Conditions: Hemophilia A and B
Keywords: Subcutaneous Prophylaxis Non-Inhibitors Inhibitors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 24
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the safety and tolerability of multiple doses of a human monoclonal antibody (BAY1093884) given under the skin in subjects with hemophilia A or B. This antibody was intended to protect from bleeds by inhibiting a substance (Tissue Factor Pathway Inhibitor, TFPI) that reduces the ability of the body to form blood clots.

Detailed description:
The primary objective of the study was to assess the safety and tolerability of multiple subcutaneous injections of BAY1093884 (anti-TFPI monoclonal antibody, immunoglobulin G2, IgG2) in patients with hemophilia A or B with or without inhibitors.

Arms:
arm 1: Subjects received BAY1093884 100 mg once a week until premature termination of the study arm 2: Subjects received BAY1093884 225 mg once a week until premature termination of the study arm 3: Subjects received BAY1093884 400mg once a week until premature termination of the study

Interventions: intervention 1: Befovacimab (BAY1093884)
Intervention descriptions: intervention 1: Once weekly doses until premature termination of the study, subcutaneous injection

Protocol document:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
Multiple escalating dose study of BAY 1093884 in adults with 
hemophilia A or B with or without inhibitors 
NCT Number: 
NCT03597022 
Document Date: 
05-APR-2019 
 


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Cover page of the integrated protocol
Multiple escalating dose study of BAY 1093884 in adults with hemophilia A or B with or 
without inhibitors
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.0, dated 22 FEB 2018

Amendment no. 1 (local amendment Japan), dated 17 APR 2018

Amendment no. 2 (local amendment United Kingdom), dated 30 APR 2018

Amendment no. 3 (local amendment Japan), dated 07 JUN 2018

Amendment no. 4 (global)
forming integrated protocol Version 2.0, dated 26 JUN 2018

Amendment no. 5 (global)
forming integrated protocol Version 3.0, dated 12 FEB 2019

Amendment no. 6 (global)
forming integrated protocol Version 4.0, dated 05 APR 2019


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1.
Title page
Multiple escalating dose study of BAY 1093884 in adults with hemophilia A or B with or 
without inhibitors
Test drug:
BAY 1093884 
Clinical study phase:
2 
Date:
05 APR 2019
Registration:
EudraCT no. 2017-003324-67 Version no.:
4.0
Sponsor’s study no.:
19580    
Sponsor:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915,
Whippany NJ 07981-0915, USA 
Sponsor’s medical expert:
Bayer SA-Brasil
Rua Cancioneiro de Évora 255- prédio E1-1º andar
Cep 04708-010
São Paulo-SP-Brasil 
Tel: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
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) may not be displayed.
Hence, the appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD


PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the 
respective center’s investigator site file.
In the protocol document, this page may remain unsigned.


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2.
Synopsis
Title
Multiple escalating dose study of BAY 1093884 in adults with hemophilia 
A or B with or without inhibitors
Clinical study phase
2 
Study objective(s)
Primary objective:
!
To assess the safety and tolerability of multiple subcutaneous 
doses of BAY 1093884 in subjects with hemophilia A or B with or 
without inhibitors. 
 
 
 
 
Test drug(s)
BAY 1093884 
Name of active ingredient
Anti TFPI monoclonal antibody (immunoglobulin G2; IgG2) 
Dose(s)
Once weekly doses:  The dose for Cohort 1 (X dose) will be 100 mg.  The 
dose for Cohort 2 (Y dose) will not exceed 250 mg, and for Cohort 3 (Z 
dose) will not exceed 400 mg.  Doses for Cohort 2 and 3 (Y and Z doses) 
will be selected based on the safety assessments from previous cohorts and 
desired duration of PD response based on 
pharmacokinetics/pharmacodynamics (PK/PD).
Route of administration
Subcutaneous injection 
Duration of treatment
Part A of 12 weeks followed by Part B of at least another 12 weeks. After 
completion of Part B of the Z dose cohort, all subjects will continue 
treatment in an extension part. The extension part will be initiated only 
after DMC evaluation of safety data from the 6 patients in the dose Z cohort 
for 6 weeks, and will continue, pending submission of safety and efficacy 
data to Health Authorities after 12 months from the start of the extension 
part, and every 12 months thereafter until Marketing Authorization.
Reference drug(s)
Not applicable. 
Name of active ingredient
Not applicable. 
Dose(s)
Not applicable. 
Route of administration
Not applicable. 
Duration of treatment
Not applicable. 
Indication
Hemophilia A and B 
Diagnosis and main criteria for 
inclusion /exclusion
Main inclusion criteria:
1.
Male severe hemophilic patients with undetectable FVIII activity 
<1% or FIX activity <2%, with or without inhibitors (any titer) are 
eligible.
CCI


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Note: Subjects with a past history of inhibitors (any inhibitor titer) 
are eligible. 
2.
Age ≥18 years. 
3.
Documentation of ≥4 bleeding episodes (any type or location of 
bleeds, treated or not) within the 6 months prior to screening. 
4.
For subjects on prophylaxis: willingness to interrupt ongoing 
prophylaxis. 
5.
For subjects on immune tolerance induction (ITI): willingness to 
interrupt ongoing ITI.
6.
Signed informed consent.
Main exclusion criteria:
1.
History of any other coagulation disorder (particularly 
disseminated intravascular coagulopathy or combined FVIII/FV 
deficiency) or platelet disorder. 
2.
History of diseases related to venous thromboembolic events (e.g., 
pulmonary embolism, deep vein thrombosis, thrombophlebitis) or 
thrombotic microangiopathy.
3.
Risk factors for venous or arterial diseases (e.g., uncontrolled 
hypertension, uncontrolled diabetes).
4.
History of cardiac, coronary and/or arterial peripheral 
atherosclerotic disease, particularly myocardial infarction, 
cerebrovascular accident, stroke, transient ischemic attack, 
congestive heart failure, angina pectoris or treatment for angina 
pectoris. 
5.
Platelet count <100,000/µL. 
6.
Human immunodeficiency virus (HIV) infection with a cluster of 
differentiation 4 (CD4+) lymphocyte count of <200/mm3. 
7.
Any planned major surgical intervention. 
8.
Subjects with known or suspected hypersensitivity to trial 
product(s) or related products. 
9.
Subjects with known autoimmune disease or on treatment with 
immune-modulatory drugs. 
10. Subjects with advanced liver disease (Child-Pugh Grade B and C) 
or with signs of liver function impairment (e.g., alanine 
aminotransferase [ALT] and aspartate aminotransferase [AST]
levels >3 × the upper limit of the normal range and/or total 
bilirubin >2 × the upper limit of the normal range). 
11. Subjects with serum creatinine >2.0 × the upper limit of the normal 
range. 
12. Treatment with an investigational drug within 3 months prior to 
screening. 
13. Subjects not willing to stop prophylaxis or ITI.
Study design
Approximately 24 adult subjects (≥18 years of age) will receive treatment 
with BAY 1093884.
For each subject, the study is structured in three parts
Part A.  Each subject will be treated with the allocated dose of BAY 
1093884 (X mg, Y mg or Z mg) for 12 weeks.  These first 12 weeks will 
allow for primary safety evaluations of each dose.
Part B.  Each subject will be treated for additional periods 12 weeks in 
duration.  After evaluation of the number of bleeds at the end of each 12-
week period, subjects can be treated with the same dose or with the next 
higher opened dose level.  The date when the last subject in Cohort 3 (Z 
dose) has completed Part B, will be the database cut-off date (i.e., primary 


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completion date).
Extension part.  After completion of Part B of the Z dose cohort, and upon 
DMC evaluation of safety data from the first 6 patients for 6 weeks in the 
dose Z cohort, all subjects will be invited to continue the treatment in an 
extension part, at the end of their ongoing Part B period.  During the 
extension, all subjects will be evaluated (number of bleeds) every 12 weeks 
and escalated to the next higher opened dose, if dose escalation criteria are 
fulfilled (as per Part B).  The extension part will continue, pending 
submission of safety and efficacy data to Health Authorities after 12 months 
from its start and every 12 months thereafter, until Marketing 
Authorization.
Any bleeding event, which should occur during the study (including the 
extension part) and which requires additional control, will be treated with 
the subject’s pre-assigned treatment (bypassing agent or replacement factor) 
prescribed by the Investigator pre-study.
Description of the dose cohorts
Eight (8) new distinct subjects are planned to be enrolled in each of the 3 
dose cohorts.  These subjects will be treated prophylactically with the X, Y 
or Z dose of BAY 1093884 once weekly for 12 weeks (Part A).  At least 1 
inhibitor subject (any titer) and 2 PK subjects (willing to undergo full PK 
evaluations) will be enrolled in each cohort.
All subjects of each cohort will continue on the dose assigned for Part A to 
obtain safety data and individual efficacy data.
At a minimum, safety/PK/PD data from 6 subjects completing 6 weeks in 
Cohort 1 (Dose X) are needed to open Cohort 2 (Dose Y).  All available 
safety information will be taken into consideration.  This may include data 
from the 2 additional subjects in the cohort who may not have reached the 6 
weeks or additional data from any of the first 6 subjects who may have been 
dosed for longer than 6 weeks.  This guideline will apply to further cohorts 
as well.  All available safety information from ongoing subjects will be used 
for safety evaluation in opening the next dose cohort.  This includes safety 
data also from the subjects who may have escalated from a previous cohort. 
Individual subject dose escalation criteria in the dose finding part of the 
study: 
Subjects will be evaluated for the number of bleeds occurring during each 
part of the study.  In particular, only the bleeds recorded as “spontaneous” 
(not related to any trauma or activity) and requiring additional treatment 
will be considered for the dose escalation efficacy evaluation, and are 
defined below as “bleeds.”
Evaluation at the end of Part A:
Subjects who present ≤2 bleeds during Part A will start Part B and continue 
on the same weekly dose; otherwise (if presenting >2 bleeds) subjects will 
escalate to the next higher opened dose.
Evaluation at the end of every 12 weeks period of part B and of extension
Subjects who present ≤1 bleed in 12 weeks, during Part B, or during 
extension part, will continue on the same weekly dose; otherwise (if 
presenting >1 bleed) subjects will escalate to the next higher opened dose.
Since dose Z is the highest dose, any subject on dose Z who meets the 
escalation criteria described above may withdraw from the study or may 
continue treatment to provide further safety and efficacy data.  The decision 


