibrinolytic activity; and assessment of the cardiovascular status of the 
participant when using factor replacement therapy is essential for two reasons: (i) when use of 
fresh-frozen plasma (FFP) is planned, volume overload might be a problem if cardiovascular 
function is compromised, and (ii) compromised cardiovascular function confers a risk of 
thrombosis when FXI concentrate is used.
Congenital FXI deficiency patients requiring minor procedures such as tooth extraction or 
skin biopsy have been safely treated with local antifibrinolytic agents alone (mouthwash (47), 
topical), however, care in use and dosing is needed for systemic dosing in ESRD patients
(e.g., aminocaproic acid, tranexamic acid). Uneventful tooth extractions were reported in 
patients with severe FXI deficiency treated with systemic tranexamic acid alone (48).
For major surgery (defined as a surgical procedure involving an organ within the cranium, 
chest, abdomen, or pelvic cavity) including kidney transplant, prophylaxis with an 
antifibrinolytic such as aminocaproic acid or tranexamic acid could be considered with careful 
consideration of appropriate use and dose in ESRD (consult the prescribing information). 
Prophylaxis with antifibrinolytics have been used in both congenital FXI deficiency (42) and 
those without FXI deficiency (49). The administration of low-dose recombinant FVIIa along 


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with tranexamic acid was also reported as a prophylaxis option in patients with severe FXI 
deficiency undergoing surgery (50, 51).
Factor replacement therapy may also be considered prophylactically, and in any case should 
be on stand-by during surgery. Factor replacement is typically with FFP, as FXI concentrate
replacement is not universally available. Careful attention to and management of ESRD 
participant’s volume status when infusing blood product is essential.  If uremic platelet 
dysfunction is suspected, adjunctive therapy could also be considered (e.g., desmopressin, 
conjugated estrogens).
Based on recommendations in congenital FXI deficiency (42), replacement therapy with FFP 
(or FXI concentrate infusions, if available) should be targeted to reach a trough FXI level of 
0.45 U/mL (or higher) for approximately 7 days after surgery. The investigator should 
recognize that the half-life of circulating Factor XI is approximately 50 hours when 
considering the potential need for re-administration, particularly of FFP or FXI concentrate. 
Additionally, the time necessary to obtain a Factor XI concentration locally (if the 
investigator chooses to unblind the participant) and to infuse FFP should be taken into 
consideration.
8.2.1.4
AV access bleeding
Severity of bleeding at the dialysis access will be assessed approximately 15 minutes after 
removal of the dialysis needle(s) from the vascular access at the end of the dialysis session on 
the visit day (or from a dialysis session within the visit window if the visit is not conducted on 
a dialysis day) according to the following categories (exploratory bleeding score):

“0” no access bleeding

“1” slow oozing

“2” overt bleeding
In the case the bleeding stops before the end of the 15-minute period after removal of the 
dialysis needle(s) from the vascular access (score 0), the assessment may be done prior to the 
end of the 15-minute period.
In case a catheter is used, the AV access bleeding is not applicable.
8.2.2
Physical Examinations
Physical examinations will be conducted in a response to new or changes in symptoms. Any 
clinically meaningful change in physical examination will be reported as an AE/SAE. Height 
will only be measured at screening visit. Weight will be measured pre- and post-hemodialysis 
(wet-weight and dry-weight, respectively).
8.2.3
Vital Signs

The investigator will assess blood pressure eligibility (Section 5.2) using the most 
appropriate method of blood pressure measurement available for the participant to 
determine the presence/absence of sustained uncontrolled hypertension.

For subsequent study visits, blood pressure measurement will be assessed post-HD on 
the visits indicated in the SoA (Section 1.3), 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.  


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
The AV graft or fistula arm cannot be used to measure blood pressure.
8.2.4
Electrocardiograms

Single 12-lead ECG will be obtained locally as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.

Any clinically meaningful change in the ECG tracings as assessed by the investigator 
relative to baseline (tracings from the Screening Period) will be reported as an 
AE/SAE.

All events of potential myocardial ischemia or infarction will be submitted to the 
CIAC for evaluation.
8.2.5
Clinical Safety Laboratory Assessments

See Section 10.2 for the list of clinical laboratory tests to be performed and refer to the 
SoA for the timing and frequency. 

Where possible, 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.

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 abnormal values considered clinically significant during 
participation in the study after the last dose of study intervention should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or the Medical Monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
sponsor notified.
o
All protocol-required laboratory assessments, as defined in Section 10.2, must 
be conducted in accordance with the laboratory manual and the SoA. 
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE or dose modification), then the results must be recorded in the 
eCRF.
8.2.6
Dialysis information
8.2.6.1
Renal Replacement Therapy Baseline Information
Information on the participant’s history of ESRD and RRT, as well as current dialysis 
prescription with be collected at screening (Visit 1) on the appropriate eCRF.


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Note: anticoagulation use during hemodialysis must be reported in the Concomitant 
Medication page in the eCRF (separate log lines for bolus applications, continuous 
application, dose changes).
8.2.6.2
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 (Section 1.3).
Note: changes in anticoagulation use during hemodialysis must be reported on the appropriate 
eCRF page.
8.2.7
Medical History
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below (but not limited to) will be collected as available to the investigator:

Start before signing of ICF

Considered relevant for the participant’s study eligibility

Pertaining to the study indication or considered relevant to the study (e.g. 
thromboembolism, major adverse cardiac events and related chronic 
conditions/diseases, major adverse limb events and related chronic 
conditions/diseases, metabolic diseases, and ESRD related diseases)

Medical history related to concomitant medication.
A targeted medical history regarding cardiovascular and thromboembolic disease history will 
be collected in the eCRF on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section.
8.3
Adverse Events and Serious Adverse Events
In order to evaluate the safety and tolerability of BAY 2976217, adverse events will be 
assessed as a secondary safety endpoint.
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 the study 
(see Section 7).
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AE/SAEs will be collected from the signing of the ICF until the final follow-up visit at the 
time points specified in the SoA (Section 1.3). Adverse events of special interest (AESI) have 
to be reported at any time after randomization (treatment, and post-treatment follow-up 
periods).
All SAEs/AESI 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.


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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 AEs of special interest (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. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.

For all studies except those utilizing medical devices investigator safety reports must 
be prepared for SUSARs 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 IECs / IRBs and investigators will be done according 
to all applicable regulations 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. Vascular Death (due to MI, stroke, PE, and SE)


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iii. Non-fatal stroke, non-fatal MI
iv. Major amputation of vascular etiology
v. Acute Limb ischemia
vi. Symptomatic VTE
vii. Thrombosis of arterio-venous grafts or fistulas
These will be recorded on the corresponding eCRF page in the participant’s eCRF.
If any of the above listed outcome events fulfil the definition of SAEs as given in Section 
10.3.2, the investigator must report them immediately (within 24 hours of the investigator’s 
awareness) to the sponsor’s pharmacovigilance department as described in Section 10.3.4. 
However, SUSARs that derive from these efficacy outcome events (as specify above ii – vii: 
vascular death, non-fatal stroke/MI, major amputation, acute limb ischemia, symptomatic 
VTE, thrombosis of arterio-venous graft or fistulas), 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 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 female partners of male 
participants will be collected after signing of the ICF and during the participant’s 
participation in this study.

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 βHCG levels are high in pregnancy and may be elevated in non-pregnant women
with ESRD undergoing hemodialysis, one measurement of high βHCG will not be sufficient 
to establish pregnancy. Several serum βHCG will be collected during the study (SoA) for this 
reason and only sequential increasing levels of βHCG will be considered for further 
investigation. If deemed necessary, a follow-up ultrasound can be performed to confirm 
pregnancy. 
If a female participant becomes pregnant, she must permanently discontinue study 
intervention. 
8.3.6
Cardiovascular and Death Events
Death will be reported with the known cause of death as a SAE. Additionally, an electronic 
adjudication package will be submitted to the CIAC. If the cause of death is unknown, then a 
cause of death will be assigned by the CIAC. In order not to delay reporting within the 
required timeframe, when the cause of death is not known, the event should be reported as 
“Death not otherwise specified.” If follow-up reports are received with the actual cause of 
death, the report will be updated.
For cardiovascular events see Section 9.4.6.1


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8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Bleeding after dialysis from arterio-venous 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.
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 75,000/mm3, or > 50% decrease in platelet from baseline

Elevation of Hepatic Enzymes (> 3 x ULN, or 3 x baseline value, if the baseline value 
was > ULN)
8.3.8.1
Thrombocytopenia
8.3.8.1.1
Criteria for Reporting Thrombocytopenia as an Adverse Event of 
Special Interest
In the event of a platelet count that is <75,000/mm3, or >50% decrease in platelet count from 
baseline, at any time after randomization (treatment, and post-treatment follow-up periods), 
the event will be reported as an AESI within 24 hours of the investigator’s awareness. Non-
serious AESI should not automatically be upgraded to serious on the AE page in the eCRF by 
the reporting investigator.
8.3.8.1.2
Stopping Rule for Thrombocytopenia
If a participant’s platelet count is <75,000/mm3, the initial measurement should be confirmed 
by drawing a repeat measurement at the next dialysis session (by local lab), and no more than 
7 days after the initial value was obtained. The repeat measurement must occur before further 
dosing of study intervention. In the event of confirmed <75,000/mm3 and the event is without 
an alternative explanation, dosing of a participant with study intervention will be stopped 
permanently; values that are not confirmed due to failure to retest or missing lab values will 
be presumed confirmed.
If the stopping rule criteria is met during the screening period, the participant should not be 
randomized and will discontinue from the study.


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8.3.8.1.3
Monitoring and Evaluation of Thrombocytopenia
If a participant’s platelet count is 100,000/mm3 or less, or there is > 50% decrease in platelet 
count from baseline, then the platelet count should be monitored weekly by local lab. 
Additional assessments can be done locally, as deemed necessary, at the investigator’s 
discretion. The following list is only a suggestion and is not limited to the lab tests outlined 
below. Only relevant local laboratory values need to be recorded in the eCRF.

Von Willebrand factor

Total globulins, total IgA, IgG and IgM

Serology for:  
o
Hepatitis B, Hepatitis C, HIV 
o
Rubella 
o
Cytomegalovirus 
o
Epstein–Barr virus
o
Parvo B19 
o
Helicobacter pylori (IgG serum test) 

Auto-antibody screen: 
o
Antiphospholipid 
o
Rheumatoid factor 
o
Anti-dsDNA 
o
Anti-thyroid 
Central labs to be performed if platelet count < 75,000/mm3: 

Complement: total C3, total C4, Bb, C5a
To be performed at specialty lab(s) 

Antiplatelet antibodies and Anti-PF4 assay 

Anti-ASO antibody 
In the event of a platelet count < 50,000/mm3, platelets are to be monitored daily (local lab)
until 2 successive values show improvement, then monitored every 2-3 days until the platelet 
count is stable. 
A stable platelet count is considered when at least 2 consecutive values measured are 
> 100,000/mm3 with no downward trend. 
8.3.8.1.4
Remedial Treatment for Thrombocytopenia
It is recommended that the participant receive glucocorticoid therapy to accelerate the 
recovery in the platelet decline (strongly recommended if platelet count < 25,000/mm3). 
Treatment guidelines for immune thrombocytopenia recommend dexamethasone 40 mg daily 
for 4 days every 2-4 weeks for 1-4 cycles; prednisolone 0.5-2 mg/kg/day for 2-4 weeks then 
taper; or methylprednisolone 30 mg/kg/day for 7 days (note: may require continuation with 
oral corticosteroids after methylprednisolone) (54).


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All additional platelet values, results of evaluations, and remedial treatments will be reported 
to the Sponsor as unscheduled laboratory visits and by updating the AESI report with all 
additional information, within the required timelines for follow-up information.
8.3.8.2
Elevation of Hepatic Enzymes
In the event of an ALT or AST measurement that is > 3 x ULN, or 3 x baseline value (if the 
baseline value was > ULN), at any time after randomization (treatment, and post-treatment 
follow-up periods), the event will be reported as an AESI and the following monitoring, 
evaluation, and stopping rules will apply. The following rules are adapted from the draft 
guidance for industry, “Drug-Induced Liver Injury: Premarketing Clinical Evaluation,” issued 
by the U.S. Department of Health and Human Services, Food and Drug Administration, July 
2009 (55).
8.3.8.2.1
Criteria for Reporting Elevation of Hepatic Enzymes as an Adverse 
Event of Special Interest
In the event of an ALT or AST measurement that is > 3 x ULN, or 3 x baseline value (if the 
baseline value was > ULN), at any time after randomization (treatment, and post-treatment 
follow-up periods), the event will be reported as an AESI.
8.3.8.2.2
Stopping Rule for Elevation of Hepatic Enzymes
The initial measurement(s) should be confirmed by drawing a repeat measurement at the next 
dialysis session (local lab- unscheduled visit), and no more than 7 days after the initial value 
was obtained. The repeat measurement must occur before further dosing of study intervention. 
Hepatic enzyme values that are not confirmed due to failure to retest or missing lab values 
will be presumed confirmed. In the event of confirmed laboratory results meeting the 
following criteria, and the event is without an alternative explanation, dosing of a participant
with study intervention will be stopped permanently.
Liver Chemistry:
1. ALT or AST > 8 x ULN, which is confirmed
2. ALT or AST > 5 x ULN or 5 x baseline value (if the baseline value was >ULN), 
which is confirmed and persists for ≥ 2 weeks
3. ALT or AST > 3 x ULN or 3 x baseline value (if the baseline value was >ULN), 
which is confirmed and total bilirubin > 2 x ULN or 2 x baseline value (if the baseline 
value was >ULN),
4. ALT or AST > 3 x ULN, which is confirmed (or 3 x baseline value if the baseline 
value was > ULN) with the new appearance (i.e., onset coincides with the changes in 
hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or concomitant eosinophilia (> ULN)
In the event that the stopping rule criteria are met during the screening period, the participant
should not be randomized and will discontinue from the study.
8.3.8.2.3
Monitoring and Evaluation of Elevation of Hepatic Enzymes
If the participant has confirmed post-baseline ALT or AST levels > 3 x ULN, or 3 x baseline 
value (if the baseline value was > ULN) that are continuing to rise, they should have their 
liver chemistry tests (ALT, AST, INR and total bilirubin) retested at least once-weekly by 


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local lab until ALT and AST levels become ≤ 1.2 x ULN or ≤ 1.2 x baseline (if the baseline 
value was > ULN). 
If the participant has discontinued treatment due to achieving stopping rule (see Section 
8.3.8.2.2) they will still be monitored until ALT and AST levels become ≤ 1.2 x ULN or ≤ 1.2 
x baseline (if the baseline value was > ULN).
Additionally, for participants with confirmed ALT or AST levels > 3 x ULN (if baseline 
values ≤ULN) or > 3 x baseline (if baseline value was > ULN) during the treatment and post-
treatment follow-up periods, the following evaluations should be performed:
1. Obtain a more detailed history of symptoms and prior and concurrent diseases
2. Obtain further history for concomitant drug use (including nonprescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets
3. Obtain a history for exposure to environmental chemical agents and travel
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic 
computed tomography or magnetic resonance imaging scans, may be performed at the 
discretion of the investigator. Repetition of the above evaluations should be considered if a 
participant’s ALT and/or AST levels further increase and reach > 5 x ULN (or 5 x baseline 
value, if baseline value was > ULN).
All additional hepatic enzyme values and results of evaluations will be reported to the 
Sponsor as unscheduled laboratory visits and by updating the AESI report with all additional 
information, within the required timelines for follow-up information.
8.3.9
Injection-related events
An injection site event is defined as:
(a) 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
(b) any AE at the injection site, regardless of severity, that led to discontinuation of Study 
Drug, where the AE at the injection site was the principal reason for discontinuation.  
8.3.10
AEs requiring submission of an adjudication package to the CIAC
All deaths, and events suspected to be related to cardiovascular disease, or other arterial or 
venous thrombosis (including arterio-venous access thrombosis) occurring after 
randomization, but not limited to these, will be submitted to the CIAC for adjudication. 
Additionally, all bleeding events (except a participant’s normal/expected post-dialysis 
bleeding from arterio-venous access) will be submitted to the CIAC for adjudication. Details 
for the adjudication process are described in the adjudication charter and additional study 
specific guidance documents. 
8.4
Treatment of Overdose
For this study, any dose of study intervention given in addition to the pre-defined regular 
monthly administration of BAY 2976217 will be considered an overdose. The Sponsor does 
not have a general recommendation for treatment of an overdose especially in the absence of 
any signs or symptoms.