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on treatment continuation is at the subject’s and investigator’s discretion.
The first injection of any new or escalated dose will be given under medical 
supervision.
If a subject qualifies for dose escalation based on the number of bleeds, but 
the next higher dose cohort has not been opened, the subject must stay on 
the current dose and then escalate to the next higher dose only after it is 
opened.
Methodology
Throughout the study, data on the occurrence of bleeds (including type of 
bleed [spontaneous, non-spontaneous/non-traumatic, traumatic], location 
[joint, muscle, skin or mucosa, internal, other], severity [mild, moderate, 
severe]) and treatment of bleeds (drug, dose, number of injections) will be 
collected.
Safety data to be collected include data on adverse events (AEs, including 
changes in laboratory data, vital signs and findings from physical 
examination).
PK evaluations will be made in at least 2 subjects in each cohort (PK 
subjects) after the first and last doses of the first 12-week period with 
additional samples during the 12 weeks.  Sparse samples for PK will be 
collected from all other subjects not participating in the PK evaluation.
PD samples will be collected from all subjects.
Type of control
None 
Data Monitoring Committee
Yes.
Based on the safety data in the respective subset of subjects, a DMC will 
decide on dose escalation of BAY 1093884 for the subsequent dose step.
DMC will also evaluate safety of the highest dose (dose Z) after the first 6 
subjects have completed the first 6 weeks of treatment, and consequently 
advise on the continuation of the study through the extension part.
DMC will meet and decide on safety issues that may arise during the study 
(including the extension part).
Number of subjects
Approximately 24 hemophilia A or B subjects with or without inhibitors on 
OD or prophylaxis treatment will receive treatment with BAY 1093884.  In 
particular, 8 subjects will be assigned to each cohort, but more subjects (2-4 
additional subjects) may be required.  If additional safety evaluation is 
needed, a maximum number of 40 subjects may be included. 
Primary variable(s)
The frequency of drug-related AEs, SAEs, adverse events of special interest 
(AESIs), and clinically relevanta abnormal laboratory values. 
a “Clinically relevant “implies the presence of a clinical sign or symptom that requires medical 
action.
Time point/frame of 
measurement for primary 
variable(s)
Throughout the study, including the extension part, all subjects will be 
closely monitored for safety. 
Plan for statistical analysis
All data will be listed and study summary tables will be provided where 
appropriate.  Variables measured on continuous scales will be summarized 
using descriptive statistics that will include: the number of non-missing 
observations, the arithmetic mean, the sample standard deviation, the 
median, the minimum and maximum, as well as the first and third quartiles.  


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Frequency tables will be provided for variables measured on ordinal or 
nominal scales.  Tables will display the number and percentage of subjects 
falling within a particular category.
Data will be displayed by dose level and by study medication actually 
received during the study parts and the corresponding visits.
Safety
Vital signs, AEs and laboratory data will be analyzed by descriptive 
statistics.  All AEs will be tabulated according to the affected system organ 
class and preferred term, as coded by Medical Dictionary for Regulatory 
Activities (MedDRA).  Separate descriptions will be delivered for the 
different dose levels.  Special interest will be given to safety observations 
after application of rescue medication during the treatment phase with BAY 
1093884.
Efficacy
The main focus will be the number of spontaneous bleeds requiring 
additional treatment.
Further details of Efficacy analysis are listed in the Statistical Analysis Plan 
(SAP).
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Protocol amendment summary of changes
Table of main changes
Section # and name
Description of change
Brief rationale
Section 2  Synopsis
Section 6.1  Inclusion criteria
Inclusion criterion 1 was modified 
to further specify that only 
subjects diagnosed with severe 
hemophilia, with or without 
inhibitors, are eligible.
Criterion updated to ensure that 
only hemophilic patients who are 
diagnosed as severe are included 
in the study.
Typographical, grammatical, and other minor edits are not identified.


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Table of contents
Cover page of the integrated protocol.....................................................................................1
1.
Title page ............................................................................................................................2
Signature of the sponsor’s medically responsible person......................................................3
Signature of principal investigator..........................................................................................4
2.
Synopsis...............................................................................................................................5
Protocol amendment summary of changes...........................................................................10
Table of tables .........................................................................................................................14
Table of figures........................................................................................................................14
List of abbreviations ...............................................................................................................15
3.
Introduction......................................................................................................................17
4.
Study objectives................................................................................................................20
5.
Study design......................................................................................................................21
6.
Study population..............................................................................................................26
Inclusion criteria.............................................................................................................26
6.1
Exclusion criteria............................................................................................................26
6.2
Withdrawal of subjects from study.................................................................................27
6.3
6.3.1
Withdrawal..................................................................................................................27
6.3.2
Replacement................................................................................................................28
Subject identification......................................................................................................28
6.4
7.
Treatments........................................................................................................................29
Treatments to be administered........................................................................................29
7.1
7.1.1
Prophylaxis treatment with BAY 1093884.................................................................29
7.1.2
Treatment of bleeds.....................................................................................................30
7.1.3
Treatment for PK/PD assessments..............................................................................31
7.1.4
Treatment for minor and major surgery......................................................................31
Identity of study treatment..............................................................................................32
7.2
Treatment assignment.....................................................................................................33
7.3
Dosage and administration .............................................................................................33
7.4
7.4.1
Selection of doses in the study....................................................................................33
PK/PD criteria for dose recommendation................................................................34
7.4.1.1
Blinding..........................................................................................................................35
7.5
Drug logistics and accountability...................................................................................35
7.6
Treatment compliance ....................................................................................................35
7.7
8.
Non-study therapy ...........................................................................................................36
Prior and concomitant therapy (including treatment of bleeds) .....................................36
8.1
Post-study therapy ..........................................................................................................36
8.2


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9.
Procedures and variables................................................................................................37
Tabular schedules of evaluations....................................................................................37
9.1
Visit description..............................................................................................................37
9.2
9.2.1
Visit description for non-PK subjects .........................................................................37
Visit 1 – Screening visit...........................................................................................41
9.2.1.1
Eligibility check (2-3 weeks prior to Visit 2) ..........................................................42
9.2.1.2
Visit 2 – Start of BAY 1093884 treatment at the respective dose (≤6 weeks after 
9.2.1.3
Visit 1) .....................................................................................................................42
Visit 3 (1 week 1 day after Visit 2).......................................................................43
9.2.1.4
Visit 4 (3 weeks 2 days after Visit 2) ...................................................................43
9.2.1.5
Visit 5 (6 weeks 2 days after Visit 2) ...................................................................43
9.2.1.6
Phone call (3 weeks 2 days after Visit 5) .............................................................43
9.2.1.7
Visit 6 (12 weeks 1 day after Visit 2) assessment of dose escalation...................44
9.2.1.8
Visit 7 (24 weeks 7 days after Visit 2) assessment of dose escalation.................45
9.2.1.9
Every 12 weeks visit (7 days calculated from Visit 2).........................................45
9.2.1.10
Additional safety visits after dose escalation (if applicable) ...................................45
9.2.1.11
Final visit or early termination visit.........................................................................46
9.2.1.12
Follow-up phone call (4 weeks ± 2 days after “final or early termination visit”) ...46
9.2.1.13
9.2.2
Visit description for PK–subjects................................................................................46
Visit 1 – Screening visit...........................................................................................51
9.2.2.1
Eligibility check (2-3 weeks prior to Visit 2) ..........................................................51
9.2.2.2
Visit 2.1 – Start of BAY 1093884 treatment at the respective dose (≤6 weeks 
9.2.2.3
after Visit 1) and 1st PK day 0..................................................................................51
Visit 2.2 – 1st PK Day 1 (24 h).................................................................................52
9.2.2.4
Visit 2.3 – 1st PK Day 4 (96 h).................................................................................52
9.2.2.5
Visit 3.1 – 1st PK Day 7 (168 h)...............................................................................52
9.2.2.6
Visit 4 (3 weeks 1 day after Visit 2).....................................................................53
9.2.2.7
Visit 5 (6 weeks 1 day after Visit 2).....................................................................54
9.2.2.8
Phone call (3 weeks 2 days after Visit 5) .............................................................54
9.2.2.9
Visit 6.1 (11 weeks 1 day after Visit 2) 2nd PK Day 0..........................................54
9.2.2.10
Visit 6.2 – 2nd PK Day 1 (24 h)................................................................................55
9.2.2.11
Visit 6.3 – 2nd PK Day 4 (96 h)................................................................................55
9.2.2.12
Visit 6.4 – 2nd PK Day 7 (168 h) and assessment of dose escalation ......................56
9.2.2.13
Visit 7 (24 weeks 7 days after Visit 2) assessment of dose escalation.................57
9.2.2.14
Every 12 week visit (7 days calculated from Visit 2)...........................................57
9.2.2.15
Additional safety visits after dose escalation (if applicable) ...................................57
9.2.2.16
Final visit or Early Termination visit.......................................................................58
9.2.2.17
Follow-up phone call (4 weeks ± 2 days after “final or early termination visit”) ...58
9.2.2.18
Population characteristics...............................................................................................58
9.3
9.3.1
Demographic...............................................................................................................58
9.3.2
Medical history............................................................................................................58
9.3.3
Disease history ............................................................................................................58
9.3.4
Medication history ......................................................................................................59
9.3.5
Pharmacogenetic testing - optional .............................................................................59
Efficacy...........................................................................................................................60
9.4
9.4.1
Electronic patient diary (EPD)....................................................................................60


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9.4.2
Dose of pre-study hemophilia medication administered and number of injections 
needed to stop a bleeding event ..................................................................................61
9.4.3
Assessment of adequacy of hemostasis during minor surgical interventions.............61
9.4.4
Hemophilia joint health score (HJHS)........................................................................62
Pharmacokinetics/pharmacodynamics ...........................................................................63
9.5
9.5.1
Pharmacokinetics ........................................................................................................63
Drug measurements .................................................................................................63
9.5.1.1
Pharmacokinetic evaluation.....................................................................................63
9.5.1.2
9.5.2
Pharmacodynamics and biomarkers............................................................................64
Safety..............................................................................................................................64
9.6
9.6.1
Adverse events ............................................................................................................65
Definitions................................................................................................................65
9.6.1.1
Classifications for adverse event assessment...........................................................67
9.6.1.2
Assessment and documentation of adverse events ..................................................69
9.6.1.3
Adverse events of special safety interest .................................................................70
9.6.1.4
Reporting of medical device failures.......................................................................71
9.6.1.5
Dose-limiting toxicities............................................................................................71
9.6.1.6
Adverse events requiring an ad hoc DMC meeting.................................................71
9.6.1.7
9.6.2
Pregnancies .................................................................................................................72
9.6.3
Further safety ..............................................................................................................72
Clinical laboratory assessments...............................................................................72
9.6.3.1
Physical examination ...............................................................................................73
9.6.3.2
Vital signs ................................................................................................................73
9.6.3.3
Electrocardiogram....................................................................................................73
9.6.3.4
Other procedures and variables ......................................................................................73
9.7
Appropriateness of procedures/measurements...............................................................74
9.8
10. Statistical methods and determination of sample size..................................................74
General considerations ...................................................................................................74
10.1
Analysis sets ...................................................................................................................74
10.2
Variables and planned statistical analyses......................................................................75
10.3
10.3.1
Baseline.......................................................................................................................75
10.3.2
Extent of exposure.......................................................................................................75
10.3.3
Analysis of efficacy.....................................................................................................75
10.3.4
Analysis of PK/PD parameters....................................................................................76
10.3.5
Analysis of safety........................................................................................................76
Determination of sample size.........................................................................................77
10.4
Planned interim analyses ................................................................................................77
10.5
11. Data handling and quality assurance.............................................................................77
Data recording ................................................................................................................77
11.1
Monitoring......................................................................................................................79
11.2
Data processing ..............................................................................................................79
11.3
Missing data....................................................................................................................79
11.4
Audit and inspection.......................................................................................................79
11.5
Archiving........................................................................................................................80
11.6
12. Premature termination of the study...............................................................................80
13. Ethical and legal aspects..................................................................................................81


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Investigators and other study personnel .........................................................................81
13.1
13.1.1
Investigators ................................................................................................................81
13.1.2
External bodies............................................................................................................81
Funding and financial disclosure....................................................................................82
13.2
Ethical and legal conduct of the study............................................................................82
13.3
Subject information and consent ....................................................................................83
13.4
Publication policy and use of data..................................................................................85
13.5
Compensation for health damage of subjects/insurance ................................................85
13.6
Confidentiality................................................................................................................85
13.7
14. Reference list ....................................................................................................................86
15. Protocol amendments ......................................................................................................88
Amendment 4 .................................................................................................................88
15.1
15.1.1
Overview of changes to the study ...............................................................................88
15.1.2
Changes to the protocol text........................................................................................91
16. Appendices........................................................................................................................94
Hemophilia Joint Health Score.......................................................................................94
16.1
Table of tables
Table 5–1 Prophylaxis treatment with BAY 1093884............................................................29
Table 5–2 Wash-out times prior to the first BAY 1093884 injection.....................................29
Table 7–1 Visit schedule overview.........................................................................................37
Table 7–2 Tabular schedule of assessments (subjects not participating in PK evaluations; 
Screening and Part A) ............................................................................................39
Table 7–3 Tabular schedule of assessments (subjects not participating in PK evaluations; 
Part B through end of study)..................................................................................40
Table 7–4 Tabular schedule of assessments (subjects participating in PK evaluations; 
Screening and Part A) ............................................................................................48
Table 7–5 Tabular schedule of assessments (subjects participating in PK evaluations; Part B 
through end of study).............................................................................................49
Table 7–6 Criteria for the assessment of efficacy in minor surgery (5)..................................62
Table of figures
Figure 3–1:Design overview ....................................................................................................22


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List of abbreviations
ABR
Annualized bleeding rate
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
aPCC
Activated prothrombin complex concentrate
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
aTFPI
Antibody against tissue factor pathway inhibitor
aTFPI-Ab
Antibody against aTFPI
AUC
Area under the curve
BU
Bethesda unit
BUN
Blood urea nitrogen
Cmax
Maximum concentration
Cmin
Minimum concentration
CAT
Calibrated automated thrombogram
CBC
Complete blood count
CD4+
Cluster of differentiation 4
Cl
Chloride
CL
Clearance from plasma
CO2
Bicarbonate
CRO
Contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
D
dose
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
ECG
Electrocardiography, -gram
eCRF
Electronic case report form
EPD
Electronic patient diary
EU
European Union
FEIBA
Factor eight inhibitor bypassing activity
FII
Prothrombin
FIIa
Thrombin
FIX
Factor IX
FV
Factor V
FVIIa
Activated factor VII
FVIII
Factor VIII
FX
Factor X
FXa
Activated factor X
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
Human immunodeficiency virus
HJHS
Hemophilia Joint Health Score
hsCRP
High sensitive C-reactive protein
IB
Investigator’s Brochure
ICF
Informed consent form
IEC
Independent Ethics Committee
IgG2
Immunoglobulin G2
IL-6
Interleukin 6
IMP
Investigational medicinal product


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IRB
Institutional Review Board
ISR
Injection site reaction
ITI
Immune tolerance induction
IV
Intravenous
IWRS
Interactive web responding system
K
Potassium
Kx
Kunitz domain
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LOS
Listing only set
mAb
Monoclonal antibody
MedDRA
Medical dictionary for regulatory activities
MRT
Mean residence time
Na
Sodium
NCI
National Cancer Institute
OD
On demand
PD
Pharmacodynamics
PgX
Pharmacogenetics
PK
Pharmacokinetics
PPP
Platelet-poor plasma
PPS
Per protocol set
QA
Quality assurance
QC
Quality control
rFVIIa
Recombinant activated factor VII
SAE
Serious adverse event
SAF
Safety (set)
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SUSAR
Suspected unexpected serious adverse reaction
tlast
Last measurable concentration
TAT
Thrombin-antithrombin complex
TF
Tissue factor
TFPI
Tissue factor pathway inhibitor
TGA
Thrombin generation assay
TMA
Thrombotic microangiopathy
US
United States (of America)
VTE
Venous thromboembolic event
vWF
Von Willebrand’s factor
Vss
Volume at steady state
Vz
Volume during terminal phase
WHO
World Health Organization


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3.
Introduction
Background
Hemophilia A and B are genetic bleeding disorders caused by the deficiency of Factor VIII 
(FVIII) or Factor IX (FIX), respectively.  Persons with mild hemophilia (6% – 49% Factor 
level) may have excessive bleeding following dental procedures, injury or surgery, while 
moderate (1% to 5% factor activity) and severe (< 1% factor activity) hemophilia are 
typically characterized by more frequent and severe bleeding complications. Persons with 
severe hemophilia may experience not only bleeding after injury, trauma or surgery, but also 
spontaneous bleeding into joints, muscles and internal organs, including the brain.  Recurrent 
bleeding into joints results in chronic debilitation.  
The standard treatment for hemophilia A or B is replacement therapy, with intravenous (IV) 
administration of plasma-derived or recombinant FVIII or FIX, respectively.  Some subjects 
treat bleeding episodes as they occur (i.e., on-demand [OD] treatment), while others treat 
themselves prophylactically to prevent bleeding according to the recommendations from the 
World Health Organization.  In recent years, prophylactic treatment has become the 
prevailing type of hemophilia treatment in most developed countries.  Currently, prophylaxis 
starting in early childhood with the primary goal to prevent bleeding that leads to end-stage 
joint disease is recommended in most developed countries (1-3).
The proven clinical benefits of prophylaxis have led to a shift in treatment paradigm from OD
treatment to the use of prophylaxis in many countries (4, 5).  
Better outcomes of prophylaxis versus OD treatment regimen are proven, but three major 
challenges characterize prophylactic treatment: the need for IV injections, the relatively high 
bleeding rate and the most significant treatment complication, the development of inhibitors.
Despite frequent and painful IV injections (and the subsequent frequent need for central 
venous access devices in young children), subjects on prophylaxis still bleed, with a median 
annualized bleeding rate (ABR) of up to 6 bleeds, thus, leaving a high unmet medical need 
for better protection (6).  A higher level of protection is in some cases achievable only by 
increasing the burden of treatment (more frequent injections), to reduce the clotting factor 
fluctuations that characterize replacement factors treatment (presence of peaks and troughs). 
Effective treatment options are significantly lower if inhibitory antibodies against the FVIII 
or FIX (inhibitors) develop.  The inhibitors interfere with the infused factor concentrates 
rendering them ineffective and requiring the use of more costly and less effective alternative 
hemostatic agents, defined as “bypassing agents” (7).  The incidence of new FVIII inhibitors 
in subjects with severe FVIII deficiency is up to 45%.  In the SIPPET trial (Survey of 
Inhibitors in Plasma-Products Exposed Toddlers, “A Randomized Trial of Factor VIII and 
Neutralizing Antibodies in Hemophilia A”), the overall cumulative inhibitor rate for all 
recombinant FVIII products was 44.5% (95% confidence interval: 34.7 - 54.3) over 
50 exposure days (8).  Inhibitor development is currently the most significant treatment 
complication seen in subjects with hemophilia.  While improvements in hemostatic agents for 
subjects with inhibitors have resulted in decreased mortality, inhibitors are still associated 
with significant morbidity, including a higher rate of bleeding complications, increased 
disability, and a decreased quality of life (9-11).


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It is possible that inhibitors may be transient or resolve with high repeated doses of factor 
concentrates (immune tolerance induction [ITI]), but in 10–15% of hemophilia A subjects, 
FVIII inhibitors remain clinically significant (high titer antibodies) and cannot be managed 
by ITI; ITI is much less effective in managing FIX inhibitors (12).
The pharmacodynamics (PD) effect of the currently available bypassing agents (coagulation 
Factor VIIa (rFVIIa; e.g., NovoSeven) for hemophilia A and B, and activated prothrombin 
complex concentrates (aPCC; e.g., human plasma derived Factor VIII inhibitor bypassing 
agent [FEIBA]) for hemophilia A) can be highly variable, and dose levels do not correlate 
well to clinical benefit (13, 14).  As such, these bypassing agents are effective in most cases, 
but neither agent is universally effective and there is no prophylaxis option for subjects with 
hemophilia B and inhibitors, as NovoSeven is not licensed for prophylaxis in EU and US.  
HEMLIBRA (emicizumab-kxwh) is currently approved in the US for subcutaneous routine 
prophylaxis in hemophilia A subjects with inhibitors, however, mimicking the action of 
activated FVIII (FVIIIa), it does not provide a steady state protection (variable rates of 
fluctuation with potential low levels at the end of the injection interval).  Additionally, it 
carries a black box warning of thrombotic microangiopathy and thromboembolism when used 
with aPCC/FEIBA for the treatment of breakthrough bleeds (15).
There is currently no treatment available to provide constant protection against bleeding 
episodes, to lower burden of treatment, and to avoid risk of FVIII/FIX inhibitor development 
for the entire hemophilia population, regardless of the FVIII or FIX deficiency status or the 
presence of FVIII or FIX inhibitors.
BAY 1093884 may address all these unmet needs, representing a valid treatment option for 
all subjects with hemophilia. 
The coagulation cascade and the role of tissue factor pathway inhibitor (TFPI)
In the cell-based model, the coagulation is initiated (the Initiation Phase) by the formation of 
a complex between the tissue factor (TF), exposed on the surface of fibroblasts as result of 
vessel injury, and activated factor VII (FVIIa), normally present in the circulating blood.  The 
TF-FVIIa complex converts factor X (FX) in activated FX (FXa), which activates 
prothrombin (FII) to thrombin (FIIa).  In this Amplification Phase, due to this limited amount 
of thrombin, FVIII and FIX are activated and involved in the following Propagation Phase, 
where full thrombin generation takes place, enabling for clot formation.
According to this model, the TF extrinsic pathway is the principal cellular initiator of normal 
blood coagulation in vivo, and the major regulator of hemostasis and thrombogenesis, with 
the intrinsic pathway playing an amplification role.
In people with hemophilia, the TF initiated extrinsic coagulation pathway is intact, so a 
question may rise on why these people do bleed.  The explanation is provided by the fact that 
the TF activity and the extrinsic pathway of blood coagulation are regulated by a specific and 
natural coagulation inhibitor: the tissue factor pathway inhibitor – TFPI. 
In healthy individuals TFPI maintains a normal hemostatic balance (it is in fact considered a 
natural anticoagulant) while in people with hemophilia it further reduces the already 
insufficient thrombin due to the lack of FVIII or FIX.
Already in 1991, in vitro evidence has demonstrated that the reduction of the inhibitory effect 
of TFPI is an important step for the prevention of bleeding in subjects with hemophilia (16).  