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In the event of an overdose, the investigators should:
1. Contact the Sponsor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
BAY 2976217 can no longer be detected systemically (at least 20 weeks).
3. Obtain a plasma sample for PK analysis within 21 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis).
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

Plasma and dialysate samples will be collected for measurement of plasma and 
dialysate concentrations of BAY 2976217 and its metabolites (e.g. in plasma as 
total full-length oligonucleotide, including fully conjugated, partially conjugated, 
and unconjugated BAY 2976217) as specified in the SoA. Samples will be 
collected in all participants. A subset of at approximately 24-40 participants will 
be participating in an alternative PK&PD sampling group with the first dose on a 
non-dialysis day (Section 8.5.1.2).

Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The exact actual date and time (24-hour clock time) of each sample 
will be recorded. In addition, the actual date and time of study intervention intake 
on the visit day will be documented in the eCRF.

Non-compartmental PK parameters will not be evaluated in this study. However, 
plasma concentration data will be used to evaluate the PK of BAY 2976217 (as 
total full-length oligonucleotide, including fully conjugated, partially conjugated, 
and unconjugated BAY 2976217) using population PK. PK and PD data obtained 
from this study will be subject to PK and/or PK/PD modeling and simulation. 
Details of the model development and evaluation will be described in a separate 
evaluation plan and the results will be reported in a separate evaluation report.
Optionally, BAY 2976217 metabolites (e.g. unconjugated BAY 2976217) may be 
analyzed in an exploratory fashion. If measured, results will be reported separately.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Details about the collection, processing, storage and shipment of samples will be provided 
separately (e.g. sample handling sheets or laboratory manual).


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8.5.1
Sampling time for PK, PD and immunogenicity
Table 8–1: Overview PK/PD and immunogenicity, sampling
Main treatment period
Sampling
Type
V1
V2a
V3a
V4a
V5
V6
V7
V8
V9
V10
V11 V12 V13 V14 V16 V18
V19
V20
V21
V22
Plasma PD
At any time
●
●
●
●
Plasma PK/PD
pre-dose (trough)
●
●
●
●
●
●
●b
3-4 h post administration c
●
●
5-6 h post administration d
●
●
22-32 h post administration
●
At any time during the visit
●
●
●
●
●
●
●
●
●b
Dialysate PK
15 min to 30 min after the 
start of dialysis
●
(●)e
●
30 min to 0 min prior to the 
end of dialysis
●
(●)e
●
Immunogenicity
Pre-dose
●f
●
●
●b
At any time
●
Extension treatment and Follow-up period
V23
V24
V25
V26
V27 V28 FU1 FU4 ET
Plasma PK/PD
pre-dose (trough)
●
●
●
●
●
PK/PD 
Any time during the visit
●
●
●
●
Immunogenicity
Pre-dose
●
●
At any time
●
●
●
ET = early termination visit, min = minute(s), h = hour(s), PD = Pharmacodynamic(s), PK = Pharmacokinetic(s)
a Visits 2, 3 and 4 are only applicable before implementation of amendment 1, for patients enrolled as of amendment 1 these visits are not performed.
b At Visit 22, plasma PK and PD, and immunogenicity sampling will be done before dosing (trough sample) if the participant receives study intervention. In cases when the 
participant does not receive study intervention at Visit 22, sampling can occur at any time during the visit.
c 3-4 hour PK sample should be taken very close to the 3 hour timepoint if possible.
d If routine care procedures are incompatible with the 5-6 hour time window, the sample may be taken earlier but not before 4 1/2 hours after study drug administration.
e Samples will be collected on V6 for patients in alternative PK&PD sampling group, as they will have dialysis on V6.
f At V5 Immunogenicity sample will be drawn pre-hemodialysis, before the first dose of study intervention.


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8.5.1.1
PK, PD and immunogenicity sampling (all participants)

Visit 5 will be conducted on a dialysis day. The first dose of study intervention will be 
administered on Visit 5, prior to the start of the dialysis session. Visit 5 plasma PK/PD
samples will be drawn at timepoints described in Table 8–1. Dialysate effluent will be 
collected 15 minutes to 30 minutes after the start of dialysis, and during the final 30 
minutes of dialysis. Visit 5 immunogenicity sample will be drawn pre-HD, before the 
first dose of study intervention. 

Visit 6 will be conducted the day after Visit 5, on a non-dialysis day. The Visit 6 
plasma PK/PD sample will be drawn 22-32 hours after the first dose of Study 
intervention administration on Visit 5.

Visit 10 will be conducted on a dialysis day. Dosing on Visit 10 will occur prior to the 
start of the dialysis session. Visit 10 plasma PK/PD samples will be drawn at 
timepoints described in Table 8–1. Dialysate effluent will be collected at 15 min to 30 
min after the start of dialysis and during the final 30 minutes of dialysis. The total 
dialysis volume should be recorded.

At Visit 12, Visit 14, Visit 16, Visit 18 (main treatment period) and Visits 23-27 
(extended treatment period) plasma PK and PD, and immunogenicity (when 
applicable) sampling will be done before dosing (trough sample), at other visits 
sampling can occur at any time during the visit.

At Visit 22, plasma PK and PD, and immunogenicity sampling will be done before 
dosing (trough sample) if the participant receives study intervention. In cases when the 
participant does not receive study intervention at Visit 22, sampling can occur at any 
time during the visit.
8.5.1.2
PK, PD and immunogenicity sampling, participants from the 
alternative PK&PD sampling group starting on a non-dialysis day

For these participants, study intervention will be administered on a non-dialysis day 
preceding a scheduled dialysis day.

Visit 5 will be conducted on a non-dialysis day preceding a scheduled dialysis day. 
The first dose of study intervention will be administered on Visit 5. Visit 5 plasma 
PK/PD samples will be drawn at timepoints described in Table 8–1. Immunogenicity 
samples will be drawn before the first dose of study intervention on Visit 5. 

Visit 6 will be conducted the day after Visit 5, on a dialysis day. The Visit 6 plasma 
PK/PD sample will be drawn 22-32 hours after the first study intervention
administration on Visit 5, and whether the sample was taken before, during or after 
dialysis will be recorded. Dialysate effluent will be collected at 15 min to 30 min after 
the start of dialysis and during the final 30 minutes of dialysis. The total dialysis 
volume should be recorded.

Visit 10 will be conducted on a dialysis day. Dosing on Visit 10 will occur prior to the 
start of the dialysis session. Visit 10 plasma PK/PD samples will be at timepoints 
described in Table 8–1. Dialysate effluent will be collected at 15 min to 30 min after 
the start of dialysis and during the final 30 minutes of dialysis. Visit 10
immunogenicity sample will be drawn pre-HD, before dosing.


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
At Visit 12, Visit 14, Visit 16, Visit 18 (main treatment period) and Visits 23-27 
(extended treatment period) plasma PK, PD, and immunogenicity (when applicable)
sampling will be done before dosing (trough sample), at other visits sampling can 
occur at any time during the visit.

At Visit 22, plasma PK and PD, and immunogenicity sampling will be done before 
dosing (trough sample) if the participant receives study intervention. In cases when the 
participant does not receive study intervention at Visit 22, sampling can occur at any 
time during the visit.
8.6
Pharmacodynamics
Blood sampling for PD parameters is scheduled for the time points as given in Section 8.5.1.
The actual date and time of blood sampling will be documented 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 PD parameters, the results of quality control samples will be reported together with 
analyte concentrations in the Clinical Study Report of this study.
Analyte results are calculated according to the method description. Detailed method 
descriptions of all PD methods will be filed with the study report.
8.6.1
Secondary pharmacodynamic parameters:
The following parameters will be used to assess the PD effects after administration of the 
investigational drug, but may be performed optionally and/or only in a subset of participants:

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 BAY 297621

FXI antigen concentration will be measured via enzyme-linked immunosorbent assay
using polyclonal antibodies
8.6.2
Other Pharmacodynamic parameters:
The following parameters will be used to assess the PD effects after administration of the 
investigational drug, but may be performed optionally and/or only in a subset of participants:

aPTT will be measured using a standard 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 BAY 297621

AXIA will be analyzed using a kaolin-trigger and a fluorogenic substrate readout

PT (seconds and INR) will be determined using standard methods

D-Dimer will be measured using an immunoturbidometric method

TAT and F1.2, will be analyzed using immunoassays

SQCS will be analyzed as described below


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Semi-quantitative Clotting Score: Extent and frequency of clotting on the dialysis filters 
& circuit
The rate/frequency of clotting on the dialysis filters and circuit will be measured as an 
exploratory PD analysis. The effect of BAY 2976317 on the clotting in the dialysis circuit 
will be assessed by the SQCS. The clotting assessment is a quantitative scale by descriptive 
category that is performed by trained personnel.
At the end of the hemodialysis procedure, at specified time points, the filter and line 
(including drip chamber/air trap) will be examined by the hemodialysis nurse (or respective 
appropriate personnel) after rinsing the circuit. 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”.
Overall score is the highest of the individual component scores:
Inspection Site 
Category 0
Category 1
Category 2
Category 3
Drip chamber
(also referred to 
as air trap)
No visible clots in
the drip chamber
Trace (e.g.-
fibrinous ring with 
no clot formation on 
venous chamber)
Intermediate (e.g.-
clot formation on 
venous chamber, 
more than “1” but not 
fully clotted)
Fully clotted 
system (treatment 
cannot continue 
without new 
setup) 
Dialyzer 
Clean dialyzer 
Trace (e.g.- blood 
stripes affecting 
less than 
approximately 5% 
of the fibers seen at 
the surface of the 
dialyzer)
Intermediate (e.g.-
blood stripes affecting 
approximately 5% or 
more of the fibers 
seen at the surface of 
the dialyzer, but not 
fully clotted)
Fully clotted filter 
Only one (highest) score will be documented in the eCRF.
The clotting score will be recorded as specified in the SoA. The dialyzer and drip chamber/air 
trap will be assessed for clotting score at the end of the dialysis session on the visit day (or 
from a dialysis session within the visit window if the visit is not conducted on a dialysis day).
For information on PD sampling see Section 8.5.
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 will be part of the biomarker investigations in this 
study. Genetic investigations may be of any kind, except for whole genome sequencing.
8.8
Biomarkers
Exploratory biomarker analyses (scheduled for the time points as given in Section 1.3), that 
might be performed optionally and/or only in a subset of participants are: 


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
FVIII, FIX and FXII activity using clotting assay (V5 only)

vWF antigen and vWF risocetin cofactor activity (V5 only)

TAFI and C1 inhibitor activity, measured using chromogenic substrate assays
In addition to the biomarkers described above, further biomarkers related to the mode of 
action or the safety of BAY 2976217 and similar drugs may be examined. 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, PD, monitoring, or 
potentially predictive biomarkers.
Furthermore, some PD markers listed under Section 8.6 may also be analyzed using 
alternative reagent/analyzer manufacturers in order to assess potential systematic influences 
of the analysis technology. The additional analyses may include genetic as well as non-
genetic biomarkers. Results will be reported under separate cover, if the evaluations are 
performed.
Details on the collection, processing, storage, and shipment of biomarker samples will be 
provided in separate documents (e.g., sample handling sheets or lab manual). Samples may be 
stored for a maximum of 15 years (or according to local regulations) following the end of the 
study at a facility selected by the sponsor to enable further analyses.
8.9
Immunogenicity Assessments
Antibodies to BAY 2976217 will be evaluated in samples collected from all participants 
according to the SoA (Section 1.3). Additionally, samples should also be collected at the final 
visit from participants who discontinued study intervention or were withdrawn from the 
study. These samples will be tested by the sponsor or sponsor's designee.
Samples will be screened for antibodies binding to BAY 2976217 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to BAY 2976217 and/or further characterize the immunogenicity of 
BAY 2976217.
The detection and characterization of antibodies to BAY 2976217 will be performed using a 
validated assay method by or under the supervision of the sponsor. Samples collected for 
detection of antibodies to study intervention may also be evaluated for BAY 2976217
concentration to enable interpretation of the antibody data. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
intervention. Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility selected by the 
sponsor to enable further analysis of immune responses to BAY 2976217.
For information on immunogenicity sampling see Section 8.5.1.
8.10
Health Economics
Not applicable


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9.
Statistical Considerations 
9.1
Statistical Hypotheses
There is no plan for statistical hypothesis testing for this study.
9.2
Sample Size Determination 
No formal statistical samples size estimates were performed.
The sample size was selected based on prior experience in ESRD with the unconjugated ASO. 
This study is planned to ensure the safety, tolerability, and PK/PD relationships are assessed 
adequately while minimizing unnecessary participant exposure. There is no plan for statistical 
hypothesis testing for this study. In this study, the number of subjects is considered based on 
the ISIS 416858-CS5 study design.
Approximately 288 participants (96 [72 active+24 placebo] per cohort) will be randomly 
assigned to study intervention so that an estimated 240 participants will complete the main 
treatment period. A participant will be evaluated once he/she was randomized and received at 
least one dose of study intervention, the number of evaluable and randomized participant is 
assumed to be similar. Considering an approximately 15% dropout rate, an estimated total of 
60 participants per intervention group and the placebo group will complete the main treatment 
period. All participants will be randomized to 1 of 3 dose cohorts in a 1:1:1 ratio (Cohort A,
Cohort B, and Cohort C). Within each dose cohort, subjects will be randomized in a 3:1 ratio 
to receive treatment with either BAY 2976217 or placebo.
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Table 9–1 summarizes 95% expected range for the true population proportion of participants 
with the composite of MB and CRNMB bleeding. For example, with 60 participants, if 5% 
had the composite of MB and CRNMB bleeding during the main treatment period and the 
desired confidence level is 95%, the corresponding confidence interval would be ± 5.51, i.e. 
the range of 0.0 % to 10.51%. If multiple samples were drawn from the same population and a 
95% CI calculated for each sample, we would expect the true population proportion to be 
found within 95% of these CIs.
Table 9–1: Confidence Interval for proportion of participants with composite of MB and 
CRNMB Bleeding
Sample Size 
Observed 
Proportion *
Desired 
Confidence level
Corresponding two-sided 
confidence interval
Range for the true 
population proportion
60
2%
95%
±3.54
0.0% to 5.54%
3%
95%
±4.32
0.0% to 7.32%
4%
95%
±4.96
0.0% to 8.96%
5%
95%
±5.51
0.0 % to 10.51%
6%
95%
±6.01
0.0% to 12.01%
7%
95%
±6.46
0.54% to 13.46%
8%
95%
±6.86
1.14% to 14.86%
CRNMB = clinically relevant non-major bleeding, MB = major bleeding
* The range of observed proportion is considered based on the Interim report of ISIS 416858-CS5 study 
where composite of MB and CRNMB bleeding proportion for Placebo was 5.7% and for total ISIS 
treated= 4.5% (ISIS treated with 200mg, 250mg and 300 mg doses were 3.8%, 5.6% and 4.0% 
respectively)


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9.3
Populations for Analyses 
The following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Full analysis set 
All participants randomized who have received at least 
1 dose of study intervention. Participants will be 
analyzed according to the intervention they were 
randomized.
Safety analysis set
All participants randomly assigned to study 
intervention and who took at least 1 dose of study 
intervention. Participants will be analyzed according to 
the intervention they received.
Pharmacokinetic set
All LICA-treated participants with at least 1 PK 
sample in accordance with the PK sampling schedule 
(Section 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 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.
9.4
Statistical Analyses
The statistical analysis plan will be finalized prior to database lock 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.
For the primary analysis: an unblinded data snapshot will be conducted after all participants
complete the 24-week main treatment period to assess the safety and PK/PD, and exploratory 
efficacy of the results. The analysis will be executed with controlled dissemination to ensure 
the integrity of ongoing data collection while maintaining sufficient blinding in the study. The 
partial data of a participant’s extended treatment period up until primary completion may be 
presented in separate tables. More details on the primary analysis are provided in the SAP. No 
formal interim report will be written.
The investigator, study staff, participants, monitors, members of the Sponsor's clinical 
operations team and CIAC will remain blinded until the end of the study. 
The final data analysis will be conducted once all participants complete the follow-up period 
(the last participant’s last follow-up visit). At the end of the study completion, statistical 
analysis will include all data, including the main treatment period, extension period, and the 
follow-up period appropriately.