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Besides, anti –TFPI antibody has shown to shorten the bleeding time in rabbits with 
antibody-induced hemophilia A (17).
Thus, the inhibition of TFPI through the administration of anti-TFPI antibodies 
(BAY 1093884) is expected to restore the hemostatic balance toward normal thrombin 
generation, and thus a potential mechanism to restore hemostasis in hemophilia subjects.
The product
BAY 1093884 is a human monoclonal IgG2 antibody with a novel mechanism of action 
based on blocking the function of endogenous TFPI. 
TFPI usually consists of 3 Kunitz domains (K1, K2, K3).  The primary anticoagulant 
properties of TFPI are mediated through the K1 and K2 domains.  BAY 1093884 binds to 
both K1 and K2 domains, blocking TFPI inhibition of key factors (FXa via K2, and FVIIa/TF 
complex via K1) in the tissue factor initiated coagulation pathway.  K3 binds to Protein S, 
which is not directly inhibiting the protease function.
BAY 1093884 has been optimized for affinity.  In vitro, the antibody exhibits high affinity 
binding to human TFPI (<10 pM), and is highly specific.  The effect of neutralizing TFPI 
with BAY 1093884 has been evaluated and demonstrated in several in vitro and in vivo 
studies, showing prolonged efficacy compared to current bypass therapies.  As a monoclonal 
antibody (mAb), BAY 1093884 also offers the opportunity of subcutaneous (SC) 
administration, while other currently available hemophilia treatments have to be administered 
intravenously.
The goal of TFPI inhibition is to restore normal levels of FXa, and thus correct the low levels 
of thrombin generated due to deficiency of either FVIII or FIX, independent of whether the 
deficiency results from ineffective production, or results from presence of inhibitory 
antibodies directed against either protein.  TFPI inhibition targets a normal regulatory protein, 
and consequently is not a pro-coagulant.  Thus, normal events that lead to initiation of 
coagulation at a site of injury are unaffected.  Additionally, TFPI inhibition does not interfere 
with downstream mechanisms that protect from or turn off thrombin generation, thus 
regulation of thrombin and fibrinolysis remain intact, with a consequent favorable safety 
profile.
The overall nonclinical toxicology and safety profile of BAY 1093884 lends to support 
clinical studies with repeated administration of BAY 1093884 in subjects with hemophilia A 
or B with or without inhibitors.
The First in Man Phase 1 study is ongoing and is conducted in hemophilia A or B subjects 
(deficient in FVIII or FIX) with or without inhibitors, to evaluate safety, tolerability, and 
pharmacokinetics (PK) of a single-escalating dose of BAY 1093884.  In this study, the single 
dose IV doses of 0.3 mg/kg and 1 mg/kg, SC doses of 1, 3, and 6 mg/kg were evaluated in 
hemophilia subjects without inhibitors.  Single SC doses of 1 and 3 mg/kg were also 
evaluated in hemophilia subjects with inhibitors.  In addition, a multiple dose cohort was also 
evaluated following 150 mg SC once weekly dose given for 6 weeks. Safety information is 
available in the current version of the IB. 
All 32 subjects in the study have received the doses.  Of these 32 subjects, 30 have completed 
the study.  Two are ongoing and have follow-up visits remaining.  There were no SAE, no 
deaths or AEs leading to discontinuation.  There were no clinically significant findings in the 


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other safety laboratory values during the treatment and there were no clinically significant 
changes in vital signs and ECG.  
Overall, results from the Phase 1 study support that subjects with FVIII or FIX deficiency and 
inhibitor subjects exhibit similar response to BAY 1093884 with regard to both PK and 
pharmacodynamics (PD) profile.  At the highest investigated dose, complete inhibition of 
TFPI (defined as TFPI levels below the lower limit of quantification of the assay and 
corresponding to at least 82-87% of inhibition) was observed in all subjects for at least 7 
days.
These results confirm that due to its mode of action, the clinical effect of BAY 1093884 is 
expected to be similar in all subjects, irrespective of the underlying factor deficiency or the 
presence of inhibitory antibodies. 
The elevation in D-dimers seen in some subjects is an expected mechanistic outcome of 
BAY 1093884 administration, as TFPI inhibition is predicted to shift coagulation balance 
toward more thrombin activation, and thus production of fibrin.  The goal of potentiating 
thrombin activation is correction of the underlying bleeding disorder, and should be safe 
provided that the normal compensatory mechanisms, such as fibrinolysis, are not impaired.  
Importantly, none of the laboratory measures in any of the subjects in this cohort suggested a 
shift towards uncompensated coagulation.  Specifically, fibrinogen levels and platelet counts 
remained in normal range, and clinically meaningful changes in anti-thrombin III, protein C 
or FV were not observed.  The laboratory studies suggest that BAY 1093884 did shift 
hemostatic balance towards greater thrombin generation, as intended, but that this shift was 
compensated by intact mechanisms of anticoagulation and fibrinolysis.
The absence of changes in vital signs, electrocardiograms (ECG), or changes in any lab 
values other than fibrinogen and D-dimer, confirmed in all dosed subjects the clear 
mechanistic effect of BAY 1093884 and the absence of any pathologic suspect or finding.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
4.
Study objectives
Primary objective:
!
To assess the safety and tolerability of multiple subcutaneous doses of BAY 1093884 
in subjects with hemophilia A or B with or without inhibitors. 
 
 
 
 
CCI


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5.
Study design
This is an open-label Phase 2 study with multiple escalating doses of BAY 1093884 in 3 
cohorts.  The goal of the study is to evaluate the safety of multiple escalating doses of 
BAY 1093884 and identify a dose (or doses) to be used in the pivotal Phase 3 study.
The study has 2 main components - a multiple dose escalation component and a dose-finding
component.
Multiple-dose escalation component: Eight (8) new distinct subjects are planned to be 
enrolled in each of the 3 dose cohorts.  Opening of the new cohort will only enroll new 
subjects.  An initial dose of 100 mg SC has been selected for Dose X based on safety and 
PK/PD data from the Phase I study.  Safety data from Dose X in N=6 subjects after 1x/week 
SC dose for 6 weeks will be the basis for opening the cohort for Dose Y.  When acceptable 
safety and tolerability has been achieved in the first 6 subjects after 6 weeks of dosing, the 
cohort for Dose Y (not to exceed 250 mg) will be opened for enrollment of 8 new subjects.  
The opening of cohort to Dose Z (dose not to exceed 400 mg) follows the same process and 
will be based on safety/tolerability data from N=6 subjects given Dose Y once weekly for 
6 weeks.
The DMC will review all available safety data and the proposed dose based on PK/PD prior 
to opening any cohort.  Safety evaluation, including stopping criteria, is described in Sections
9.6.1.7 and 13.1.2. 
Dose-finding component: This portion of the study is designed to allow for identification of 
the appropriate dose(s) for the Phase 3 study.  The dose selection for Phase 3 will be based on 
both the assessment of safety and evidence of efficacy based on bleeding control assessed 
over a 12-week period of dosing.  In each cohort at dose level X, Y and Z the subjects will 
continue at that dose for at least 12 weeks and efficacy information from all 8 subjects at each 
dose level will be used for the assessment of efficacy (based on number of bleedings).  
Although acceptable safety and tolerability data of 6 weeks in at least 6 subjects at Dose X is 
required to open the next cohort – Dose Y, all 8 subjects at Dose X will remain at dose level 
X for at least 12 weeks to assess the efficacy.  If the next dose level is open, patients in dose 
level X or Y will be allowed to escalate to the next dose level after 12 weeks of treatment 
with BAY 1093884 if specific conditions are satisfied. First, safety criteria as defined in the 
protocol must be met.  Second, the patient must have experienced >2 bleeds during the first
12 weeks of treatment or experienced >1 bleed during any 12-week interval after the first 12 
weeks of treatment at a particular dose level.  The safety criteria to be assessed for this 
portion of the study (individual dose escalation after 12 weeks of dosing in that particular 
dose cohort) are provided later in this section.
For each subject, the study is structured in three parts
Part A.  Each subject will be treated with the allocated dose of BAY 1093884 (X mg, Y mg 
or Z mg) for 12 weeks.  These first 12 weeks will allow for primary safety evaluations of 
each dose.
Part B.  Each subject will be treated for additional periods of 12 weeks in duration.  After 
evaluation of the number of bleeds at the end of each 12-week period, subjects can be treated 
with the same dose or with the next higher opened dose level.  The date when the last subject 
in Cohort 3 (Z dose) has completed Part B, will be the database cut-off date (i.e., primary 
completion date).


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Extension part.  After completion of Part B of the Z dose cohort, and upon DMC evaluation 
of safety data from the first 6 patients for 6 weeks in the dose Z cohort, all subjects will be 
invited to continue the treatment in an extension part, at the end of their ongoing Part B 
period.  During the extension, all subjects will be evaluated (number of bleeds) every 12 
weeks and escalated to the next higher opened dose, if dose escalation criteria are fulfilled (as 
per Part B).  The extension part will continue, pending submission of safety and efficacy data 
to Health Authorities after 12 months from its start and every 12 months thereafter, until 
Marketing Authorization.
Any bleeding event, which should occur during the study (including the extension part) and 
which requires additional control, will be treated with the subject’s pre-assigned treatment 
(bypassing agent or replacement factor) prescribed by the Investigator pre-study.
Figure 5–1 shows a schematic overview of the study design.
Figure 5–1:
Design overview
DMC = Data Monitoring Committee.
Black boxes:
Part A: Initial 12 weeks of treatment with BAY 1093884 (no escalation)
Grey boxes:
Part B: all subsequent groups of 12 weeks of treatment with BAY 1093884 (first 
escalation allowed)
White boxes:
Extension part with evaluations every 12 weeks (further escalations allowed)
Solid line arrows:
Option for dose escalation, if the next higher dose is approved and the subject meets 
the escalation criterion (>2 bleeds in Part A). 
Dotted line arrows:
Option for dose escalation, if the next higher dose is approved and the subject meets 
the escalation criterion (>1 bleed in 12 weeks).
At least 24 adult subjects (≥18 years of age) will be enrolled.  If additional safety evaluation 
is needed, a maximum number of 40 subjects may be included.
Eight (8) new distinct subjects are planned to be enrolled in each of the 3 dose cohorts.
Opening of the new cohort will only enroll new subjects.  These subjects will be treated 
prophylactically with the X Y or Z dose of BAY 1093884 once weekly for 12 weeks (part A).  
At least 1 inhibitor subject (any titer) and 2 PK subjects (willing to undergo full PK 
evaluations) will be enrolled in each cohort. 
All subjects of each cohort will continue on the dose assigned for Part A (12 weeks) to obtain 
safety data and individual efficacy data.
Individual subject dose escalation criteria in the dose finding part of the study: 
I Primary Study Completion I 
! 
.____________,.--------------;~-~!~! -------.----~I 
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In this portion of the study, the objective is to identify the appropriate dose(s) for the Phase 3 
study.  The dose selection for Phase 3 will be based on both the assessment of safety and 
evidence of efficacy based on individual bleeding control assessed over a 12-week period of 
dosing for each patient. 
Subjects will be evaluated for the number of bleeds occurring during each part of the study.  
In particular, only the bleeds recorded as “spontaneous” (not related to any trauma or 
activity) and requiring additional treatment will be considered for the dose escalation efficacy 
evaluation, and are defined below as “bleeds.” 
Evaluation at the end of Part A: 
Subjects who present ≤2 bleeds during Part A will start Part B and continue on the same 
weekly dose; otherwise (if presenting >2 bleeds) subjects will escalate to the next higher 
opened dose cohort. 
Evaluation at the end of every 12-week period of Part B and extension: 
Subjects who present ≤1 bleed in 12 weeks, during Part B, or during the extension part, will 
continue on the same weekly dose; otherwise (if presenting >1 bleed) subjects will escalate to 
the next higher opened dose cohort. 
Since dose Z is the highest dose, any subject on dose Z who meets the escalation criteria 
described above may withdraw from the study or may continue treatment to provide further 
safety and efficacy data.  The decision on treatment continuation is at the subject’s and 
investigator’s discretion. 
The first injection of any new or escalated dose will be given under medical supervision 
If a subject qualifies for dose escalation based on the number of bleeds, but the next higher 
dose cohort has not been opened, the subject must stay on the current dose and then escalate 
to the next higher dose only after it is opened. 
Dose selection for cohorts: 
Results from studies on hemophilia animal models support the development of clinical 
studies with repeated administration of BAY 1093884 in subjects with hemophilia A or B 
with or without inhibitors.
Results from the Phase 1 study support that subjects with FVIII or FIX deficiency and
inhibitor subjects exhibit similar response to BAY 1093884 with regard to both PK and 
pharmacodynamics (PD) profile. 
Considering the results from these studies, the dose for Cohort 1 (X dose) will be 100 mg, for 
Cohort 2 (Y dose) will not exceed 250 mg and the dose for Cohort 3 (Z dose) will not exceed 
400 mg.  Doses for Cohort 2 and 3 (Y and Z doses) will be selected based on the safety 
assessments from previous cohorts, PK/PD model and the criteria described in detail in 
Section 7.4.1.1, together with the criteria for evaluating safety rules. 
Throughout the study, the safety rules for an occurrence of a single drug-related SAE (SAR) 
related to study drug, or two severe or clinically significant AEs considered to be at least 
possibly related to study drug will be followed.  In the event that a subject is suspended from 
the dosing of BAY 1093884, dosing will not resume until a full review is done by DMC and 
the risk-benefit is deemed acceptable for that patient.  During suspension of dosing, the 
subject will be treated with his previous hemophilia treatment and any other event will be 


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treated in accordance with the local standard of care.  If dosing resumes following DMC 
review, the subject should return to the clinic for their next sequential scheduled visit to 
restart study drug.
Data Monitoring Committee
A DMC will regularly review key safety data and give recommendations on:

Dose escalation (opening the next dose cohort);

Opening of the Extension Part
In addition, the DMC will meet on an ad hoc basis as appropriate to ensure subject safety 
oversight in the trial.
The DMC may recommend modifying or stopping the study early due to safety concerns at 
any time, based on these periodic and ad hoc data reviews. 
The full description of DMC review is provided in Sections 9.6.1.7 and 13.1.2, and in the 
DMC charter. 
Justification of study design
At the highest dose investigated in the Phase 1 study, complete inhibition of TFPI (defined as 
TFPI levels below the lower limit of quantification of the assay and corresponding to at least 
82-87% of inhibition) was observed in all subjects for at least 7 days. 
These data support the rationale for this open-label Phase 2 study, with the aim to evaluate 
the safety and explore the efficacy of multiple escalating doses of BAY 1093884 in 3 cohorts. 
The Phase I study utilized weight-based dosing.  The proposed study will use fixed doses.  
Like most monoclonal antibodies, BAY 1093889 is expected to distribute predominately to 
the blood plasma and extracellular fluids due to its large molecular weight (18).  Preliminary 
estimations of the volume of distribution at steady-state (Vss, calculated as [dose/AUC]*MRT 
after IV administration) are in the range of 0.05 to 0.08 L/kg, corresponding to absolute 
volumes of approximately 3.5 to 5.6 L for a 70 kg individual, and support this expectation.  
Although blood volume is increased in obese and decreased in underweight individuals when 
compared to normal weight individuals, these changes are less than proportional with the 
change in body weight (18).  As a consequence, body composition and the presence of excess 
body weight are of less importance for an antibody when compared to small molecules.  
Physiologically-based pharmacokinetic (PBPK) modelling was used to predict the variability 
of PK parameters (AUC, Cmax and Cmin) and free TFPI levels following a body-weight 
normalized dose (1 mg/kg) and a flat dose (70 mg) in a population of virtual male individuals 
with an age range between 18 and 45 years and a weight range between 50 and 110 kg.  The 
flat dosing resulted in slightly lower inter-individual variabilities in BAY 1093884 PK 
parameters and free TFPI concentrations.  Based on general physiological considerations of 
the distribution properties of antibodies and predictions of the BAY 1093884 PBPK model, it 
is justified to administer BAY 1093884 in a fixed dose regimen in this dose escalation study.
Data from the Phase 1 study has been used to build a PK/PD model to allow for initial 
selection of the starting dose (dose X) and it will be further refined with available data 
generated from the multiple dose levels in this study to select the doses for the subsequent 
dose levels.  The model will be used to project doses that will result in certain duration of 


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TFPI inhibition and improvement in parameters measured with the thrombin generation assay 
(TGA) following weekly SC administration.  For this projection, to safely evaluate the 
potential accumulation following multiple administration of BAY 1093884, the lower dose X 
will provide preliminary safety information, while is not expected to result in meaningful 
control of bleeding episodes over 7 days.  The following Y dose is expected to provide both 
safety and efficacy data over the 7 days after BAY 1093884 administration.  The last dose, Z, 
is supposed to provide additional efficacy information and safety margin, without exceeding 
the highest evaluated dose in the Phase 1 study.
The reason to start with 100 mg dose is that this dose is expected to result in 3-5 days of TFPI 
inhibition.  In addition, all subjects have been exposed to 100 mg or more in the Phase 1
study, where the safety of this dose has been established.  In fact, single doses of 1 mg/kg 
(68 - 91 mg), 3 mg/kg (213 - 270 mg) and 6 mg/kg (401 - 510 mg) have been administered in 
the Phase 1 study.  
The rationale to include in the study both subjects treated on demand and subjects on 
prophylaxis who present at least 4 bleeding episodes in the previous 6 months is to ensure 
enrollment of subjects with high unmet need (at least 8 bleeds per year).  It is well known that 
the annualized bleeding rate in subjects on prophylaxis is between 1 and 3 for non-inhibitor 
subjects (19, 20) and approximately 5 for inhibitor subjects (21). 
Subjects treated on demand with previously assigned products will switch to prophylaxis with 
BAY 1093884, which is expected to lead to similar or lower bleeding rates.  Subjects 
previously treated prophylactically may benefit from the study drug because of their high 
bleeding rate (despite frequent regular injections).  In any case, any occurring bleed that will 
need additional control will be treated with their pre-study treatment (with already proven 
response) and subjects will be always allowed to continue the study or to interrupt it, based 
on their response to treatment and treatment satisfaction.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).
Primary completion
The primary completion event for this study is when the last subject in Cohort 3 has 
completed 24 weeks of treatment (end of Part B).
Communication plan 
A communication plan is in place to outline how the safety data and dose escalation decision 
will be communicated to all investigator sites. 
Routine updates via email, newsletter, or teleconference will be provided to the investigators 
throughout the course of the study to facilitate communication of new safety data from 
treated patients from the ongoing studies.  DMC recommendations, including dose escalation 
decision, will be communicated to the investigators in a timely manner.


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6.
Study population
Inclusion criteria
6.1
1.
Male severe hemophilic patients with undetectable FVIII activity <1% or FIX activity 
<2%, with or without inhibitors (any titer) are eligible.
Note: Subjects with a past history of inhibitors (any inhibitor titer) are eligible. 
2.
Age ≥18 years. 
3.
Documentation of ≥4 bleeding episodes (any type or location of bleeds, treated or not) 
within the 6 months prior to screening. 
4.
For subjects on prophylaxis: Willingness to interrupt ongoing prophylaxis. 
5. For subjects on ITI: willingness to interrupt ongoing ITI
6.
Signed informed consent.
Exclusion criteria
6.2
1.
History of any other coagulation disorder (particularly disseminated intravascular 
coagulopathy or combined FVIII/FV deficiency) or platelet disorder. 
2.
History of diseases related to venous thromboembolic events (e.g., pulmonary embolism, 
deep vein thrombosis, thrombophlebitis) or thrombotic microangiopathy.
3.
Risk factors for venous or arterial diseases (e.g., uncontrolled hypertension, uncontrolled 
diabetes).
4.
History of cardiac, coronary and/or arterial peripheral atherosclerotic disease, 
particularly myocardial infarction, cerebrovascular accident, stroke, transient ischemic 
attack, congestive heart failure, angina pectoris or treatment for angina pectoris. 
5.
Platelet count <100,000/µL. 
6.
Human immunodeficiency virus (HIV) infection with a cluster of differentiation 4 
(CD4+) lymphocyte count of <200/mm3. 
7.
Any planned major surgical intervention. 
8.
Subjects with known or suspected hypersensitivity to trial product(s) or related products. 
9.
Subjects with known autoimmune disease or on treatment with immune-modulatory 
drugs. 
10. Subjects with advanced liver disease (Child-Pugh Grade B and C) or with signs of liver 
function impairment (e.g., alanine aminotransferase [ALT] and aspartate 
aminotransferase [AST] levels >3 × the upper limit of the normal range and/or total 
bilirubin >2 × the upper limit of the normal range). 
11. Subjects with serum creatinine >2.0 × the upper limit of the normal range. 
12. Treatment with an investigational drug within 3 months prior to screening visit.
13. Subjects not willing to stop prophylaxis or ITI.


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Withdrawal of subjects from study
6.3
6.3.1
Withdrawal
Withdrawal criteria
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative.  At 
any time during the study and even without giving reasons, a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result. 

Development of an inhibitory antibody to BAY 1093884 that neutralizes the activity 
sufficiently to interfere with effective treatment.

Failure to comply with scheduled appointments for study-related testing or with 
Electronic Patient Diary (EPD) data entry to an extent that compromises collection of 
critical data 

Significant concurrent illness or deterioration in the subject’s condition, including 
laboratory values that the investigator deems to be incompatible with the subject’s 
continued safe participation in the study. 
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in 
the subject's medical records
At the time of discontinuation, the subject should be scheduled to perform the procedures and 
evaluations required at the final study visit.
Subjects may be withdrawn from the study if any of the following occurs:

Violation of eligibility criteria; 

Withdrawal of a subject at the specific request of the Sponsor; 

Withdrawal of a subject at the Investigator’s request.  As examples: If the 
Investigator considers that the subject’s health is compromised by remaining in the 
study or if a subject on the highest dose (without possibility for dose escalation) 
presents excessive uncontrolled bleeding; or the subject is not sufficiently 
cooperative; 

Withdrawal of a subject from the study if the subject is lost to follow-up. 
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure.”  
Re-starting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed – with the following exceptions:


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
The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after 
prior therapy.