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9.4.1
General considerations
9.4.1.1
Planned Methods of Analysis
Descriptive statistics will be provided by treatment group for all demographic variables, 
safety endpoints, and exploratory endpoints. The placebo groups from each cohort will be 
combined, so that there are four treatment groups to be included for analysis– 40 mg, 80 mg, 
120 mg, and placebo, all equal in size.

The safety analysis set will be used for all safety endpoints, including the primary 
endpoint. 

The full analysis set will be used for the exploratory endpoints or otherwise specified. 

The PK analysis set will be used for the pharmacokinetic endpoints, and 

The PD analysis set will be used for the pharmacodynamics endpoints.
For categorical variables, frequencies and proportions will be provided by treatment group. 
For continuous variables, means, medians, standard deviations, standard error of mean, 
interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) will be 
provided by treatment group. For continuous variables collected at multiple time points, the 
descriptive statistics will be provided at each time point.
All analyses and tabulations will be performed using SAS@ Version 9.2 or higher or if 
applicable, other software.
9.4.1.2
Incomplete or Missing Data
In general, missing data values will not be imputed. Incomplete data handling rules will be 
described in the specified section in the SAP if needed.
9.4.1.3
Inter-current event 
The list of possible inter-current events identified in this study are:

Unblinding to study intervention: the study allows unblinding of the treatment 
assignment if the investigator deemed it necessary related to a bleeding event or AE.

Premature treatment discontinuation or kidney transplant or death

Lowering high dose study intervention from 120 mg to either 100 mg or 80 mg based 
on DMC recommendation.
Other inter-current events will be described in the specified section where appropriate. 
9.4.1.4
Demographic and Baseline characteristics 
Demographic and baseline characteristics including dialysis and ESRD disease characteristics 
obtained before the first study intervention administration, e.g.; 

age, gender, ethnicity, race, weight, height, BMI, 

current hemodialysis characteristics,

medical condition that most likely led to RRT,

time since the start date for renal replacement therapy, 
will be summarized using descriptive statistics by treatment group and all participants for full 
analysis set population and safety population.


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Age for each participant will be defined as the number of years between informed consent 
date and birth date.
For summarizing race, if multiple races are recorded in the database, then 'multiple race' will 
be used in the summary table.
The study sample sizes will be summarized by the trial unit (site) for enrolled participants. All 
participants with signed ICF will be included in the enrolled participants.
9.4.1.5
Definition of Baseline
Generally, measurements taken before first dose will be considered baseline values unless 
otherwise specified. For further details see the SAP.
9.4.1.6
On treatment
The "on-treatment" period is defined as the period between first administration of study 
intervention up to 28 days after the last administration of study intervention.
9.4.2
Primary endpoint(s)
The primary endpoint is the incidence of the composite of major bleeding and clinically-
relevant non-major bleeding, as assessed by blinded CIAC.
Estimand for the primary safety endpoint:
The five attributes of the estimand are as follows:

Population: ESRD patients as described by the inclusion/exclusion criteria given in 
Section 5.

Variable: The incidence of composite of MB and CRNMB during the main treatment 
period, as assessed by CIAC.

Treatment: Three dose groups of BAY 2976217 or placebo 

Intercurrent events:
o
Unblinding to study intervention: the study allows unblinding of the 
intervention code: regardless of whether such an event occurs (treatment-
policy strategy)
o
Early definitive discontinuation of study treatment or death or kidney 
transplant: until the occurrence of the intercurrent event (while on-treatment 
strategy)
o
Dose reduction: regardless of whether such an event occurs (treatment-policy 
strategy). 

Population-level summary: Proportion of subjects with a bleeding event by study 
intervention groups. 


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The primary objective is to assess the safety of the three different doses of BAY 2976217 
given once a month which is expected to be maintained during a chronic treatment. The 
primary safety analysis is based on a descriptive proportion of subjects with bleeding events
based on the Safety analysis population. (see Section 9.3). 

All suspected events of bleeding will be reported as an AE or SAE as per adverse 
event reporting procedure in Section 8.3. Additionally, an adjudication package will 
be sent to the CIAC. The CIAC will classify bleeding as defined in Section 8.2.1. 

Proportion of subjects with bleeding events including the following categories will be 
tabulated by treatment as assessed by the CIAC: 
o
Composite of MB and CRNMB
o
MB
o
CRNMB 
o
Minor bleeding 

For the primary safety analysis, primary safety outcomes will be considered during the 
main treatment period and while on-treatment. Incidences of MB, CRNMB, minor 
bleeding will be analyzed similarly.
The frequency and percentage of participants with bleeding will be reported where the 
denominator will be total number of participants in each treatment group in the safety analysis 
set. The corresponding exact binomial 95% confidence interval will be provided. 
In addition, exposure adjusted bleeding rate analysis will be performed for the primary 
endpoint (for example, 100 person-years bleeding rate) and for the MB, CRNMB, minor 
bleeding, separately. 
9.4.3
Secondary endpoints

The incidence of composite of major bleeding and clinically-relevant non-major 
bleeding during the main and extended treatment periods and within the on-treatment 
time window. Similar additional analyses will also be done for MB, CRNMB, minor 
bleeding, separately. 

TEAE are defined as AEs that occurred or worsened after first dosing until 20 weeks 
after the last study intervention dose. For the primary analysis, TEAEs will be 
analyzed during the on-treatment time window within the main treatment period in the 
safety analysis set. In addition, TEAEs will be analyzed during the main and extended 
treatment periods and within the on-treatment time window. Results will be presented 
as incidence tables. All TEAEs, all TEAEs potentially related to study intervention, all 
TEAEs potentially related to ESRD, all TESAEs, and all TESAEs potentially related 
to study intervention (BAY 2976217 or placebo), TEAEs leading to early withdrawal 
of study intervention will be summarized by treatment group and by MedDRA 
preferred term and system organ class. Listings will be also provided.


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9.4.4
Pharmacokinetic endpoints
Trough (pre-dose) concentrations (Ctrough) for 3 dose levels of BAY 2976217 will be 
summarized descriptively by dose level and visit (i.e. V12, V14, V16, V18). Details will be 
specified in SAP.
9.4.5
Pharmacodynamic endpoints
The PD profile will be assessed as described in Section 8.6.

Changes in FXI antigen levels and FXI activity levels:
Maximum change in FXI activity and antigen levels during the main treatment period 
will be summarized by treatment groups.
9.4.6
Tertiary/exploratory endpoints
Further details on exploratory endpoints ( e.g. biomarker and immunogenicity analyses) are 
described in the SAP.
9.4.6.1
Exploratory efficacy endpoints
The exploratory efficacy endpoints, as assessed by the CIAC, are: 

Incidence of composite and event types of death due to MI, stroke, PE and SE, and 
non-fatal stroke, non-fatal MI, VTE, major amputation of vascular etiology, and acute 
limb ischemia 

Incidence of thrombosis of the arterio-venous grafts or fistulas.
9.4.6.2
Other pre-specified safety endpoints
All safety analyses will be made on the Safety Population.

Incidence and severity of AESIs:
Hepatic enzyme elevation, thrombocytopenia

Changes in blood pressure, laboratory assessments:
Laboratory tests (see Section 8.2.4) to ensure subject safety including chemistry/liver 
panel, coagulation panel, hematology panel etc., will be summarized by study visits 
for each treatment group. These safety variables will also be presented as change and 
percent change from Baseline over time after study intervention (BAY 2976217 or 
placebo) administration, as appropriate. In addition, the number of subjects who 
experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group.

Incidence and severity of bleeding of the arterio-venous grafts or fistulas:
All events of arterio-venous graft or fistula bleeding, in excess of expected post-
dialysis bleeding or requiring additional hemostatic measures than usual, will be 
reported as an AE or SAE as per adverse event reporting procedure in Section 8.3. The 
incidence and severity of the events will be summarized by treatment group. 
Additionally, assessment of the severity of bleeding at the dialysis access following the 
hemodialysis procedure will be done at specified visits. Severity of bleeding at the dialysis 
access will be assessed approximately 15 minutes after removal of the dialysis needle(s) 
from the AV access according to the following categories (exploratory bleeding score):


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“0” no access bleeding
“1” slow oozing
“2” overt bleeding
The proportion of the participants with the bleeding at the dialysis access following the 
hemodialysis procedure will be summarized by treatment group according to the above 3 
bleeding score categories.
9.4.6.3
Pre-specified PD endpoints

Changes in PT, INR, and aPTT:
Maximum change in PT, INR, and aPTT levels during the main treatment period will 
be summarized by treatment group.

Extent and frequency of clotting on the dialysis filters & circuit:
The extent and occurrence of clotting on the dialysis filters and circuit will be 
summarized descriptively by category scoring (SQCS) as described in Section 8.6. For 
a change from baseline to evaluation period analysis, the baseline for liver enzymes, 
platelets, PD biomarkers including the clotting score, AV access bleeding score will be 
the mean of measurements taken during the 1-week screening period. The final 4 
weeks (Visits 19-22) would be the evaluation period from which a mean value can be 
determined from measurements taken during this period.

Changes in d-dimers:
Change and percent change in d-dimers will be tabulated by treatment group by study 
visit.

TAT

F1.2
9.4.7
Other analyses
Analysis of COVID-19 Patients
Analysis to evaluate the COVID-19 impact on the study primary safety and exploratory 
efficacy endpoints will be performed by comparing the descriptive statistics among confirmed 
COVID-19 versus non-COVID-19 patient population. Additional COVID-19 analysis 
considerations will be described in the SAP.
9.5
Interim Analyses
No formal interim analysis is planned. 
9.6
Data Monitoring Committee (DMC)
An independent data monitoring committee will monitor the safety of the participants. For 
details on DMC, see Section 10.1.5.


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10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH Good Clinical 
Practice and national and international regulations.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements, ICH guidelines, the IRB/IEC, and all other applicable local 
regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 


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
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act 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.

Participants who are rescreened are required to sign a new ICF.

The following ICFs are available for the study:
o
Regular ICF for study entry; 
o
Regular ICF for study entry for alternative PK&PD sampling group;
o
Pregnancy ICF for female participants for follow-up data;
o
Pregnancy ICF for male participants for follow-up data.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Committees Structure
The primary role of the DMC is to periodically review the safety data and ensure the safety of 
the participants in the ongoing study including unblinded data. The full description of the 
DMC structure and tasks is provided in the DMC charter.
A Study Steering Committee will be established to provide medical consultancy. The full 
description of the Steering Committee structure and tasks is provided in the Steering 
Committee charter.
CIAC is blinded for treatment allocation and will objectively assess the incidence of major 
bleeding and clinically relevant non-major bleeding as well as all suspected bleeding and 
thrombosis events. The full description of the CIAC structure and tasks is provided in the 
CIAC charter.


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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 EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
participant-level clinical trial data, study-level clinical trial data, and protocols from clinical 
trials in patients for medicines and indications approved in the United States (US) and 
European Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate 
research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative. 
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g.,
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor. 


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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 eCRF 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 a source document check 
list.
10.1.9
Study and Site Start and Closure
First Participant First Visit is considered the first act of recruitment and will be the study start 
date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the 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.


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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10–1 will be performed by the central laboratory.

Local laboratory results are required if central laboratory kits are not available, or
central laboratory results are not available. If a local sample is required, if possible 
a sample for central analysis should be obtained at the same time. Additionally, if 
the local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the eCRF. Local laboratory 
results should not be used for eligibility check.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing, See Section 5.1 for screening pregnancy criteria.
Table 10–1: Protocol-Required Safety and Routine Laboratory Assessments
Laboratory 
assessments
Parameters
Hematology
Hemoglobin, Hematocrit, Red blood cell count (MCV
MCH, MCHC, %Reticulocytes), Platelets, white blood cell count with differential 
(Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils)
Blood Chemistry1
Sodium, Potassium, Phosphorus, Magnesium, calcium, chloride, bicarbonate,
Creatinine, BUN, 
Total protein, Albumin
Amylase, lipase
Creatine kinase, high-sensitivity C-reactive protein, troponin T, NT-pro BNP
Lactate dehydrogenase
Liver enzymes
AST (=ASAT / GOT), ALT (=ALAT/GPT), alkaline phosphatase (ALP), γ-GT, GLDH,
TBL, Direct bilirubin, Indirect bilirubin
Carbohydrate 
metabolism
HbA1c
Lipids
Total cholesterol, Triglyceride, HDL-cholesterol, LDL-cholesterol
Dialysate effluent
BAY 2976217 concentrations, 3‘- and 5‘- 10-mers, and 3‘- and 5‘- 5-mers
PK / PD / 
immunogenicity 
sampling / 
biomarkers
FXI antigen, FXI activity, AXIA, FXI concentration, plasma concentrations of BAY 
2976217 (as total full-length oligonucleotide, including fully conjugated, partially 
conjugated, and unconjugated BAY 2976217), Antibodies to BAY 2976217, TAFI and 
C1 inhibitor activity, TAT and F1.2, Prothrombin time (Quick), aPTT, Fibrinogen, INR, 
d-dimer.
Other Screening 
Tests

Highly sensitive serum human chorionic gonadotropin (HCG) pregnancy test (as 
needed for WOCBP)

Genetic analysis
1: Details of liver chemistry assessment and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.3.8.2. 
ALAT = alanine aminotransferase; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = 
activated partial thromboplastin time; ASAT = Aspartate-aminotransferase; AST = aspartate 
aminotransferase; AXIA = Activated Factor XIa activity, BUN = Blood urea nitrogen; FXI = Coagulation factor 
XI, GLDH = Glutamate dehydrogenase; GOT = serum glutamic oxaloacetic transaminase; GPT = Garment 
package test; γ-GT = glutamyltransferase, HbA1c = Hemoglobin A1c; HDL = high-density lipoprotein; INR= 
international normalized ratio, LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin, MCHC = 
mean corpuscular hemoglobin concentration, MCV = mean corpuscular volume, NT-pro BNP = NT-proB-type 
Natriuretic Peptide, TAFI = Thrombin-activatable fibrinolysis inhibitor; TAT = Thrombin-antithrombin complex;
TBL = total bilirubin, WOCBP = Women of childbearing potential
If the platelet value or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis 
or quantity not sufficient) or missing, a repeat blood specimen should be re-drawn as soon as 


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possible (ideally at the next dialysis session) and reviewed prior to dosing. Valid platelet 
counts and liver enzymes must be obtained at least every 2 weeks and reviewed prior to 
dosing.
Investigators must document their review of each laboratory safety report.
PD results including coagulation parameters that could unblind the study will not be reported 
to investigative sites or other blinded personnel until the study has been unblinded.
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 though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
Also, “lack of efficacy” or “failure of expected pharmacological action” also 
constitutes an AE or SAE.