The in-/exclusion criteria preventing the subject’s initial attempt to participate have 
been changed (via protocol amendment).
Thus, participation of an initial “screening failure” subject at a later time point even if he 
meets all selection criteria upon re-screening is not acceptable.
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.  In addition, the subject must re-sign the 
informed consent form during re-screening, even if it was not changed after the subject’s 
previous screening.  If a subject is re-screened, he will be assigned a new subject number.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout”, if the subject has received at least 1 dose of BAY 1093884.
General procedures
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject's medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Completer
A subject is defined as completer if he has completed at least Part A, a minimum of one Part 
B, and has performed a final visit.  
6.3.2
Replacement
If fewer than 6 subjects per cohort will complete 6 weeks, additional subjects will be 
recruited to achieve the target sample size of 6 subjects for DMC review. Subjects may be 
replaced only if they have not withdrawn from the study for drug-related safety concerns.  
If inhibitor subjects with less than 24 weeks of treatment or PK subjects with less than 
12 weeks of treatment drop out, additional subjects will be recruited to ensure that at least 
2 PK subjects (with complete PK evaluations) and at least 1 evaluable inhibitor subject are 
included in each dose cohort.
Subject identification
6.4
Upon enrollment, each subject will receive a unique subject number.  Screening procedures 
will be performed and eligibility for the study confirmed.  Once assigned to a subject the 
unique subject number must not be used for another subject within this study.
The subject number is a 9-digit number consisting of:
Digits 1 to 5 = Unique center number


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Digits 6 to 9
= Current subject number within the center
7.
Treatments
Treatments to be administered
7.1
7.1.1
Prophylaxis treatment with BAY 1093884
Table 7–1 displays the treatment administered during the study.
Table 7–1
Prophylaxis treatment with BAY 1093884
Cohort
No. of subjects 
to be treated
Dose of 
BAY 1093884
Route
Frequency of 
administration
Dose X
8
100 mg per dose
subcutaneous
every 7 days ± 1 day
Dose Y
8 + escalated subjects
Y mg per dose
subcutaneous
every 7 days ± 1 day
Dose Z
8 + escalated subjects
Z mg per dose
subcutaneous
every 7 days ± 1 day
Prophylaxis infusions (either with BAY 1093884 or any other pre-assigned treatment) in 
addition to the planned weekly infusions (e.g., before certain physical activities like sports)
are not allowed.
The dose range will be 100 mg (X dose) to ≤400 mg (Z dose).  The Y and Z doses will be 
defined based on the safety of the preceding dose level and PK/PD model.
In all cohorts and for each escalated dose, the first injection of every BAY 1093884 dose 
level will be administered under medical supervision with a post-dose observation period of 
30-60 minutes.
To allow for appropriate PD evaluations, the following wash-out times of FVIII, FIX 
products and FEIBA must be observed (Table 7–2).
Table 7–2
Wash-out times prior to the first BAY 1093884 injection
Product
Wash-out Times
FVIII
72 h
(3 days)
EHL FVIII
120 h
(5 days)
FIX
96 h
(4 days)
EHL FIX
480 h
(20 days)
Emicizumab
30 days
(30 days)
rFVIIa
24 h
(1 day)
FEIBA
96 h
(4 days) 
EHL = Extended half-life, FEIBA = Factor eight inhibitor bypassing activity, FIX = Factor XIV, FVIII = Factor VIII, 
rFVIIa = Recombinant activated factor VII
Dose cohorts will be opened subsequently, based on an initial safety review (by the Sponsor 
and a Data Monitoring Committee [DMC]) of the data from the first 6 subjects with at least 
6 weeks of dosing in the respective cohort. 
All subjects in Cohort 1 and 2 will continue on their initial dose for 12 weeks (Part A) to 
obtain safety data and efficacy data.  Thereafter, in Part B, subjects will remain on this dose, 
unless they meet the dose escalation criteria as specified in Section 5.  No dose escalation is 
possible for subjects in Cohort 3 who are allocated to the highest dose.  All subjects in Cohort 


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3 will be treated with this dose for at least 24 weeks (Part A and Part B) and then continue the 
study in the extension part. 
During the extension part, subjects will continue treatment with BAY 1093884 either on their 
current dose or escalate to the next higher opened dose (dose Y for subjects currently on dose 
X, dose Z for subjects currently on dose Y), after safety and efficacy evaluations every 
12 weeks (including DMC evaluation, where appropriate), if dose escalation criteria are met.  
The extension part will be initiated only after DMC evaluation of safety data from the 
6 patients in the dose Z cohort for 6 weeks, and continued pending submission of safety and 
efficacy data to Health Authorities after 12 months from the start of the extension part, and 
every 12 months thereafter until Marketing Authorization.
For further details, see Section 5.
7.1.2
Treatment of bleeds
The occurrence of bleeds of different cause, severity and site is a typical characteristic of 
subjects with hemophilia, being the clinical manifestation of the disease itself. 
Bleeds will be classified into the following types:
Spontaneous: Not attributable to any trauma or activity
Non-spontaneous/non-traumatic: Not related to a trauma, but due to activity (walk, run, 
sport, gym, etc.)
Traumatic: Related to an identified trauma
Throughout the study, all bleeds will be recorded, but only the bleeds recorded as 
“spontaneous” (not related to any trauma or activity) and “requiring additional treatment” 
will constitute the base for the efficacy evaluation. 
All bleeds occurring in subjects receiving prophylactic treatment with BAY 1093884 after 
Visit 2 (“Start of treatment with BAY 1093884”) which require additional treatment will be 
treated according to the subject’s pre-study treatment as outlined in Section 8.1.  Given the 
potential additive effect of BAY 1093884 and concomitant medication, it is recommended to 
treat the bleeds with the lowest approved doses of the prescribed replacement factor or 
bypassing agent, and repeat the dose, if additional doses will be needed, at the investigator’s 
judgment.
For the same reason, the investigator must carefully consider the intensity and the location of 
a trauma for which bleeding has not yet occurred before the preventive use of a replacement 
factor or a bypassing agent during treatment with BAY 1093884.  Careful oversight of bleed 
treatment by the Investigators will ensure the patients’ safety.
If a bleed occurs on a day of the planned injection of BAY 1093884, the subject should treat 
the bleed with his usual medication and administer the scheduled prophylactic injection of 
BAY 1093884.  The injection schedule with BAY 1093884 will not be affected by the 
treatment of bleeds.


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7.1.3
Treatment for PK/PD assessments
PK assessment using dense sampling will be done in a subset of 2 subjects (PK subjects) after
the first administration and after the last administration of BAY 1093884 during Part A of 
each dose cohort (X mg, Y mg, or Z mg).  Sparse PK samples will also be collected from the 
all other subjects in the study.
The wash-out times for FVIII, FIX products and FEIBA as listed in Section 7.1, Table 7–2,
must be observed prior the first injection of BAY 1093884.
For PK subjects: Blood samples will be drawn pre-dose and 4 h (Visits 2.1 and 6.1, 
respectively), 24 h (Day 1; Visits 2.2 and 6.2, respectively), 96 h (Day 4; Visits 2.3 and 6.3, 
respectively) and 168 h (Day 7; Visits 3.1 and 6.4, respectively) post-dose after the first and 
the last dose in the first 12-week period.  Further PK samples will be collected during the 
visits at Weeks 3 and 6.  After the first 12-week period, at each planned visit in the hospital, 
one sparse PK sample will be drawn in all subjects (including non-PK subjects) regardless of 
the wash-out time for bypassing agents or replacement factors (if taken for the treatment of 
bleed).  At all these visits, subjects should come to the site prior to the scheduled BAY 
1093884 injection.  
For non-PK subjects: The wash-out times for FVIII, FIX products and FEIBA as listed in 
Section 7.1, Table 7–2, must be observed prior the first injection of BAY 1093884.  
Following the collection of the baseline sample, one sparse PK sample will be drawn at each 
planned site visit regardless of the wash-out of bypassing or replacement agents (if taken for 
treatment of bleed).  Sparse PK samples will also be drawn regardless of study drug intake, 
except for Visit 6, Visit 7 and the Every 12-week Visit, when the subject should come to the 
site prior to the scheduled BAY 1093884 injection.  
PD assessments will be done in all subjects as outlined in Section 9.
7.1.4
Treatment for minor and major surgery
In the event a subject requires an unplanned minor surgery during the interventional part of 
the study, the treatment schedule with BAY 1093884 will not be affected.  As for the 
treatment of bleeds (see Section 7.1.2), the subject’s pre-study hemophilia treatment can be 
administered, as required.  It may be tailored to the subject’s individual response.  
The appropriate treatment of minor surgery is left to the discretion of the treating physician
and/or local clinical practice.
Minor surgery is defined as any surgical procedure that does not meet the definition of 
major (see below), and may include (but is not restricted to) dental extractions, incision and 
drainage of an abscess, or excisions.
Major surgery is defined as any surgical or invasive procedure (elective or emergent) in 
which the overall bleeding risk may be excessive, would require a general anesthetic in an 
individual without a bleeding disorder, penetrates or exposes a major body cavity, could 
result in substantial impairment of physical or physiological functions, or requires special 
anatomic knowledge or manipulative skill (e.g., tonsillectomy, laparotomy, thoracotomy, 
joint replacement).
If major surgery is required during the subject’s first 24 weeks of treatment (i.e., during 
Part A and B), the subject will be withdrawn from the study.  If major surgery is required 


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after the first 24 weeks, the subject may use his own hemophilia medication and prophylaxis 
treatment with BAY 1093884 will be interrupted.  In this case, following surgery, the subject 
may re-enter the study and restart prophylaxis with BAY 1093884 after discussion with the 
sponsor. 
Identity of study treatment
7.2
Code name:
BAY 1093884 
Manufacturer of drug product:
Bayer AG
Muellerstrasse 178
D-13353 Berlin
Germany
Manufacturer of the Investigational Medicinal Product (IMP): 
Fisher Clinical Services GmbH
Steinbuehlweg 69
CH - 4123 Allschwil
Switzerland
Final release of the IMP – EU, International and Emerging Markets: 
Bayer AG
Muellerstrasse 178
13353 Berlin
Germany
Importation and final release (US and Canada): 
Bayer HealthCare LLC, Berkeley, California (CA)
800 Dwight Way
Berkeley, CA
USA
Dosage form:
Ready-to-use liquid for subcutaneous injection
Strength:
BAY 1093884 will be provided in vials containing either 100 mg/mL 
or 150 mg/mL 
Description:
10 mL colorless glass vials containing either 1.6 mL of BAY 1093884 at a 
concentration of 100 mg/mL or 1.8 mL of BAY 1093884 at a concentration 
of 150 mg/mL
Storage:  
2°C - 8°C
Until dispensed to the subjects, the study medication will be stored in a securely locked area, 
accessible to authorized personnel only.
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.


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For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients.  Lists linking all numbering levels 
will be maintained by the sponsor’s clinical supplies Quality Assurance (QA) group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
Treatment assignment
7.3
Enrollment will start with recruitment into Cohort 1, followed by enrollment into Cohorts 2 
and 3, according to the decisions of the DMC.
An interactive web responding system (IWRS) will be used to assign at least 1 inhibitor 
subject and 2 PK subjects to each cohort.
Dosage and administration
7.4
The dose selections for this study are based on the results of the Phase 1 study or are 
extrapolated from experience with BAY 1093884 in the Phase 1 study. 
Except for injections administered at study visits, subjects will self-inject the study drug by 
themselves in their home, or will be injected by caregivers at home or other facility near to 
subject’s home, or by the investigator or delegate.  Subjects/caregivers will receive detailed 
information regarding the administration of the study medication.
The potential side effects associated with subcutaneous injections and of BAY 1093884 are 
detailed in the core informed consent, and will be updated as needed.  All subjects/caregivers 
are expected to review this information at the time of study enrollment.  Study site personnel 
should review the following topics with the subjects/caregivers: subcutaneous injection 
practices and needle disposal, how to use and store the medication, how to respond to the 
potential side effects of BAY 1093884, provide instructions on when and how to contact the 
treatment center for questions or concerns, and how to obtain emergency medical care if 
required.
7.4.1
Selection of doses in the study
The study has 2 main components – a multiple dose escalation component and a dose-finding
component. 
A DMC will review key safety data from the first 6 subjects after 6 weeks of dosing in each 
cohort before recommending opening a cohort at a higher dose.  Any available data from 
subjects continuing in the study will also be included in the DMC review. 
The sponsor will provide dose recommendations based on the PK/PD model and safety 
evaluation, taking into consideration the criteria described in Section 7.4.1.1.  The DMC will 
be asked to recommend next dosing cohort using the criteria specified in this section, and 
may review the safety data anytime during the course of the study per the criteria described in 
this section. 
In the event that a subject is suspended from the dosing of BAY 1093884, dosing will not 
resume until a full review is done by DMC and the risk-benefit is deemed acceptable for that 
patient.  During suspension of dosing, the subject will be treated with his previous hemophilia 


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treatment and any other event will be treated in accordance with the local standard of care.  If 
dosing resumes following DMC review, the subject should return to the clinic for their next 
sequential scheduled visit to restart study drug.
PK/PD criteria for dose recommendation
7.4.1.1
The selection of doses for the multiple dose escalation is based on several considerations.
Hemophilia animal models suggest that complete inhibition of TFPI is required to restore 
hemostasis.  PK/PD modeling using data from the first in man study suggests that TFPI 
inhibition can be maintained at or above 100 μg/L concentration of BAY 1093884.
Data from the first-in-man study has been used to build a PK/PD model to allow for initial 
selection of the starting dose (dose X).  The model will be refined with data generated from 
the completed dose levels in this study to select the doses for the subsequent dose levels for
this study.  The model will be used to project doses that will result in certain duration of TFPI 
inhibition and improvement in TGA parameters following weekly SC administration.  
Assuming that improvement in TGA parameters can be achieved with only partial TFPI 
inhibition, the following criteria will be considered for selecting dose Y and Z for the Cohort 
2 and 3, keeping in mind that the desired frequency for prophylaxis is SC administration once 
weekly:
Cohort 1 (dose X)
A dose that would result in at least 3-5 days of PD effect (i.e., improvement in thrombin 
generation parameters or TFPI complete inhibition) over a 7-day period has been selected for 
this cohort.  This dose is not expected to be completely ineffective based on the current 
understanding of the changes in mechanistic and PD markers.  Current projections based on 
the PK/PD model suggest that a dose of 100 mg once per week will results in 3-5 days of PD 
effect.  Therefore, a dose of 100 mg has been chosen for the Cohort 1.
Cohort 2 (dose Y)
A dose that would result in at least 7 days of PD effect (e.g., improvement in thrombin 
generation parameters or TFPI complete inhibition) over a 7-day period will be selected for 
this cohort.  The dose for this cohort will not exceed 250 mg (2.5-fold higher than the dose 
for Cohort 1).
Cohort 3 (dose Z)
A dose that achieves higher anti-TFPI mAb levels at steady state compared to Y-dose to 
establish a margin of safety.  This dose should also result in at least 7 days of PD effect (e.g., 
TGA improvement or TFPI complete inhibition) over a 7-day period.  This dose level will not 
exceed 400 mg dose.  This dose is less than the dose of 6 mg/kg that was given in a cohort of 
the Phase 1 single dose escalation study and did not have any SAE or AE leading to 
discontinuation. 
A DMC will review key safety data and dose recommendation before recommending 
escalation to the next dosing cohort. 
At a minimum, safety/PK/PD data from 6 subjects completing 6 weeks in Cohort 1 (Dose X) 
are needed to open Cohort 2 (Dose Y).  All available safety information will be taken into 
consideration.  This may include data from the 2 additional subjects in the cohort who may 


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not have reached the 6 weeks or additional data from any of the first 6 subjects who may have 
been dosed for longer than 6 weeks. This guideline will apply to further cohorts as well.  All 
available safety information from ongoing subjects will be used for safety evaluation in 
opening the next dose cohort.  This includes safety data also from the subjects who may have 
escalated from a previous cohort.  Details on the criteria for dose escalation can be found in 
the DMC charter.
Any subject from dose cohort X can escalate to the dose level Y only after dose Y has been 
opened (i.e., after data from 6 subjects is available after 6 weeks of treatment), the subject in 
dose cohort X has been treated for at least 12 weeks and meets the individual dose escalation 
criteria described in the study design section.  Equally, any subject from dose cohort Y can 
escalate to the dose level Z only after dose Z has been opened and the subject in dose cohort 
Y has been treated for at least 12 weeks at dose level Y.
The current PK/PD model will be updated with data from a minimum of 6 subjects dosed for 
6 weeks in each cohort and will include any additional data from all ongoing subjects prior to 
decision for opening a cohort.  This updated model will be used to propose the next dose 
level for the new cohort.
Blinding
7.5
Not applicable in this open-label study.
Drug logistics and accountability
7.6
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor (or its affiliate/clinical research organization [CRO]), and will be 
inaccessible to unauthorized personnel.  Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the sponsor’s study file; the site-relevant 
elements of this information will be available in the investigator site file.  On the day of 
receipt, the responsible site personnel will confirm receipt of study drug via IWRS.  The 
personnel will use the study drug only within the framework of this clinical study and in 
accordance with this protocol.  Receipt, distribution, return and destruction (if any) of the 
study drug must be properly documented according to the sponsor’s agreed and specified 
procedures.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.
Treatment compliance
7.7
Any discrepancies between actual and expected amount of returned study medication must be 
discussed with the subject at the time of the visit, and any explanation must be documented in 
the source records.
Subjects will be issued an electronic patient diary (EPD) to record date and time of 
self-administration of study drug as well as every bleeding episode with details of the 
bleeding and applied medications.  The EPD will be reviewed at every subsequent 
visit/regular contact with the subject during the study.  Used and unused vials of study 
medication will be returned to the clinic for accounting beginning at the Week 12 visit 
through the end of the study.


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8.
Non-study therapy
Prior and concomitant therapy (including treatment of bleeds)
8.1
No immunomodulatory drugs are allowed as concomitant medication.
Treatment of bleeds
If bleeds requiring additional control occur, subjects will treat these bleeds with their
previously assigned treatment (treatment in place before enrollment).  An exception will be 
made for subjects previously treated with emicizumab, whose bleeds will be treated with 
rFVIIa. 
The dose level, dose interval, and number of doses of FVIII, FIX (in subjects without or with 
low-titer inhibitors), rFVIIa, and aPCC will take into account the subject’s pre-study regimen.  
However, given the potential additive effect of BAY 1093884 and concomitant medication, it 
is recommended to treat bleeds with the lowest approved doses of the prescribed replacement 
factor or bypassing agent, and that dose can be repeated if bleeding is not resolved, upon 
investigator’s judgment.
For the same reason, the investigator must carefully consider the intensity and the location of 
a trauma for which bleeding has not yet occurred before the preventive use of a replacement 
factor or a bypassing agent during treatment with BAY 1093884.  Careful oversight of bleed 
treatment by the Investigators will ensure the patients’ safety
All medications used for the treatment of bleeds during the study will be documented in the 
subject EPD.
Any other treatments used during bleeding episodes such as painkillers, must be reported by 
the subject to the Investigator, and must be documented in the corresponding CRF.
Post-study therapy
8.2
Subjects who completed the study may continue treatment with BAY 1093884 throughout the 
extension part until Marketing Authorization.  During this period, safety and efficacy 
evaluations will be performed every 12 weeks (see Section 7.1.1).
Subjects who discontinued prematurely the study will discontinue treatment with BAY 
1093884 and will revert to their pre-study treatment or will receive any other treatment at the 
physician’s discretion.  


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9.
Procedures and variables
Tabular schedules of evaluations
9.1
Table 9–1 gives an overview on the visit schedules of PK and non-PK subjects.
Table 9–1
Visit schedule overview
Non-PK Subject
PK Subject
Visit 1*
Screening
Screening
Visit 2
Start treatment = Day 0
―
Visit 2.1
―
Start treatment – PK Day 0 (pre and 4h post-
dose)
Visit 2.2
―
PK Day 1 (= 24 h post-dose)
Visit 2.3
―
PK Day 4 (= 96 h post-dose)
Visit 3
Week 1
―
Visit 3.1
―
PK Day 7 (= 168 h post-dose)
Visit 4
Week 3
Week 3, incl. PK pre-dose
Visit 5
Week 6
Week 6, incl. PK pre-dose
Phone call
Week 9
Week 9
Visit 6.1
―
Week 11 – PK Day 0 (pre and 4h post-dose)
Visit 6.2
―
PK Day 1 (= 24 h post-dose)
Visit 6.3
―
PK Day 4 (= 96 h post-dose)
Visit 6.4
―
PK Day 7 (= 168 h post-dose)
(Week 12 – dose decision)
Visit 6
Week 12 – dose decision
―
Visit 7
Week 24 – dose decision
Week 24 – dose decision
Every 12 weeks
until end of study*
Recurring visit – dose decision
Recurring visit – dose decision
If required*
1 week and 6 weeks after dose 
escalation visit
1 week and 6 weeks after dose escalation 
visit 
Final Visit*
or Early Termination visit
or Early Termination visit
Follow-up Call*
Follow-up call
Follow-up call
PK = pharmacokinetic
* Identical procedures for non-PK subjects and PK subjects.
Detailed tabular presentations of the study visits are provided in Table 9–2 and Table 9–3
(non-PK subjects) and Table 9–4 and Table 9–5 (PK subjects).
Visit description
9.2
9.2.1
Visit description for non-PK subjects
The following flow chart and visit descriptions apply to non-PK subjects.  The corresponding 
visit descriptions for PK subjects are provided in Section 9.2.2.
Note: For many visits, the same general assessments apply for PK subjects compared with 
non-PK subjects, however, PK subjects must always come to site on the day of the scheduled 


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injection, without having injected yet for the first 12 weeks.  While for non-PK subjects this 
only applies at Visits 2 and 6.  Therefore, the visit windows are often more stringent for PK 
subjects (see Table 9–4, and Table 9–5 for details).  From “Part B” onwards, visits for PK 
and non-PK subjects are the same.