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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant was at risk of death at the time of the event. It does not 
refer to an event, which hypothetically might have caused death, if it were more 
severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.


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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 by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that 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 for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse.
10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information 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.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the 
medical records before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.


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
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

The investigator will also assess the relationship between each occurrence of 
each AE/SAE to the presence of ESRD or the hemodialysis procedure.

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 and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 


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care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide the sponsor with a copy of any 
post-mortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to the sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) 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 the 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.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., 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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement 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:
WOCBP with their partner must agree to use a highly effective contraception method from 
the time signing of ICF until 20 weeks after the participant’s last dose of study treatment (due 
to long terminal half-life and once monthly dosing).
If engaged in sexual activity with childbearing potential partner, male participants with their 
female partner must use highly effective contraception from the time of signing the ICF until 
20 weeks after the participant’s last dose of study treatment.
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


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Male participants with partners that are pregnant must use condoms as contraception to ensure 
that the fetus is not exposed to the study intervention. Also, male participants with female 
partners who are breast feeding must use condoms.
Collection of Pregnancy Information:
The investigator must report to the sponsor any pregnancy occurring in a study participant, or 
in the study participant's partner, during the participant’s participation in this study using the 
pregnancy reporting form. The report should be submitted within the same timelines as an 
SAE, although a pregnancy per se is not considered an SAE. The outcome of the pregnancy 
should be followed up carefully, and any outcome of the mother or child should be reported. 
For the pregnancy of a study participant's partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent.
Male participants with partners who become pregnant 

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed ICF 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. 


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
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.
10.5
Appendix 5: Country-specific Requirements 
China:

Study sites in China are excluded from exploratory biomarker analyses and 
pharmacogenetic sample collection
10.6
Appendix 6: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
10.6.1
Amendment 1: (29 SEP 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
This amendment was prepared to address the change in the new contraception guidance as 
requested by Health Authorities. Additionally, the number of procedures and visits was 
decreased to reduce the burden on the participants. This reduction does not impact the 
participants’ safety nor affect the benefit-risk assessment.
Key changes
Section #
and Name
Description of Change
Brief Rationale
10.4 Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Contraception was changed into 
highly effective (removing the 
barrier method as example for 
contraception)
Request from Health Authorities 
1.3. Schedule of 
Activities (SoA) + 
throughout the 
protocol
Visits 2, 3 and 4 removed; 
screening period shortened to 7 
(+6) days with provision that some 
procedures can be done on more 
than one day
To reduce the burden on the participants. The 
visits are reduced during screening before 
randomization therefore there is no safety 
concern.


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Section #
and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities (SoA)
ECG assessments removed on 
Visits 5, 10, 14, 15, 16, 23, 24, 25, 
26, 27, FU1
To reduce the burden on the participants. 
Frequent ECGs was initially deemed necessary 
for the documentation of efficacy outcomes. 
However, since the efficacy outcomes are 
mainly based on symptomatic events, the use of 
pre-planned ECGs is not expected to contribute 
to an adequate assessments of suspected 
outcomes. For unsuspected changes on the 
ECGs related to the study drug, the protocol 
requires 4 routine ECGs to be done during the 
main treatment phase.
1.3 Schedule of 
Activities (SoA), 
8.2.3 Vital Signs
Post HD BP measurements 
changed from average of 3 blood 
pressure readings to one post HD 
BP measurement; temperature, 
pulse and heart rate measurements 
removed => vital signs comprise 
only post HD BP measurements.
To reduce the burden on the participants. The 
patients are seen at the center at least 3 times a 
week (9 hours/week) and post-HD blood 
pressure will be collected on a regular basis. 
Therefore, collection of vital signs is redundant.
5.2 Exclusion 
Criteria
Pregnancy added as an exclusion 
criterion
Ensure safety as there is no information about the 
effect of the study intervention on pregnant 
women
6.5 Concomitant 
Therapy
Prohibited medications should be 
stopped 5 days before the study 
drug administration, not 28 days
5 days is sufficient for the drugs listed as 
prohibited during the study.
6.5 Concomitant 
Therapy
Thrombolytic drugs for systemic use 
(e.g., streptokinase, alteplase, 
tenecteplase, etc.) removed from 
the list of prohibited drugs
Thrombolytic therapy is not a routine therapy but 
an emergency therapy provided for acute care of 
myocardial infarction/stroke. These patients will 
not be eligible at that time. The protocol cannot 
prohibit a life-saving treatment in the event of 
emergency.
7.1 Discontinuation 
of Study 
Intervention
If a patient discontinues study 
intervention, he/she should continue 
with the scheduled visits
To collect efficacy and safety data according to 
intent-to-treat principle
8.2.1.1 Stopping 
Rules for Bleeding 
Events
In the event of clinically significant 
bleeding, dosing of study 
intervention does not necessarily 
have to be suspended. Instead, the 
investigator should carefully assess 
whether a participant can continue 
with the study intervention.
Many clinically relevant non-major bleeds occur 
at home and are resolved at the time of 
reporting. Study treatment should only be 
stopped if the patient is considered to be at high 
risk for continued / deterioration of bleeding.
8.3.8.1.3 Monitoring 
and Evaluation of 
Thrombocytopenia, 
8.3.8.2.3 Monitoring 
and Evaluation of 
Elevation of Hepatic 
Enzymes
Several lab tests done at central lab 
in the event of thrombocytopenia or 
elevation of hepatic enzymes 
removed; they can be performed at 
local lab if needed, at the 
investigator’s discretion
To reduce the burden on the participants. In the 
event of thrombocytopenia or elevation of 
hepatic enzymes a patient will be individually 
followed to ascertain appropriate documentation.
9.4.1.4
Demographic and 
Baseline 
characteristics
Disease characteristics to be 
collected at baseline updated.
According to SAP version 1.0.
10.2 Clinical 
laboratory tests
Mean platelet volume (MPV) and 
platelet distribution width (PDW) 
measurements removed  
Sensitivity and specificity of these tests are poor 
and most of the time it is difficult to interpret the 
results. It does not impact safety.
10.2 Clinical 
laboratory tests
Follicle stimulating hormone and 
estradiol (in women of non-
childbearing potential) removed
Action to evaluate the potential for pregnancy is 
at the discretion of the investigator.
AV = arterio-venous, BP =blood pressure, ECG = electrocardiogram, HD = hemodialysis, PD = 
pharmacodynamic(s), PK = pharmacokinetic(s), SPA = statistical analysis plan


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Clarifications to the protocol
Section # 
and Name
Description of Change
1.3 Schedule of Activities (SoA), 
Table 1-3
A note added to the table („Day“ row) that at sites participating in the 
PK&PD sampling group, days marked with an asterisk are as listed in the 
table +1 day.
1.3 Schedule of Activities (SoA), 
8.3.1 Time Period and Frequency 
for Collecting AE and SAE 
Information
Clarification added that AESIs have to be reported after randomization until 
the end of follow-up period.
1.3 Schedule of Activities (SoA), 
Table 1-3, 8.2 Safety 
Assessments, 8.2.5 Clinical 
Safety Laboratory Assessments
Frequency of measuring platelet count and ALT/AST during follow-up 
period is 4 weeks; 2-week frequency is during extended treatment period, 
with local lab monitoring at unscheduled visits.
8.5.1 Sampling time for PK, PD 
and immunogenicity
Sampling clarified for: 
Plasma PK/PD and immunogenicity at V22 time points (whether to be 
collected pre-dose or at any time)
Immunogenicity time points (whether to be collected pre-dose or at any 
time)
Dialysate PK (for patients in alternative PK&PD group collected on V6)
AE = adverse event, AESI = adverse events of special interest, PD = pharmacodynamic(s), PK = 
pharmacokinetic(s), SAE = serious adverse event, ULN = upper limit of normal, V = visit
Corrections of inconsistencies and minor corrections (editorial corrections not detailed):
Section # 
and Name
Description of Change
1.3 Schedule of Activities (SoA)
“URR and KtV” changed to “URR or KtV” in comments field.
1.3 Schedule of Activities (SoA), 
Table 1-3, 8.2 Safety Assessments, 
8.2.5 Clinical Safety Laboratory 
Assessments
Platelet count and ALT/AST are to be measured every 2 weeks, local 
lab monitoring or central lab at unscheduled visits can occur between 
the scheduled visits that are scheduled every 4 weeks ..
1.3 Schedule of Activities (SoA)
Vital status line removed from the table 
2.3.1 Risk Assessment
No clinically significant bleeding (MB, CRNMB) observed so far in 
healthy volunteers with BAY 2976217, or in multiple populations with 
BAY 2306001
6.5 Concomitant Therapy
If initiation of prohibited medication is medically necessary during the 
treatment period, the participant will be discontinued from study 
intervention…
2.2.3 BAY 2976217
„Co-development partner“ changed to „collaboration partner“
5.1 Inclusion Criteria
„Male and/or female“ changed to „Male or female“
Section 6.1 Study Intervention(s) 
Administered 
Volume of the vial changed from 1.0 mL to 1.05 mL, and consequently 
the volume of overfill from 0.2 mL to 0.25 mL for consistency with IMPD.
7.1.1 Events Requiring Definitive 
Discontinuation of Study 
Intervention, 8.2.1 Bleeding events, 
9.4.1.3 Inter-current event, 9.4.2 
Primary endpoint(s)
Major surgery removed as an event requiring definite discontinuation of 
the study intervention. The participant will be discontinued in the event 
of surgery that in the judgement of the investigator necessitates 
permanent discontinuation of the study intervention.
7.2 Participant Discontinuation
/Withdrawal from the Study
... "Death of participant, in which case only relevant eCRF pages will be 
completed for the Early Termination Visit...“
8.1 Efficacy Assessments
Wording corrections without change in content
8.2.1 Bleeding Events
Major bleeding is defined as symptomatic overt bleeding and: ....
8.2.1.4 AV access bleeding
A paragraph deleted, which stated that the bleeding severity will be 
recorded for all dialysis sessions during screening, observation and at 
the end of the main treatment periods. Bleeding severity is recorded at 
the planned study visits only.
8.2.4 Electrocardiogram
Third bullet point (“Atypical symptomatic presentation…”) deleted 
8.3.1 Time Period and Frequency 
for Collecting AE and SAE 
Information
All AE/SAEs will be collected from the signing of the ICF until the final
follow-up visit… (added “final”).
All SAEs/AESI will be recorded and reported to the sponsor or designee 
immediately... (added “AESI”)


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Section # 
and Name
Description of Change
8.3.7 Disease-Related Events 
and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs
Bleeding after dialysis from arterio-venous 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
• Elevation of Hepatic Enzymes (> 3 x ULN, or 3 x baseline value, if the 
baseline value was > ULN) (“if the baseline value was >ULN” added)
8.3.8.2.2 Stopping Rule for 
Elevation of Hepatic Enzymes
2. ALT or AST > 5 x ULN or 5 x baseline value (if the baseline value was 
>ULN), which is confirmed and persists for ≥ 2 weeks
3. ALT or AST > 3 x ULN or 3 x baseline value (if the baseline value was 
>ULN), which is confirmed and total bilirubin > 2 x ULN or 2 x baseline 
value (if the baseline value was >ULN)
4. ALT or AST > 3 x ULN, which is confirmed (or the greater of 2 3 x 
baseline value if the baseline value was > ULN) with the new 
appearance
8.3.8.2 Elevation of Hepatic 
Enzymes
"In the event of an ALT or AST measurement that is > 3 x ULN, or 3 x 
baseline value (if the baseline value was > ULN), at any time after 
randomization during the study (treatment, and post-treatment follow-up 
periods), the event will be reported as an AESI...“
8.5.1.2 PK, PD and immunogenicity 
sampling from the alternative 
PK&PD sampling group starting on 
a non-dialysis day
In alternative PK&PD sampling group, at Visit 10 dialysate effluent to be 
collected as for all participants, i.e. at 15 to 30 minutes after the start of 
dialysis and during the final 30 minutes of dialysis.
8.6.2 Other Pharmacodynamic 
parameters
Clotting score documentation corrected to be as in the SoA. 
Clarification added that only the highest score will be documented.
9.4.1.3 Inter-current event
Unblinding to study intervention: the study will allow unblinding of the 
treatment assignment if the investigator deemed necessary after a 
bleeding event or major surgery AE („major surgery“ replaced by „AE“)
9.4.2 Primary endpoint(s)
Minor bleeding will be further categorized as injection site and non-
injection site bleeding events.
9.4.3 Secondary endpoint(s)
TEAE definition changed to AEs that occurred or worsened post-dose 
until 20 weeks after the last study intervention dose (i.e. 4 weeks after 
the last dose plus 16-week post-treatment follow-up period) A 
paragraph added describing the primary analysis of TEAEs.
9.4.6.1 Exploratory efficacy 
endpoints, 9.4.6.2 Other pre-
specified safety endpoints
Sections re-worded, in particular, sentences specifying that endpoints 
will be summarized by treatment group removed. 
9.4.7 Other analyses
Analysis to evaluate COVID-19 impact added 
10.4 Contraceptive Guidance and 
Collection of Pregnancy Information
The first 2 paragraphs removed from the contraceptive guidance.
AE = adverse event, AESI = adverse event of special interest, ALT = alanine aminotransferase, AST = aspartate 
aminotransferase, CIAC = central independent adjudication committee, CRNMB = clinically relevant non-major 
bleeding, eCRF = electronic case report form, HIV = human immunodeficiency virus, ICF = informed consent 
form, IMPD = investigational medicinal product dossier, KtV = value used to quantify hemodialysis and peritoneal 
dialysis treatment adequacy, MB = major bleeding, PD = pharmacodynamic(s), PK = pharmacokinetic(s), SAE = 
serious adverse event, ULN = upper limit of normal, URR = urea reduction ratio
Administrative changes
Section # 
and Name
Description of Change
Title page
Investigational New Drug (IND) number added
Title page
Sponsor’s responsible person changed
Title page
Wet ink signature replaced with electronic signature on a content approval form (filed separately)


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10.7
Appendix 7: Abbreviations
2'-MOE
2'-O-methoxy-ethyl
AE
Adverse event
AESI
Adverse event of special interest
AFib
Atrial fibrillation
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ASA
Acetylsalicylic acid
ASO
Anti-sense oligonucleotide
AST
Aspartate aminotransferase
AUC
Area under the curve
AV
Arterio-venous
AXIA
Activated Factor XIa activity
BMI
Body mass index: weight [kg] / (height [m])²
C
Concentration
CAD
Coronary artery disease
CBC
Complete blood count
CI
Confidence interval
CIAC
Central Independent Adjudication Committee
CFR
Code if Federal Regulations
CHF
Congestive heart failure
Cmax
Maximum concentration
COVID-19
Coronavirus disease of 2019
CRF
Case report form
CRNMB
Clinically relevant non-major bleeding
CV
Cardiovascular
DM
Diabetes mellitus
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DOAC
Direct oral anticoagulant
dsDNA
Double stranded DNA
DVT
Deep vein thrombosis
e.g.
Exempli gratia (for example)
ECG
Electrocardiogram
eCRF
Electronic case report form
ESRD
End stage renal disease
EudraCT
EU data repository for clinical trials
F1.2
Prothrombin fragment 1 + 2
FFP
Fresh frozen plasma
FSH
Follicle stimulating hormone
FU
Follow-up
FVII
Coagulation factor VII
FVIII
Coagulation factor VIII
FIX
Coagulation factor IX
FXI
Coagulation factor XI
FXIa
Coagulation factor XIa
FXI-D
FXI deficiency
GalNAc
N-acetyl galactosamine
GCP
Good clinical practice
Hb
Hemoglobin
HBsAg
Hepatitis B surface antigen
HCG
Human chorionic gonadotropin
HD
Hemodialysis
HIV
Human immunodeficiency virus
hsCRP
High-sensitivity C-reactive protein
HRT
Hormonal replacement therapy
ICF(s)
Informed consent form(s)
ICH
International Council on Harmonization