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Table 9–2
Tabular schedule of assessments (subjects not participating in PK 
evaluations; Screening and Part A)
Non-PK subjects
Screening
Part A
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Phone 
call
Visit 6
Visit Name
Screening
Eligibility 
check
Start of 
treatment
Week 1
Week 3
Week 6
Week 9
Week 12
Time
≤6 wks 
before V2
2-3 wks 
before V2
≤6 wks 
after V1
1 wk 
± 1 d 
after V2
3 wks 
± 2 d 
after V2
6 wks 
± 2 d 
after 
V2
3 wks 
± 2 d 
after 
V5
12 wks 
± 1 d 
after 
V2
Procedures
Informed consent 
X
Eligibility check 
X
X a
X a
Demographic data 
X
Med., disease and surgical 
history
X
Medication history
X
Physical examination
X
X m
X
X
X
X m
Vital signs
X
X b
X
X
X
X b
Blood sampling
X f,g,h
X g,i,j,k,m
X g,i,j
X g,i,j
X g,i,j
X
g,i,j,m
Adverse events
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
EPD device: training and 
dispense
X
EPD device: review
X
X
X
X
X
X
EPD device: return
Remind subject on wash-out 
from pre-study product 
before next visit
X
Subject to come to site 
taking wash-out from pre-
study product into account
X
X
Body weight
X
X
X
Local 12-lead ECG 
X
X
X
X
X
Confirm eligibility in IWRS to 
trigger first shipment of study 
drug
X
HJHS
X
Administration of study drug
X
X c
Dispense study drug for 
home infusions
X
X
Return used and unused 
vials of study drug
X
Plan next visit on day of 
scheduled injection with BAY 
1093884. Reminder to 
subjects to come next visit 
un-injected
X
X d
Subject to come un-injected
X
Evaluate dose escalation 
criteria
X
Start 4-weekly contact with 
subjects
X d
Schedule additional safety 
visits 1 week ± 1 day and 6 
weeks ± 1 day after dose 
escalation
X e
Abbreviations: d = day, ECG = Electrocardiogram, EPD = Electronic patient diary, HJHS = Hemophilia Joint Health Score, 
IWRS = Interactive web responding system, PK = Pharmacokinetic, V = visit, wk = week


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Table 9–3
Tabular schedule of assessments (subjects not participating in PK 
evaluations; Part B through end of study)
Non-PK subjects
Start of Part B 
to End of Study
Study Part Independent Visits
Visit Number
Visit 7 and
every 12 weeks after Visit 7
Additional 
safety visits
Final visit or
Follow-up 
phone call
Visit Name
Week 24 onward
if dose 
escalated
Early 
termination visit
Time
24 wks ± 7 d after V2 n
Every 12 wks ± 7 d after V2 n
1 wk ± 1 d after 
previous visit and 6 
wks ± 1 d
4 wks ± 2 d after 
Final/Early 
Termination visit
Procedures
Physical examination
X m
X
X
Vital signs
X b
X
X
Local 12-lead ECG
X
X
Body weight
X
Blood sampling
X g,i,j,m
X g,i,j
X g,i,j
Adverse events
X
X
X
X
Concomitant medication
X
X
X
X
EPD device: training and 
dispense
EPD device: review
X
X
X
EPD device: return
X
HJHS
X
Administration of study drug
X c
Dispense study drug for home 
infusions
X
Return used and unused vials 
of study drug
X
X
Plan next visit on day of 
scheduled injection with BAY 
1093884. Reminder to 
subjects to come next visit un-
injected
X d
X
Subject to come un-injected
X
Evaluate dose escalation 
criteria
X
Start 4-weekly contact with 
subjects
X d
X
Schedule additional safety 
visits 1 week ± 1 day and 6 
weeks ± 1 day after dose 
escalation
X e
a
Confirmation of eligibility including check of laboratory test results 
b
To be performed before and 30-60 minutes after study drug administration 
c
If the subject meets the dose-escalation criteria, the subject will receive the next higher dose; to be done under medical 
supervision 
d
If subject maintains current dose 
e
If subject is escalated to higher dose 
f
Only in subjects who consented to the optional pharmacogenetic research project: Blood sampling for pharmacogenetics 
(PgX).  Once consent is obtained, the sample may be taken at any time point during the study.
g
Blood sampling for CBC, platelets, serum chemistry
h
Blood sampling for FVIII/FIX level and FVIII/FIX inhibitor level
i
Blood sampling for aTFPI-Ab
j
Blood sampling for PK, PD and exploratory biomarkers
k
Blood sampling for low-density lipoprotein (LDL)
m
To be performed prior to study drug administration
n
Visit windows of ±7 days (calculated from Visit 2) are allowed, but the next scheduled BAY 1093884 injection must be kept 
in mind to ensure subjects will not have >8 days in between 2 injections of BAY 1093884.


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Visit 1 – Screening visit
9.2.1.1
The screening visit should not take place more than 6 weeks prior to Visit 2 (start of 
treatment).  If required, the data to be recorded at this visit may be collected over more than 
one day. 
The following procedures will be performed and data recorded:

Obtain written informed consent from the subjects/legal representative. 
Note:  No screening procedures can be performed unless written informed consent has 
been obtained. 

Eligibility check.  No subject may start treatment with study drug until all inclusion and 
exclusion criteria are met as listed in Sections 6.1 and 6.2.  Confirmation of selection 
criteria may be based on medical records for some conditions, but laboratory test results 
must be available for the listed items to confirm eligibility.  For FVIII/FIX level and for 
inhibitor levels, subjects should not have received pre-assigned treatment within the 
times specified in Section 7.1.1, Table 7–2.  In subjects whom screening laboratory does 
not confirm the severity of hemophilia (due to inadequate washout), the diagnosis must 
be supported by acceptable documentation.

Demographic data:  Year of birth, age at informed consent, sex, race and ethnicity (as 
allowed by local  regulation), height, weight

Medical history (see Section 9.3.2)

Disease history (see Section 9.3.3)

Medication history (see Section 9.3.4)

Physical examination (see Section 9.6.3.2)

Adverse events (see Section 9.6.1)

Concomitant medications

Vital signs (see Section 9.6.3.3)

Blood samples for laboratory tests: 
-
Complete blood count (CBC; see Section 9.6.3.1), platelets, serum chemistry (see 
Section 9.6.3.1)
-
FVIII/FIX level
-
FVIII/FIX inhibitor level.
Note: If a subject has a documented inhibitor positivity and is tested inhibitor 
negative at this visit, he is still eligible for enrolment as “subject with inhibitors”, 
provided he is on treatment with a bypassing agent.
-
Optional pharmacogenetic testing (PgX; see Section 9.3.5).  Sample may be 
obtained at any point during the study once the separate informed consent form has
been signed by the subject.

Training on and dispense of EPD device

Remind subject on wash-out from his pre-study product before next visit (see Table 7–2
in Section 7.1.1).


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Eligibility check (2-3 weeks prior to Visit 2)
9.2.1.2
This is not an on-site visit for the subjects, but a reminder for site staff to evaluate laboratory
results from the screening visit and to confirm eligibility in the IWRS for triggering first 
shipment of study drug to the site.
Visit 2 – Start of BAY 1093884 treatment at the respective dose 
9.2.1.3
(≤6 weeks after Visit 1)
This visit should take place within 6 weeks of Screening visit.  The wash-out times for FVIII, 
FIX products and FEIBA as listed in Section 7.1.1 (Table 7–2) must be observed prior to the 
first injection of BAY 1093884.
The following procedures will be performed and data recorded:

Confirmation of eligibility including check of laboratory test results

Concomitant medications

Adverse events (see Section 9.6.1)

Review of EPD entries

Local 12-lead ECG 

Body weight 

Hemophilia joint health score (HJHS; see Section 9.4.4)

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o Complete blood count (CBC), platelets, serum chemistry 
o Antibody against aTFPI (aTFPI-Ab)
o Blood sampling for PD and exploratory biomarkers 
o PK sampling 
o Blood sampling for LDL

Administration of study drug

Procedures 30-60 minutes after administration of study drug:
-
Vital signs

Dispense study drug for home injections for 12 weeks


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Visit 3 (1 week 1 day after Visit 2)
9.2.1.4
This visit should take place 1 week 1 day after Visit 2 (Start of treatment).
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Physical examination (see Section 9.6.3.2)

Vital signs (see Section 9.6.3.3)

Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
-
CBC, platelets, serum chemistry 
-
aTFPI-Ab
-
PD and exploratory biomarkers
-
PK sample
Visit 4 (3 weeks 2 days after Visit 2)
9.2.1.5
This visit should take place 3 weeks 2 days after Visit 2 (Start of treatment).
The same procedures as at Visit 3 will be performed and data recorded.  Please refer to 
Section 9.2.1.4.  Please note difference in time window compared with Visit 3.
Visit 5 (6 weeks 2 days after Visit 2)
9.2.1.6
This visit should take place 6 weeks 2 days after Visit 2 (Start of treatment).
The same procedures as at Visit 3 will be performed and data recorded.  Please refer to 
Section 9.2.1.4.  Please note difference in time window compared with Visit 3.
Phone call (3 weeks 2 days after Visit 5)
9.2.1.7
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Plan next visit on day of scheduled injection with BAY 1093884.  Reminder to subject to 
come next visit without having injected yet.


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Visit 6 (12 weeks 1 day after Visit 2) assessment of dose escalation
9.2.1.8
The subject’s eligibility for dose escalation will be assessed at this visit.  Therefore, subjects 
need to come to the site prior to the scheduled BAY 1093884 injection.
The following procedures will be performed and data recorded 12 weeks ± 1 day after Visit 
2:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Body weight 

Decision if subject will stay on the current dose or if escalation is required (does not 
apply for subjects in Cohort 3 on Z dose; refer to Section 7.1.1 for dose escalation 
criteria)

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o Complete blood count (CBC), platelets, serum chemistry 
o Antibody against aTFPI (aTFPI-Ab)
o Blood sampling for PD and exploratory biomarkers
o PK sampling 

Administration of study drug
-
If the subject meets dose-escalation criteria, and the DMC has approved the next 
higher dose, the subject will receive the next higher dose under medical supervision.
-
If the subject does not meet dose-escalation criteria, or the DMC has not approved 
the next higher dose, the subject will receive their current dose, does not necessarily 
need to be injected under medical supervision.

Procedures 30-60 minutes after administration of study drug (in case of dose escalation):
-
Vital signs (see Section 9.6.3.3)

Return of all used and unused study medication since the last visit

Dispensation of new study medication for next 12 weeks

In case of dose maintenance:
-
Start documented regular contact with the subject every 4 weeks to discuss adverse 
events, concomitant medication, EPD review and number of untreated bleeds.
-
Plan next visit on day of scheduled injection with BAY 1