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IEC
Independent ethics committee
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalized ratio
IRB
Institutional review board
ISTH
International Society on Thrombosis and Haemostasis
IWRS
Interactive web response system
LICA
Ligand conjugated antisense oligonucleotide
LLOQ
Lowest level of quantification
LMWH
Low molecular weight heparin
MB
Major bleeding
MedDRA
Medical Dictionary for Regulatory Activities 
MI
Myocardial infarction
MOE
Methoxyethyl
mRNA
Messenger RNA (Ribonucleic acid)
PAD
Peripheral arterial disease
PD
Pharmacodynamics(s)
PE
Pulmonary embolism
PF4
Platelet factor 4
PID
Participant identification code
PK
Pharmacokinetics
popPK
Population pharmacokinetics
PT
Prothrombin time
RNAi
RNA interference
RRT
Renal replacement therapy
SAE(s)
Serious adverse event(s)
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SC
Subcutaneous
SE
Systemic embolism
SoA
Schedule of activities
SOP
Standard operating procedure
SQCS
Semi-quantitative clotting score
SUSAR
Suspected unexpected serious adverse reaction
TAFI
Thrombin-activatable fibrinolysis inhibitor
TAT
Thrombin-antithrombin complex
TEAE(s)
Treatment-emergent adverse event(s)
TESAE(s)
Treatment-emergent serious adverse event(s)
TIA
Transient ischemic attack
TKA
Total knee arthroplasty
tmax
Time to reach Cmax
UFH
Unfractionated heparin
ULN
Upper limit of norm (upper limit of normal laboratory values)
VKA
Vitamin K antagonists
VTE
Venous thromboembolism
vWF
Von Willebrand factor
WOCBP
Women of childbearing potential


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11.
References
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Zoccali C, Mallamaci F, Tripepi G. Inflammation and atherosclerosis in end-stage 
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3.
Seliger SL, Gillen DL, Longstreth WT, Jr., Kestenbaum B, Stehman-Breen CO. 
Elevated risk of stroke among patients with end-stage renal disease. Kidney Int. 
2003;64(2):603-9.
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.
5.
United States Renal Data System. 2019 USRDS annual data report: Epidemiology of 
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2'-O-Methoxyethyl Oligonucleotides on Renal Function in Humans. Nucleic Acid 
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34.
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of 2'-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human 
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Zhang H, Lowenberg EC, Crosby JR, MacLeod AR, Zhao C, Gao D, et al. Inhibition 
of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel 
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al. Effects of tranexamic acid on death, vascular occlusive events, and blood 
transfusion in trauma patients with significant haemorrhage (CRASH-2): a 
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treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol. 
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Livnat T, Tamarin I, Mor Y, Winckler H, Horowitz Z, Korianski Y, et al. 
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SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal 
Disease Patients on Hemodialysis: A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled Study of the Safety, 
Pharmacokinetics, and Pharmacodynamics of Multiple Doses of 
Fesomersen 
NCT Number: 
NCT04534114 
Document Date: 
31 MAY 2022 
 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 1 of 34
 
 
                   Title page 
Factor XI LICA to Reduce Thrombotic Events in End-Stage Renal 
Disease Patients on Hemodialysis: A Phase 2, Randomized, Double-
Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and 
Pharmacodynamics of Multiple Doses of Fesomersen 
Acronym: RE-THINC ESRD 
Bayer study drug 
BAY 2976217* 
INN 
Fesomersen 
Study purpose: 
Safety 
Clinical study 
phase: 
IIb 
Date: 
31 MAY 2022 
Study No.: 
 
21170 
Version: 
4.0 
Authors: 
 
 (Version 1.0) 
 
 (Version 1.0) 
 (from Version 2.0) 
 (from Version 2.0) 
 
* The Drug Substance BAY 2976217 (ION-957943) is the icosasodium salt of a 20-base residue 
(20-mer) oligonucleotide conjugated at its 5′-end via an aminohexylphosphate linker to a GalNAc 
THA cluster. For the Drug Product, the label claim of 100 mg BAY 2976217 is defined on a free 
acid, anhydrous, solvent-free, and sodium acetate-free basis. 
 
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
PPD
PPD
PPD
PPD


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 2 of 34
 
 
Table of Contents 
 
Title page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
Table of Tables ..................................................................................................................... 3 
Table of Figures .................................................................................................................... 3 
Abbreviations ........................................................................................................................ 4 
1. 
Introduction ................................................................................................................... 6 
2. 
Study Objectives ............................................................................................................ 7 
3. 
Study Design ................................................................................................................ 10 
4. 
General Statistical Considerations ............................................................................ 13 
4.1 
General Principles ...................................................................................................... 13 
4.2 
Handling of Dropouts ................................................................................................ 13 
4.2.1 
Permanent Discontinuation of Study Intervention ................................................. 13 
4.2.2 
Lost to Follow Up ................................................................................................... 13 
4.3 
Handling of Missing Data .......................................................................................... 14 
4.4 
Interim Analyses and Data Monitoring ..................................................................... 14 
4.5 
Data Rules .................................................................................................................. 14 
4.5.1 
Analysis Dates ........................................................................................................ 14 
4.5.2 
Data Scopes ............................................................................................................ 15 
4.6 
Blind Review ............................................................................................................. 16 
4.7 
Sample Size Determination ....................................................................................... 16 
5. 
Analysis Sets ................................................................................................................ 18 
5.1 
Assignment of Analysis Sets ..................................................................................... 18 
6. 
Statistical Methodology .............................................................................................. 20 
6.1 
Population Characteristics ......................................................................................... 20 
6.1.1 
Disposition .............................................................................................................. 20 
6.1.2 
Demographic and Baseline Characteristics ............................................................ 20 
6.1.3 
Definition of Baseline ............................................................................................. 21 
6.1.4 
Medical History ...................................................................................................... 21 
6.1.5 
Protocol Deviations ................................................................................................ 21 
6.1.6 
Prior and Concomitant Medications ....................................................................... 21 
6.1.7 
Extent of Exposure and Compliance ...................................................................... 22 
6.1.8 
Baseline Renal Replacement Therapy .................................................................... 22 
6.2 
Efficacy ...................................................................................................................... 22 
6.2.1 
Analysis of Exploratory Efficacy Variable(s) ........................................................ 22 
6.2.2 
Sensitivity and Supplementary Efficacy Analysis.................................................. 23 
6.2.3 
Analysis of COVID-19 Patients ............................................................................. 25 
6.3 
Pharmacokinetics/Pharmacodynamics. ...................................................................... 25 
6.3.1 
Pharmacokinetics Analysis ..................................................................................... 25 
6.3.2 
Pharmacodynamic Analysis ................................................................................... 26 
6.4 
Safety ......................................................................................................................... 27 
6.4.1 
Analysis of the Primary Safety Variable ................................................................ 27 
6.4.2 
Analysis of Secondary Safety Variable(s) .............................................................. 30 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 3 of 34
 
 
6.4.3 
Sensitivity and Supplementary Safety Analysis ..................................................... 31 
6.4.4 
Analysis of Other Pre-Specified Safety Variable(s) ............................................... 31 
6.4.5 
Subgroup Analysis .................................................................................................. 32 
6.4.6 
Analysis of COVID-19 Patients ............................................................................. 32 
6.5 
Data affected by the war in Ukraine .......................................................................... 32 
7. 
Document History and Changes in the Planned Statistical Analysis ..................... 33 
8. 
References .................................................................................................................... 33 
Table of Tables 
Table 2-1: Objectives and Endpoints ......................................................................................... 7 
Table 4-1: Confidence Interval for proportion of participants with a composite of MB and 
CRNMB Bleeding ................................................................................................. 17 
Table 5-1: Populations ............................................................................................................. 18 
Table 5-2: Sketch of the planned analyses on the endpoints .................................................... 19 
Table 6-1: Clotting scale score ................................................................................................. 26 
 
Table of Figures 
Figure 3–1: Study Design ......................................................................................................... 12 
 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 4 of 34
 
 
Abbreviations 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AFib 
Atrial fibrillation 
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid 
ASO 
Anti-sense oligonucleotide 
AV 
Arterio-venous 
BMI 
Body mass index: weight [kg] / (height [m])² 
CAD 
Coronary artery disease 
CHF 
Congestive heart failure 
CIAC 
Central Independent Adjudication Committee 
CNS 
Central nervous system 
Cmax 
Maximum concentration 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
CRNMB 
Clinically relevant non-major bleeding 
csRHR 
Cause-specific relative hazard reduction 
Ctrough 
Trough plasma concentration 
CV 
Cardiovascular 
DM 
Diabetes mellitus 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
EoT 
End of treatment 
EP 
Extension period data scope 
ESRD 
End stage renal disease 
F1.2 
Prothrombin fragment 1 + 2 
FAS 
Full analysis set 
FP 
Follow up period data scope 
FU 
Follow-up 
FXI 
Coagulation factor XI 
GalNAc 
N-acetyl galactosamine 
HD 
Hemodialysis 
ICH 
International Council on Harmonization 
INR 
International normalized ratio 
ISTH 
International Society on Thrombosis and Haemostasis 
LLOQ 
Lower limit of quantification 
LMWH 
Low molecular weight heparin 
MACE 
Major adverse cardiovascular event 
MB 
Major bleeding 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Myocardial infarction 
OA 
Data scope according to overall analysis principle 
PAD 
Peripheral arterial disease 
PA 
Data scope according to primary analysis principle 
PD 
Pharmacodynamics(s) 
PE 
Pulmonary embolism 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
RRT 
Renal replacement therapy 
SAE(s) 
Serious adverse event(s) 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SE 
Systemic embolism 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 5 of 34
 
 
SOC 
System organ class 
SOP 
Standard operating procedure 
SQCS 
Semi-quantitative clotting score 
TA 
Data scope according to total treatment analysis principle 
TAT 
Thrombin-antithrombin III complex 
TEAE(s) 
Treatment-emergent adverse event(s) 
TIA 
Transient ischemic attack 
VTE 
Venous thromboembolism 
%CV 
Percent coefficient of variation 
 
 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 6 of 34
 
 
1. 
Introduction 
Patients with ESRD on hemodialysis are at a high risk for arterial and venous 
thromboembolic complications. However, because of the documented high risk for bleeding, 
no antithrombotic regimen has ever been evaluated in this group in a large clinical trial 
setting.  
ESRD is associated with high CV comorbidity including CAD and PAD each associated with 
high mortality. Dialysis is associated with a prothrombotic state driven by inflammation, 
uremia-induced endothelial dysfunction and contact between blood and the dialysis circuit 
(Zoccali et al., 2003). Compared to the general population, patients receiving dialysis are at 
higher risk of thrombotic events including stroke (4-10x higher in dialysis patients) (Seliger et 
al., 2003), MI (CAD prevalence in dialysis patients is 5-10x higher) (Foley et al., 1998), and 
amputations, limb-ischemia and chronic skin ulcers related to PAD (PAD prevalence is as 
high as 40%) (United States Renal Data System, 2019). Only 40% of patients receiving HD 
are alive five years after onset (de Jager et al., 2009), and the mortality rate for that initiating 
dialysis is 15x higher than in matched controls from the general population (Mann et al., 
2013). This high mortality is largely driven by CV causes (Mann et al., 2013). 
The investigational agent, BAY 2976217 is a ligand conjugated antisense oligonucleotide 
(LICA) targeting FXI synthesis in the liver. 
 
 
 
Given the multi-fold higher rates of CAD, PAD, stroke and AFib in patients with ESRD on 
hemodialysis coupled with an increased risk of bleeding versus the general population, there 
is a very high unmet need for therapies proven to address CV disease burden in these patients 
without increasing bleeding risk. Targeting FXI with GalNAc-conjugated FXI ASO  
(BAY2976217) may address this unmet need to reduce CV morbidity and mortality without 
increasing the risk of clinically significant bleeding (Von dem Borne et al., 1997).  
As there is currently no accepted alternative therapy to reduce thrombotic events in this 
population except the use of low-dose ASA, the appropriate standard of care for the control 
arm of each cohort is placebo with or without low-dose ASA at the discretion of the 
investigator. 
This statistical analysis plan (SAP) is based on the Global Clinical Study Protocol BAY 
2976217/21170 version 3.0 dated 07 JUL 2021 and contains definitions of analysis sets, key 
derived variables and statistical methods for the LICA study. It provides a technical and 
detailed elaboration of the principal features of the planned analyses, e.g., derivation of the 
primary endpoints. Amendments and/or appendices to this core SAP may be used to add 
additional analysis and provide more details on the coding guidelines, data-handling, and 
output tables and figures. 
Titles, mock-ups, and programming instructions for all statistical output (tables, figures, and 
listings (TLF)) are provided in a separate TLF specifications document. 
 
 
CCI


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 7 of 34
 
 
2. 
Study Objectives 
Objectives and endpoints are listed in Table 2-1. 
Table 2-1: Objectives and Endpoints 
Objectives 
Estimands/Endpoints 
Primary 
 
x To evaluate the safety of 
Fesomersen as compared to 
placebo 
Primary Endpoint 
x The incidence of major bleeding and clinically 
relevant non-major bleeding during the main 
treatment period and within the on-treatment 
time window, as assessed by blinded CIAC 
Secondary 
 
x To evaluate the safety of 
Fesomersen as compared to 
placebo 
x The incidence of the composite of major 
bleeding and clinically-relevant non-major 
bleeding during the main and extended 
treatment periods and within the on-treatment 
time window, as assessed by blinded CIAC 
x Incidence and severity of TEAEs during 
o the main treatment period and within 
the on-treatment time window 
o the main and extended treatment 
periods and within the on-treatment 
time window 
o the main and extended treatment 
periods and until 20 weeks after the last 
study intervention dose 
x To evaluate the PK and PD 
of Fesomersen  
Pharmacokinetic Endpoints 
x Trough concentrations for 3 dose levels of 
Fesomersen 
 
Pharmacodynamic Endpoints 
x Maximum change in FXI antigen levels during 
the main treatment period 
x Maximum change in FXI activity levels during 
the main treatment period 
Exploratory 
 
x To evaluate the effect of 
Fesomersen on 
Exploratory Efficacy Endpoints  
x Incidence of the composite and event types of 
death due to MI, stroke, PE and SE, and stroke, 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 8 of 34
 
 
Table 2-1: Objectives and Endpoints 
Objectives 
Estimands/Endpoints 
thromboembolic events as 
compared to placebo 
 
MI, VTE, major amputation of vascular 
etiology, and acute limb ischemia as assessed 
by the blinded CIAC 
x Incidence of thrombosis of the arterio-venous 
grafts or fistulas, assessed by the blinded CIAC   
 
x To further evaluate the 
safety profile of Fesomersen 
as compared to placebo 
 
Other pre-specified Safety Endpoints 
x Incidence and severity of AESIs- hepatic 
enzyme elevation, thrombocytopenia 
x Changes in vital signs and, laboratory 
assessments 
x Incidence and severity of bleeding of the 
arterio-venous grafts or fistulas 
x To further evaluate the 
pharmacodynamics of 
Fesomersen as compared to 
placebo 
 
Other Pre-specified Pharmacodynamic Endpoints 
x Maximum change in PT, INR and aPTT during 
the main treatment period 
x Extent and frequency of clotting on the dialysis 
filters & circuit 
x Changes in d-dimer 
x Thrombin-antithrombin complex (TAT) and 
Prothrombin fragment 1 + 2 (F1.2) 
Other pre-specified 
 
x To further investigate 
Fesomersen (e.g. mode-of-
action-related effects, 
safety) 
and to further investigate 
pathomechanisms deemed 
relevant to cardiovascular 
and renal diseases and 
associated health problems 
x To evaluate potential 
associations between 
genotypic information and 
clinical efficacy and / or 
pharmacodynamics effects 
x Various biomarkers (e.g. diagnostic, safety, 
pharmacodynamic, monitoring, or potentially 
predictive biomarkers) 
 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 9 of 34
 
 
It is important to note, based on the current expert assessment of the COVID-19 Public Health 
Emergency, it is to be expected that only a very limited number of patients (<5) will suffer 
from confirmed COVID-19. Besides, as ESRD patients have to go to the hospital regularly, 
no increase in missing data is to be expected. For this reason, no intercurrent event linked to 
the COVID-19 Public Health Emergency is accounted for this study. However, any premature 
discontinuation will be summarized, and selected analyses will be repeated by confirmed 
COVID-19 (Yes/No) as reported by the investigator.  
 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 10 of 34
 
 
3. 
Study Design 
This is a Phase 2 multicenter, double-blind, randomized, placebo-controlled study in ESRD 
patients who are stable on HD (including hemodiafiltration) ≥ 3 months for a minimum of 9 
hours per week. Patients receiving therapeutic anticoagulation or antiplatelet therapy (other 
than ASA ≤ 150 mg/day) are excluded. Approximately 288 participants will be randomized. 
Participants will be allocated at randomization to 1 of 3 dose cohorts in a 1:1:1 ratio (Cohort 
A [40 mg], Cohort B [80 mg], and Cohort C [120 mg]), and within each cohort to receive SC 
treatment with either Fesomersen or matching placebo in a 3:1 ratio. Sponsor, participants and 
investigators are blinded with respect to active treatment versus matching placebo, but 
assignment to dose cohort will be known. The CIAC will be blinded to dose cohort allocation 
and treatment assignment. With an assumed attrition rate of 15% during the main treatment 
period, 288 randomized participants would allow for an estimated 240 evaluable participants. 
All standard of care hemodialysis therapies as prescribed by their providers, including use of 
heparins to maintain dialysis circuit patency, will be continued. 
x Cohort A: 40 mg Fesomersen or placebo SC (3:1) n~96 
x Cohort B: 80 mg Fesomersen or placebo SC (3:1) n~96 
x Cohort C: 120 mg Fesomersen or placebo SC (3:1) n~96 
Participants will be stratified at randomization for use of ASA (yes/no). The use of ASA will 
remain at the discretion of the investigator. However, all efforts should be made during the 
treatment period to avoid change in ASA use or dose, unless clinically indicated. 
Additionally, participants will also be stratified based on the presence of selected CV risk 
factors. The investigator will evaluate the presence or absence of the following at the time of 
randomization:  
(i) 
age >65 years,  
(ii) 
history of DM type I or II, 
(iii) 
history of MI,  
(iv) 
history of stroke or TIA,  
(v) 
history of CHF,  
(vi) 
history of PAD, 
(vii) 
history of Afib. 
Strata 1 – zero or one risk factor, except the presence of DM or Afib; . 
Strata 2 - either DM or Afib alone, or two or more risk factors. 
All cohorts will consist of a 1-week screening period and a 24-week main treatment period 
(visit 5 to visit 22), the last 4 weeks of which are an evaluation period for certain PD and 
safety parameters.  
The main treatment period consists of 24-weeks. Furthermore, the treatment will continue in 
an extended period, with up to an additional 24 weeks  to collect additional long-term safety 
information. The participants will continue with study intervention (Fesomersen or placebo) 
according to their original randomization group assignment.  
All participants who are in the extended treatment period will need to stop further treatment 
no later than when the last participant enrolled in the study has completed the 24-week main 


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treatment period (Visit 22). Participants in the extended treatment period will complete Visit 
28, four weeks after their last dose and then move to the 16-week post-treatment follow-up 
period (FU1 to FU4). The sponsor reserves the discretion to halt further dosing in the 
extended treatment period earlier in anticipation of the least participant completing the main 
treatment period. 
A participant is considered to be on treatment until 4 weeks after their last dose, whether they 
discontinue treatment early, complete only the main treatment period, or complete part or all 
the extended treatment period. Once the overall treatment period is completed, participants 
will have a 16-week post-treatment follow-up period. 
The data and outcomes collected in the study will be summarized for below 4 groups:  
x Pooled Placebo Group (from Cohorts A, B and C),  
x 40 mg Dose Group (Fesomersen from Cohort A),  
x 80 mg Dose Group (Fesomersen from Cohort B), and  
x 120 mg Dose Group (Fesomersen from Cohort C).  
All suspected bleeding, cardiovascular, and thromboembolic events occurring after 
randomization will be assessed by CIAC blinded to cohort and dose allocation. 
An independent DMC will monitor the participant's safety and give recommendations to the 
Steering Committee. The DMC will review unblinded data from the study regularly, as 
outlined in the DMC Charter. At any time, if there is an unexpected finding(s) in Cohort C 
(the 120 mg dose cohort), the DMC may elect to modify the Cohort C to a 100 mg or 80 mg 
dose level. If recommended by the DMC, the change will be implemented by administrative 
letter and will not require a protocol amendment. All ongoing participants will have their 
dosing modified to 100 mg or 80 mg once monthly, and all new participants will be initiate 
dosing at 100 mg or 80 mg once monthly. 
There will be an alternative PK&PD sampling group at selected sites. A target population of 
approximately 24 to 40 participants distributed among the three cohorts is sought for this 
group. Whereas all other participants will receive their first dose of study intervention on a 
dialysis day, participants in the alternative PK&PD sampling group will receive their first 
dose of study intervention on a non-dialysis day, preceding a scheduled dialysis day. 
Central lab results for PD parameters, including coagulation parameters, will not be provided 
to the sites, as these are potentially unblinding. Investigators will also avoid local testing of 
coagulation parameters, as these may be unblinding, unless clinically indicated. 
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 16-weeks post treatment follow-up period (study completion). 
The end of the study is defined as the date the last participant completes the last protocol-
defined visit/contact. 
 
 
 
 


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Figure 3–1: Study Design 
 
S = screening, R = randomization, T = treatment, EoT = end of treatment, FU = follow-up 
 
 


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4. 
General Statistical Considerations 
4.1 
General Principles 
For continuous variables, descriptive summary statistics including number of patients, mean, 
standard deviation, median, upper and lower quartiles (25th percentile, 75th percentile), and 
minimum and maximum values will be presented. For categorical variables, counts and 
percentages will be presented in frequency tables. For continuous variables collected at 
multiple time points, the descriptive statistics will be provided at each time point. All 
statistical tests will be conducted using 2-sided tests with 10% Type I error rate unless 
otherwise stated.  
Placebo-treated patients will be pooled and analyzed as a single placebo group. Therefore, 
four treatment groups will be included and presented in the analysis as 40 mg, 80 mg, 120 mg, 
and placebo. Patients who are Fesomersen-treated may be pooled and summarized as the 
pooled treatment group. 
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA) or if applicable, other software. 
4.2 
Handling of Dropouts 
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. 
4.2.1 
Permanent Discontinuation of Study Intervention 
A randomized subject who permanently discontinues Fesomersen or placebo before their 
planned Visit 28 + 5 days window (extended treatment period) or before the last scheduled 
dose for primary completion, is defined as having had a permanent discontinuation of study 
intervention (including subjects who were randomized but never started taking any study 
intervention). The reason for the discontinuation of study intervention will be recorded in the 
eCRF and source documentation. 
The investigator may temporarily discontinue study intervention. If the discontinuation 
remains necessary > 56 days from the last dose, the participant will be permanently 
discontinued from study intervention and will enter the post-treatment follow-up period.  
The number of subjects who permanently discontinue study intervention and the reason for 
discontinuation will be displayed by treatment groups. Baseline characteristics will be 
displayed by permanently discontinue study intervention (yes/no). All data collected until the 
discontinuation will be presented. 
Participants whose discontinuation reason is recorded as COVID-19 will be included and 
presented here with the reason entered in eCRF. 
 
4.2.2 
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 investigator should make all efforts to determine the survival (vital status) of any 
participant who would otherwise be lost to follow-up during the treatment period or post-


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treatment follow-up period, whether by direct contact or indirect contact with a reliable source 
(family-member, health-care provider, etc.). A participants survival status will be recorded in 
the eCRF. If no survival status is known, the contact attempt will be recorded. 
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 eCRF.  
Additional descriptive analyses in the presence of missing data 
The number of subjects who prematurely discontinue the study and study intervention for any 
reason, as well as the reasons for premature discontinuation of study and study intervention, 
will be reported.  
Kaplan-Meier plots for “lost to follow up” will be provided if there are any such incidences.  
All dropouts will be carefully evaluated with respect to:  
x baseline characteristics, 
x potential differences between the treatment groups in the proportion of patient 
withdrawals or the timing of withdrawals, and 
x the reasons for premature discontinuation of study and/or study intervention and 
potential dropout patterns will be described.  
The number, timing, pattern, and reasons for missing values of all relevant efficacy and safety 
variables will be displayed by means of descriptive statistics and visualized if applicable.  
4.4 
Interim Analyses and Data Monitoring 
No formal interim analysis is planned.  
An independent Data Monitoring Committee (DMC) will monitor the safety of the 
participants. 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. 
4.5 
Data Rules 
4.5.1 
Analysis Dates 
For the study, the following date and time window are of relevance for the analysis: 
x End of Study Date 
The end of the study is defined as the date the last participant completes the last 
protocol-defined visit/contact. 
x Primary Completion Date 
The primary completion date is the date when the last participant completes the main 
treatment period . See the below period definitions for data collection in each period. 
x Main Treatment Period (actual) 
The main treatment period includes a total of 24 weeks  


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For subjects who did not enter the extension period the main treatment period is 
defined as the period from first dose of study intervention to the last date of dose +28 
days. 
For subjects who did enter the extension period the main treatment period is defined as 
the period from first dose of study intervention to the administration of study 
intervention (and hence commencement of the extension period), at visit 22. 
x Extended Treatment Period (actual) 
The extended treatment period includes a total of up to 24 weeks,  from study 
intervention administration on visit 22 until the date of last dose +28 days or date of 
last contact (whichever comes first). 
x Post-Treatment Follow-up Period (actual) 
The post-treatment follow-up period includes a total of 16 weeks. For subjects who 
did not enter the extension period, the follow up is defined as the period from the end 
of the main treatment period +1 day to the last contact date. 
For subjects who did enter the extension period, the follow up is defined as the period 
from the end of extension period + 1 day to the last contact date. 
 
For each subject, the following individual dates are of relevance for analysis: 
x Randomization date: 
The date of randomization as recorded in the IxRS system. 
x Date of the first dose of study intervention: 
The date of the first dose of Fesomersen or placebo will be used from the appropriate 
eCRF page capturing the study intervention.  
Date of the earliest logically possible dose of study intervention administration will be 
used, in cases where the date of the first dose is missing or incomplete.  
x Date of the last dose of study intervention: 
The date of the last dose of Fesomersen or placebo will be used from the appropriate 
eCRF page capturing the study intervention. 
Date of the latest logically possible dose of study intervention administration will be 
used, in cases where the date of the last dose is missing or incomplete.  
Incomplete dates will be imputed for the analysis as appropriate based on available 
information. 
 
4.5.2 
Data Scopes 
All analyses are based on two elements: 
1) analysis set, which specifies which subjects will be included in an analysis; and 
2) data scope, which defines the time window within which data will be included in the 
analysis. 


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This section describes the coverage of the event data scopes used for the statistical analyses. 
Analysis sets are described in Section 5. 
The below data scopes are based on the 3 periods of the study, main treatment, extension 
treatment and follow up, as defined in section 4.5.1: 
Data scope according to primary analysis principle (PA) 
The PA data scope includes outcome events observed from the date of first administration of 
study intervention until the end of the main treatment period. Events occurring after the main 
treatment period will not be counted for primary analysis data scope.  
Data scope according to total treatment analysis principle (TA) 
The TA data scope includes outcome events observed from the date of first administration of 
study intervention until the end of the extension treatment period. Events occurring after the 
extension treatment period will not be counted for total treatment analysis data scope. 
Data scope according to overall analysis principle (OA) 
The OA data scope includes outcome events observed from the date of first administration of 
study intervention until the end of post-treatment follow-up period.  
4.5.2.1 
Exploratory data scopes 
Extension period data scope (EP) 
The EP data scope includes outcome events observed from the start of the extension period 
until the end of the extension period.  
Follow up period data scope (FP) 
The FP data scope includes outcome events observed from the start of the post-treatment 
follow-up period until the end of the post-treatment follow up period  
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 and 
pharmacokinetic values to be excluded from statistical analysis will be documented and 
respective flags will be incorporated in the clinical database. 
4.7 
Sample Size Determination 
No formal statistical sample size estimates were performed. 
The sample size was selected based on prior experience in ESRD with the unconjugated ASO. 
This study is planned to ensure the safety, tolerability, and PK/PD relationships are assessed 
adequately while minimizing unnecessary participant exposure. There is no plan for statistical 
hypothesis testing for this study. In this study, the number of subjects is considered based on 
the ISIS 416858-CS5 study design. 


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Approximately 288 participants (96 [72 active+24 placebo] per cohort) will be randomly 
assigned to study intervention so that an estimated 240 participants will complete the main 
treatment period. All participants will be randomized to 1 of 3 dose cohorts in a 1:1:1 ratio 
(Cohort A, Cohort B, and Cohort C). Within each dose cohort, subjects will be randomized in 
a 3:1 ratio to receive treatment with either Fesomersen or placebo. Considering an 
approximately 15% dropout rate, an estimated total of 60 participants per intervention group 
and the placebo group will complete the main treatment period. A participant will be 
evaluated once he/she was randomized and received at least one dose of study intervention. 
The number of evaluable and randomized participants is assumed to be similar.  
Table 4-1 summarizes 95% expected range for the true population proportion of participants 
with a composite of MB and CRNMB bleeding. For example, with 60 participants, if 5% of 
them had a composite of MB and CRNMB bleeding during the main treatment period and the 
desired confidence level is 95%, the corresponding confidence interval would be ± 5.51, i.e. 
the range of 0.0 % to 10.51%. If multiple samples were drawn from the same population and a 
95% CI calculated for each sample, we would expect the true population proportion to be 
found within 95% of these CIs. 
Table 4-1: Confidence Interval for proportion of participants with a composite of MB 
and CRNMB Bleeding 
Sample Size  
Observed 
Proportion * 
Desired 
Confidence 
level 
Corresponding 
two-sided 
confidence interval 
Range for the true population 
proportion 
60 
2% 
95% 
±3.54 
0.0% to 5.54% 
 
3% 
95% 
±4.32 
0.0% to 7.32% 
 
4% 
95% 
±4.96 
0.0% to 8.96% 
 
5% 
95% 
±5.51 
0.0 % to 10.51% 
 
6% 
95% 
±6.01 
0.0% to 12.01% 
 
7% 
95% 
±6.46 
0.54% to 13.46% 
 
8% 
95% 
±6.86 
1.14% to 14.86% 
CRNMB = clinically relevant non-major bleeding, MB = major bleeding 
* The range of observed proportion is considered based on the Interim report of ISIS 416858-CS5 
study where the composite of MB and CRNMB bleeding proportion for Placebo was 5.7% and 
for total ISIS treated= 4.5% (ISIS treated with 200mg, 250mg and 300 mg doses were 3.8%, 
5.6% and 4.0% respectively) 
 
 
 


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5. 
Analysis Sets 
5.1 
Assignment of Analysis Sets 
All subjects who have been randomized in the study are valid for assignment to analysis sets. 
The following populations are defined: 
Table 5-1: Populations 
Population 
Description 
Enrolled 
All participants who sign the ICF 
Full analysis set (FAS) 
All participants randomized who have received at least 
1 dose of study intervention. Participants will be 
analyzed according to the intervention they were 
randomized. 
Safety analysis set (SAF) 
All participants randomly assigned to study 
intervention and who took at least 1 dose of study 
intervention. Participants will be analyzed according to 
the intervention they received. 
If a participant was administered, in error, a different 
dose to that which they were randomized to, they will 
be analyzed according to the intervention received 
most frequently (i.e. at > 50% of visits), in cases where 
2 different doses were administered for the same 
number of visits, the participant would be excluded 
from the safety analysis set. 
Pharmacokinetic set (PK) 
All Fesomersen-treated participants with at least 1 PK 
sample in accordance with the PK sampling schedule 
(Section 8.5.1 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 set (PD) 
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. 
If the safety and full analysis sets are identical, i.e. all subjects received the treatment to which 
they were randomized, the full analysis set will not be used.  
The planned analyses for the primary, secondary, exploratory, and PK-PD endpoints are 
summarized in but not limited to Table 5-2 below 
 


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Table 5-2: Sketch of the planned analyses on the endpoints 
Endpoints 
Analysis Type 
Analysis set 
Data Scope 
Primary Endpoint(s) 
Main 
SAF 
PA a) 
 
Additional 
SAF 
TA a) 
 
Exploratory 
SAF 
OA b) 
 
Subgroup 
SAF 
PA a) 
 
 
SAF 
TA a) 
Secondary Endpoint(s) 
Main 
SAF 
PA a) 
 
Additional 
SAF 
TA a) 
 
Exploratory 
SAF 
OA b) 
Exploratory Endpoint(s) 
Main 
SAF 
PA a) 
 
Additional 
SAF 
TA a) 
 
Exploratory 
SAF 
OA b) 
 
 
FAS 
PA b) 
 
 
FAS 
TA b) 
 
Subgroup 
SAF 
PA a) 
 
 
SAF 
TA a) 
PK, PD Endpoint(s) 
Trough concentrations 
Main 
PK 
OA 
Maximum change in FXI 
antigen levels 
Main 
PD 
OA 
Maximum change in FXI activity 
levels 
Main 
PD 
OA 
PA: Data scope according to primary analysis principle, TA: Data scope according to total treatment 
analysis principle, OA: Data scope according to overall analysis principle. 
a) on-treatment estimand 
b) treatment policy estimand 
 
 


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6. 
Statistical Methodology 
The primary safety and efficacy variables will be analyzed descriptively for the following 
groups: 
x Pooled Placebo Group (from Cohorts A, B and C),  
x 40 mg Dose Group (Fesomersen from Cohort A),  
x 80 mg Dose Group (Fesomersen from Cohort B), and  
x 120 mg Dose Group (Fesomersen from Cohort C).  
For selected analyses the pooled Fesomersen treatment arms will be presented in addition.  
Incidence rates and cumulative incidences will be calculated only for endpoints with at least 1 
event in a treatment arm. Hazard ratios (cause specific and sub distribution), log-rank test and 
Gray’s test will only be calculated if there is at least 1 event in each of the compared 
treatment arms. 
6.1 
Population Characteristics 
6.1.1 
Disposition 
The following will be tabulated overall and/or by treatment group: 
x Study sample sizes (All enrolled subjects) 
x Study sample sizes by region, country, and site 
x Subject disposition (by treatment group and overall) 
x Number of subjects and primary reasons for screening failures 
x Number of subjects and primary reasons for permanent discontinuation of study 
intervention (by treatment group and overall) 
6.1.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics include: 
x Dialysis and ESRD disease characteristics obtained before the first study intervention 
administration 
x Age groups  
o <60 years,  
60-75 
>75years  
o <50yrs 
>=50-<60yrs 
>=60-<65yrs 
>=65-<70yrs 
>=70-<80yrs 
>=80yrs  
o <=65 years 
>65 years) 


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x BMI groups  
o Below 18.5 = underweight;  
18.5 to <25.0 = healthy weight;   
25.0 to <30.0 = overweight;  
>= 30.0 = obesity  
 30 to <35: obesity class 1;  
35 to <40: obesity class 2;  
>=40: obesity class 3  
x Age, Weight, Height, BMI as continuous variables 
x Gender, Ethnicity, Race 
x Time since the start date for renal replacement therapy,  
The continuous variables will be summarized using descriptive statistics, while counts and 
percentages will be provided for categorical variables. All analyses will be presented overall 
and by treatment group in both the FAS and SAF analysis sets. Other baseline characteristics 
may be added as deemed appropriate. No statistical tests will be performed to compare these 
characteristics across treatment groups. 
Age for each participant will be defined as the number of years between informed consent 
date and birth date. 
For summarizing race, if multiple races are recorded in the database, then 'multiple race' will 
be used in the summary table. 
6.1.3 
Definition of Baseline 
In general, a baseline assessment will be the last non-missing value prior to the first 
administration of study intervention (Fesomersen or placebo) on Day 1. If Day 1 values are 
not available, last screening values will be used. Furthermore, if there is more than one 
assessment at the same timepoint, the baseline value will be the mean of the recorded 
measurements prior to the administration of study intervention. 
6.1.4 
Medical History 
Medical history will be presented by the pre-specified terms, as collected in the eCRF using 
MedDRA Primary System Organ Class / Preferred Term. The summary of medical history 
data will be presented in frequency tables, showing the number of subjects with medical 
history findings (i.e., listed conditions of previous diagnoses, diseases, or surgeries) that 
started before signing of the informed consent and that are considered relevant to the study. 
6.1.5 
Protocol Deviations 
Frequency tables will present a summary of protocol deviations related to inclusion and 
exclusion criteria, as well as important protocol deviations; these will be presented by visit 
and treatment. The summary will be based on SAF analysis set. 
6.1.6 
Prior and Concomitant Medications 
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) class and coded 
terms will be used to summarize the number and percentage of subjects with prior and 


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concomitant medications. The following definitions for prior and concomitant medications 
will be used: 
x Prior medication: medication stopped prior to the date of randomization  
x Concomitant medication in main treatment period (PA), extension period (EP), 
follow-up period (FP), total treatment analysis principle (TA), overall analysis 
principle (OA) (i.e. at least one dose was administered within the respective period) 
x Concomitant medication started in main treatment period (PA), extension period (EP), 
follow-up period (FP), total treatment analysis principle (TA), overall analysis 
principle (OA) (i.e. first administration of concomitant medication occurred within the 
respective period) 
 
The frequency tables of concomitant medications will be presented by treatment group and 
time period. 
Additionally, frequency tables and listings of subjects taking prohibited concomitant 
medications (see study protocol section 6.5) will be provided. 
6.1.7 
Extent of Exposure and Compliance 
All summaries related to exposure to the study intervention will be presented by treatment 
group based on SAF analysis set. 
The treatment duration (date of last study intervention - date of first study intervention+1 day) 
will be summarized descriptively. Additionally, the number of subjects by treatment duration 
category will be given (≤4 weeks, >4-≤8 weeks, >8-≤12 weeks, >12-≤24 weeks, >24 weeks). 
The time on study intervention (treatment duration excluding days off study intervention) will 
be calculated and summarized descriptively. 
Compliance will be presented by visits as entered in the eCRF and summarized based on FAS 
analysis set. The number of subjects with at least 80% compliance will be presented. 
ܵݐݑ݀ݕ ܦݎݑ݃ ܥ݋݉݌݈݅ܽ݊ܿ݁= 100 ×
Total number of doses with injections given
Total number of doses with injections expected 
If a patient discontinued the study intervention, the total number of doses with injections 
expected is counted, per the schedule of injections, up to the last attended study visit during 
the total treatment period. 
6.1.8 
Baseline Renal Replacement Therapy  
Information on 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 
Analysis of Exploratory Efficacy Variable(s) 
Two exploratory efficacy variables will be considered.  
First exploratory efficacy composite endpoint consisting of the following components: 
x Death due to MI, ischemic stroke, pulmonary embolism (PE), non-CNS systemic 
embolism (SE) and undetermined - presumed cardiovascular death 


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x Stroke (ischemic or undetermined type) 
x MI 
x Major amputation of vascular etiology 
x Acute limb ischemia 
x Symptomatic VTE 
x Systemic embolism  
Second exploratory efficacy endpoint: 
x Thrombosis of the arterio-venous grafts or fistulas 
The frequency and percentage of participants with an exploratory efficacy event will be 
reported where the denominator will be total number of participants in each treatment group, 
within the SAF analysis set and PA data scope. The corresponding exact binomial two-sided 
95% confidence interval calculated using Blaker’s method will be provided.  
Exposure adjusted incidence rate (100 person-years) analysis will be performed by treatment 
group and overall. In addition, the analysis of the exploratory efficacy variable will be 
conducted as a descriptive time to first event analysis separately for the three Fesomersen 
dose groups and placebo, similar to the primary safety analysis (i.e. only treatment emergent 
efficacy events which occurred during the main treatment period will be considered). Thus, 
the descriptive analysis focuses on estimating the efficacy under constant BAY2976217 
concentration during chronic treatment. This analysis will be based on SAF analysis set and 
the PA data scope.   
6.2.1.1 
Other Exploratory Efficacy Analyses  
Efficacy Analysis by Component 
The single components of the main efficacy variable will be analyzed in a similar way to the 
main efficacy analysis in section 6.2.1.  
Analysis of Death Events 
The main efficacy analysis will be repeated for overall death and for its components (Death 
due to MI, stroke, pulmonary embolism (PE) and systemic embolism (SE), CV death, Non-
CV death, Undetermined death, and other reasons).  
Pre-Treatment Efficacy Summary 
Pre-treatment events between randomization and first dose of study intervention will be listed. 
6.2.2 
Sensitivity and Supplementary Efficacy Analysis 
The exploratory efficacy endpoints will be analyzed using the same method described in 
Section 6.2.1based on: 
x SAF analysis set and TA data scope,  
x SAF analysis set and OA data scope,  
x FAS analysis set and PA data scope,  
x FAS analysis set and TA data scope 


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6.2.2.1 
Stratified Efficacy Analysis 
The main efficacy analysis with Cox regression will be repeated incorporating all factors 
considered in the randomization as stratification factors without interaction terms. if the 
model converges. 
6.2.2.2 
Competing Risk Model Analysis 
The exploratory variables will be analyzed using a competing risk event model similar to the 
primary safety endpoint (see section 6.4.1.1). Death due to reasons other than MI, stroke, PE 
and SE is considered a competing event for the efficacy analysis. 
6.2.2.3 
Subgroup Analysis  
The analysis for the exploratory efficacy variables will be repeated by the following 
subgroups: 
x Age groups  
o <60 years,  
60-75 
>75years  
o <50yrs 
>=50-<60yrs 
>=60-<65yrs 
>=65-<70yrs 
>=70-<80yrs 
>=80yrs  
x BMI groups  
o Below 18.5 = underweight;  
18.5 to <25.0 = healthy weight;   
25.0 to <30.0 = overweight;  
>= 30.0 = obesity  
 30 to <35: obesity class 1;  
35 to <40: obesity class 2;  
>=40: obesity class 3  
x Gender,  
x Previous CV events (MI or stroke or TIA or VTE) 
x 
Previous MACE (MACE is defined as: prior myocardial infarction, prior stroke from 
the medical history database.)  
x History of DM, 
x History of Afib, 
x Race,   
x Time since the start date for renal replacement therapy (<1 year; >=1 year),  
x Use of low dose ASA, 
x History of COVID-19, 


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x COVID-19 during the study 
The analyses for the subgroups will be repeated for the exploratory endpoints based on SAF 
analysis set and PA data scope and SAF analysis set and TA data scope. The results will be 
presented descriptively with forest plots. 
6.2.3 
Analysis of COVID-19 Patients 
Analysis to evaluate the COVID-19 impact on the study exploratory efficacy endpoint will be 
performed by comparing the descriptive statistics among COVID-19 versus non-COVID-19 
patient population. COVID-19 cases will be recorded as adverse events in the eCRF, 
participants with a documented adverse event of COVID-19 during the study will form the 
COVID-19 population, all other participants will be included in the non-COVID-19 
population. Additional analysis on the COVID-19 will be described in the future SAP revision 
if needed. 
6.3 
Pharmacokinetics/Pharmacodynamics. 
Plasma and dialysate samples will be collected for measurement of plasma Fesomersen-eq. 
concentrations and dialysate concentrations of Fesomersen and its metabolites, respectively. 
PK- and PD- samples will be collected in all participants. A subset of at approximately 24-40 
participants will be participating in an alternative PK&PD sampling group with the first dose 
on a non-dialysis day 
There may be some inaccuracies in the actual sampling times compared to planned sampling. 
These deviations can be relevant for the interpretation of pharmacokinetic and 
pharmacodynamic data. Accepted time windows are prespecified in the guidance documents 
for PK and PD validity for study #21170 and will be referenced in the final blind review 
report. Accepted time windows for the assessment of pharmacokinetic concentrations will be 
handled analogously. 
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. Samples flagged for other reasons, as defined in respective guidance 
documents for PK and PD validity for study #21170, will be excluded from statistics 
accordingly (see also section 4.6). 
6.3.1 
Pharmacokinetics Analysis 
Plasma Fesomersen-eq. concentrations and dialysate concentrations of Fesomersen and its 
metabolites, respectively, will be summarized by visit and planned sampling time intervals, 
separated according to actual dose cohort. Descriptive statistics [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. Analysis comparing regular and 
alternative PK sampling group will be done. 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 Fesomersen-eq. trough (Ctrough) plasma concentrations will be provided by 
actual dose cohort and visit. 


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For all treatments where at least one subject with at least one confirmed ADA formation is 
included, the individual concentrations of Fesomersen 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.  
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 
document, if applicable. 
6.3.2 
Pharmacodynamic Analysis 
Analysis comparing regular and alternative PD sampling will be done. 
6.3.2.1 
The PD profile  
The effect of Fesomersen on PD profile will be assessed on maximum change in FXI activity 
levels, FXI antigen levels, PT, INR, aPTT, d-dimer, TAT, and F1.2 levels during the main 
treatment period by treatment group in PD analysis set.  
Change and percent change from baseline FXI activity levels, FXI antigen levels, PT, INR, 
aPTT, d-dimer, TAT, and F1.2 levels will be summarized by treatment and visit separately. 
Individual results will be presented in data listings by treatment. Figures of the mean levels of 
all PD parameters (FXI activity and antigen, PT, INR, aPTT, d-dimer, TAT and F1.2) as well 
as change and percent change from baseline will be provided by treatment group, and 
scheduled visit.  
Change and percent change from baseline in FXI activity levels, FXI antigen levels, PT, INR, 
and aPTT will be compared between each of the study intervention group and pooled placebo 
group using the Wilcoxon Rank Sum test.  
Frequency and percent of patients with average FXI activity ≤0.1, ≤0.2, ≤0.3, ..., ≤1.0 U/mL 
during each visit with PK/PD measurements up to last dose + 28 days will also be provided. 
The incidence and events for any aPTT>160s will be summarized by treatment and visit. 
For all treatments where at least one subject with at least one confirmed ADA formation is 
included, the PD parameters. 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.  
6.3.2.2 
SQCS Analysis 
The effect of Fesomersen on the clotting in the dialysis circuit will be assessed by the SQCS.  
The clotting assessment will be conducted on the PD analysis set and will be presented 
according to treatment group. Clotting scores will be assigned as follows: 
Table 6-1: Clotting scale score 
Clotting score 
Definition 
Clotting Score 0 
Clean filter and no visible clots in the drip chambers 
Clotting Score 1 
For traces of coagulation in the filter and/or in the drip chambers 
Clotting Score 2 
Intermediate state between 1 and 3 
Clotting Score 3 
Fully clotted extracorporal system resulting in an interruption of the 
hemodialysis session 
Adequate anticoagulation is defined by an SQCS of less or equal "1".  


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The summary of each clotting score category will be presented in frequency and the 
percentage of patients by visits.  
The overall score for individual subjects, which is the highest clotting score from all visits per 
data scope, will also be summarized. The overall clotting score will be analyzed for treatment 
comparison between each Fesomersen dose groups and placebo group using the Wilcoxon 
Rank Sum test. 
The difference in the mean of SQCSs during the main treatment period between each of the 
Fesomersen groups and the placebo group will be displayed together with the corresponding 
90% (and 95%) confidence intervals applying ANOVA with treatment group as factor. 
Furthermore, the difference in the proportion of hemodialysis sessions with adequate 
anticoagulation during the main treatment period between each of the Fesomersen dose 
groups and the placebo group will be summarized with the corresponding 90% (and 95%) 
confidence intervals using the unstratified exact method with the standardized test statistic 
and inverting a two-sided test (Agresti and Min, 2000) as exploratory analysis.  
Frequency of dialyzer filters usage will be analyzed through descriptive statistics. 
Most severe clotting category 
In order to examine the correlation of FXI activity level and clotting, a separate summary on 
the most severe clotting category will be provided for patients with average FXI activity ≤0.1, 
≤0.2, ≤0.3, ..., ≤1.0 U/mL for Fesomersen treated patients only.  
6.4 
Safety 
The primary objective is to assess the safety of the three different doses of Fesomersen given 
once a month, which is expected to be maintained during chronic treatment. The primary 
analysis of the unblinded data snapshot, will be conducted after all participants complete the 
24-week main treatment period to assess the safety and PK/PD, and exploratory efficacy of 
the results. . An unblinding plan additional to this SAP will detail the unblinding process and 
contain the study team members who will be unblinded at the time of the primary analysis. 
Additional tables, including participant's extended treatment period up until primary 
completion, will be presented. No formal interim report will be written. 
The final data analysis will be conducted once all participants complete the follow-up period 
(the last participant's last follow-up visit). At the end of the study completion, statistical 
analysis will include all data, including the main treatment period, extension period, and the 
follow-up period as well as distinctive period analysis appropriately. 
6.4.1 
Analysis of the Primary Safety Variable 
The primary analysis is based on a descriptive proportion of subjects with primary endpoints 
(independently adjudicated) based on SAF analysis set and PA data scope. For each treatment 
and bleeding category, participants reporting more than one bleeding event will be counted 
only once using the highest severity. The frequency and percentage of participants with 
bleeding will be reported where the denominator will be total number of participants in each 
treatment group.  
Estimand for the Primary Safety Endpoint: 
The five attributes of the estimand are as follows: 


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x Population: The population consists of ESRD patients as described by the 
inclusion/exclusion criteria given in study protocol. 
x Variable: The incidence of the composite of MB, CRNMB, events during the main 
treatment period, as assessed by the CIAC 
x Treatment: Three dose groups of Fesomersen or placebo on top of standard of care 
x Intercurrent events:  
o Unblinding to study intervention: the study allows unblinding of treatment 
assignment if the investigator deems necessary when related a bleeding or 
major surgery occur regardless of whether such an event occurs (treatment-
policy strategy) 
o Early definitive discontinuation of study intervention or death or kidney 
transplant: until the occurrence of the intercurrent event (while on treatment 
strategy) 
o Dose reduction: regardless of whether such an event occurs (treatment-
policy strategy).  
x Population-level summary: Incidence proportion of subjects with an event by study 
intervention group and differences between Fesomersen treatment groups and placebo 
group. For the incidence proportions the exact binomial two-sided 95% confidence 
interval using Blaker’s method will be provided. For the difference in incidence 
proportions the two-sided 95% confidence interval will be presented using the 
unstratified exact method with the standardized test statistic and inverting a two-sided 
test (Agresti and Min, 2000). 
6.4.1.1 
Additional Primary Safety Endpoint(s) Analysis: 
Estimand for Time to Event Safety Endpoint: 
The attributes constituting the estimand for this endpoint are the following: 
x Population: The population consists of ESRD patients as described by the 
inclusion/exclusion criteria given in study protocol. 
x Variable: 
o Time from first dose of intervention to MB and CRNMB events (in 
alignment with ISTH guidelines) up until 28 days after last study 
intervention 
x Treatment: Three dose groups of Fesomersen or placebo on top of standard of care 
x Intercurrent events: Of interest is the response to treatment while the participant is 
o alive (intercurrent event "death") and 
o 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:  
Death and premature end of exposure to assigned treatment (last administration of assigned 
treatment plus 28 days) considered a competing event for the safety analysis. 


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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 cumulative incidence, i.e. the probability of having a specific event, E, at or before a 
timepoint, t, ܲ(ܶ≤ݐ, ܧ= 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 40mg Fesomersen and placebo and 
80mg Fesomersen and placebo and 120mg Fesomersen 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: 
ቈ(ܣܬ
෢்ோ்(݀ܽݕ) −ܣܬ
෢஼௢௡௧௥௢௟(݀ܽݕ)) ± ݖ଴.ଽହටߪଶ(ܣܬ
෢்ோ்(݀ܽݕ)) + ߪଶ(ܣܬ
෢஼௢௡௧௥௢௟(݀ܽݕ))   ቉, 
with ܣܬ
෢்ோ்(݀ܽݕ) the Aalen-Johansen estimator for Fesomersen (TRT) at study day, ݖ଴.ଽହ the 
95% quantile of the standard normal distribution and ߪଶ(ܣܬ
෢்ோ்(݀ܽݕ)) and 
ߪଶ(ܣܬ
෢஼௢௡௧௥௢௟(݀ܽݕ)) are the estimated variances of the Aalen-Johansen estimators 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 on-treatment incidence rate will be expressed a “subjects with an event – per 100 
participant years”. For that the following formula is used: 
ܫܴ௔ௗ௝=
#ܲܽݎݐ݅ܿ݅݌ܽ݊ݐݏ ݓ݅ݐℎ ܽ݊ ݁ݒ݁݊ݐ
∑ ݐ݅݉݁ ݑ݊݀݁ݎ ݐݎ݁ܽݐ݉݁݊ݐ (݅݊ ݀ܽݕݏ)/(100 ∗365.25)
 
The 90% confidence interval for the exposure-adjusted IR will be computed as 
ቈܫܴ௔ௗ௝∗ ߯ଶ(0.05; 2݁)
2݁
; ܫܴ௔ௗ௝∗ ߯ଶ(0.95; 2݁)
2݁
 ቉, 
with ߯ଶ(ݍ; 2݁) the q quantile of a chi square distribution with 2e degrees of freedoms and e 
the number of participants with an event. (Nelson 1982) 
Hazard ratios 
With respect to the cause-specific hazards for the respective safety variable, each of the 
Fesomersen groups will be compared to the placebo group using two-sided log-rank tests. 
Due to the explorative nature of these analyses, no multiplicity adjustment will be done. 
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. 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 Fesomersen groups with the placebo group will be estimated 
based on three separate cause-specific Cox proportional hazards models as exploratory 
amalysis. Censoring will be assumed to be independent form the study intervention. For 
example, for the comparison of the 120 mg Fesomersen group with the placebo group, the 


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Protocol No.: BAY 2976217/21170 
Page: 30 of 34
 
 
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  
xi  
treatment group of subject i 
(0 corresponds to “placebo group” and 
 1 corresponds to “120mg Fesomersen 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 
Analysis of Secondary Safety Variable(s) 
The secondary safety analysis is based on secondary endpoints incidence and severity of 
TEAE by treatment and overall with SAF analysis set and PA data scope.  
The original terms used by investigators to report AEs via the CRFs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). The summary of all adverse events 
will be tabulated by the primary system organ class (SOC) and preferred term (PT) by 
treatment arm. A total column will be included in all safety summaries.   
The version number of MedDRA used for the analyses will be stored in the clinical database. 
Tables and/or listings of treatment-emergent deaths, serious and significant AEs, including 
early withdrawals due to AEs, will also be provided.  
Treatment emergent adverse events (TEAEs) 
Overall study TEAEs are defined as AEs that occurred or worsened after first dosing until 20 
weeks after the last study intervention dose.  
Main treatment period TEAE:  
The main treatment period TEAEs will be defined as those AEs that occurred after first 
dosing and those existing pre-dose AEs that worsened severity post-dose treatment period 
until 28 days after the last dose of the study drug during the main treatment period. The most 
conservative approach will be used to determine if the event occurs during the main treatment 
period. 
TEAE during overall treatment period:  
For the overall TEAE analysis the event which occurred during the main and extension 
treatment period and during the post treatment follow-up period will be considered. 


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All TEAEs, all TEAEs potentially related to study intervention, all TEAEs potentially related 
to ESRD or the hemodialysis procedure, all TESAEs, and all TESAEs potentially related to 
study intervention will be summarized by treatment group and by MedDRA SOC and PT 
terms. 
TEAEs and TESAEs leading to discontinuation and AEs of special safety interest (if 
applicable) will be listed. The date, relative date (to start of study intervention) and phase of 
the study (during treatment, post-treatment) will be included.  
Frequency tables, showing an overall summary of number of events, number of subjects with 
AEs, serious adverse events (SAEs) and adverse events of special interest (AESIs) will be 
given, and will include the following information. 
x if AE (/SAE/AESI) occurred with causal relationship to study drug; 
x if AE (/SAE/AESI) occurred with causal relationship to study procedures (renal 
replacement therapy); 
x maximum intensity for any AE / any study-drug related AE; 
x AE related deaths; 
x AE resulting in permanent discontinuation of study drug.  
6.4.3 
Sensitivity and Supplementary Safety Analysis 
To support the primary study results and to assess the robustness of the analysis, several 
additional sensitivity and supplementary analyses will be performed. 
The primary safety endpoint will be analyzed using the same method described in Section 
6.4.1.1 based on SAF analysis set and both TA and OA data scope.  
In addition, analysis will be performed with additional bleeding events on SAF analysis set 
with PA data scope, and SAF analysis set with TA data scope: 
x Minor bleeding  
o Minor bleeding will be further categorized as injection site and non-injection 
site bleeding events. 
Additional analysis on the secondary safety endpoints will be performed based on SAF 
analysis set and TA data scope.  
6.4.3.1 
Stratified Safety Analysis 
The primary safety endpoints analysis will be repeated incorporating all stratification factors, 
both with and without interaction terms. 
6.4.4 
Analysis of Other Pre-Specified Safety Variable(s) 
The additional safety endpoints analysis is based on a descriptive proportion of subjects by 
treatment group and overall with pre-specified safety endpoints based on SAF analysis set.  
x Incidence proportion of adverse events of special interests (AESIs) and severity will 
be summarized by treatment group and overall. 
x Vital sign measures (including ECG) and the change from baseline will be 
summarized by treatment group and overall. 


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x Laboratory tests variables will be summarized by study visits, by treatment group, and 
overall. It will also be presented as change and percentage change from baseline over 
time after study intervention administration, as appropriate. In addition, the number of 
subjects who experience abnormalities in clinical laboratory evaluations will be 
summarized by treatment group and overall. 
x Bleeding of the arterio-venous grafts or fistulas will be summarized by treatment 
group and overall. Additionally, assessment of the severity of bleeding at the dialysis 
access following the hemodialysis procedure will be done at specified visits. Severity 
of bleeding at the dialysis access will be assessed approximately 15 minutes (10 – 20 
minutes) after removal of the dialysis needle(s) from the AV access according to the 
following categories (exploratory bleeding score): 
i. 
"0" no access bleeding; 
ii. 
"1" slow oozing; 
iii. 
"2" overt bleeding 
Proportion of the participants with the bleeding at the dialysis access following the 
hemodialysis procedure will be summarized by treatment group according to the above 
bleeding score categories. 
6.4.5 
Subgroup Analysis 
The subgroup analyses based on baseline and demographic characteristics are planned for the 
treatment groups comparisons of the primary safety endpoints, the subgroups for the safety 
analysis are the same as those listed in section 6.2.2.3: 
The analyses for the subgroups will be performed based on SAF analysis set and PA data 
scope and SAF analysis set and TA data scope. The results will be presented descriptively 
with forest plots. 
6.4.6 
Analysis of COVID-19 Patients 
Analysis to evaluate the COVID-19 impact on the study primary safety endpoint will be 
performed by comparing the descriptive statistics among COVID-19 versus non-COVID-19 
patient population. Additional analysis on the COVID-19 will be described in the future SAP 
revision if needed. 
6.5 
Data affected by the war in Ukraine 
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 
follow-up 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 missingness 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. 
 
 
 


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7. 
Document History and Changes in the Planned Statistical Analysis 
x Approval of the SAP version 1.0 dated 25 AUG 2020 
x The following changes were made in the SAP Version 2.0 dated 15 DEC 2021: 
o Updated the data scope definitions to cover the follow up and extension 
periods alone.  
o Updated the concomitant medication period definitions 
o Adapted the safety and efficacy outcome variable sections with the exploratory 
competing risk analysis including with cause-specific and sub-distribution 
hazard models 
o Clarified definition of the subgroup of subjects with COVID-19 
o General updates based on new version of the protocol 
o Updates to the PK/PD sections based on expert opinion and review 
o Updated BAY 2976217 to ‘Fesomersen’. 
o Removed the following subgroups as they do not make sense 
 Medical condition that likely led to RRT 
 Time since the start date for most recent Hemodialysis (including 
hemodiafiltration) 
o Removed text from section 6.4.3 due to repetition and referenced the text in 
section 6.4.1. 
o Updated the safety analysis set definition to clarify how subjects who were 
mis-dosed would be handled 
x The following changes were made in the SAP version 3.0 dated 01 FEB 2022: 
o Added undetermined- presumed cardiovascular death to efficacy composite 
o Updated analysis periods and data scopes so they no longer depend on visits  
o Aligned the subgroups across safety and efficacy analyses 
x The following changes were made in the SAP version 4.0 dated 31MAY2022: 
o Added section 6.5 relating to the handling of data affected by the war in 
Ukraine. 
 
8. 
References 
 
Agresti A, Min Y. On small-sample confidence intervals for parameters in discrete 
distributions. Biometrics 2001; 57: 963-971. 
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. 
Blaker H. Confidence Curves and Improved Exact Confidence Intervals for Discrete 
Distributions. Canadian Journal of Statistics 2000; 28:783–798. 
de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, et al. 
Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA. 
2009;302(16):1782-9. 


Statistical Analysis Plan 
Protocol No.: BAY 2976217/21170 
Page: 34 of 34
 
 
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. 
Mann JF, Anderson C, Gao P, Gerstein HC, Boehm M, Ryden L, et al. Dual inhibition of the 
renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results 
of the ONTARGET trial. J Hypertens. 2013;31(2):414-21. 
Seliger SL, Gillen DL, Longstreth WT, Jr., Kestenbaum B, Stehman-Breen CO. Elevated risk 
of stroke among patients with end-stage renal disease. Kidney Int. 2003;64(2):603-9. 
United States Renal Data System. 2019 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. Available online: 
https://www.usrds.org/2019/view/USRDS_2019_ES_final.pdf. 2019. 
Von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, Bouma BN. 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. 
Zoccali C, Mallamaci F, Tripepi G. Inflammation and atherosclerosis in end-stage renal 
disease. Blood Purif. 2003;21(1):29-36. 
 


 
 
Page 1 of 2 
Statistical Analysis Plan (Amendment/Supplement)  
Approval Form 
 
Study Number (Bay No./IMP no.) 
21170 
Statistical Analysis Plan (SAP) 
Version and Date 
Version 4.0  
31st May 2022 
 
 
 
 
 
 
 
 
I have read and approve the SAP/SAP Amendment referred above.  
 
 
Name 
Signature and Date 
Author: 
Study Statistician 
 
 
Approved by: 
Statistical Project 
Lead 
 
Clinical Lead 
 
Study Medical 
Expert 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
Page 2 of 2 
Study Statistical 
Analyst 
 
 
Global safety lead  
 
Medical Writer 
 
 
PK lead 
 
  
PD lead 
 
 
  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD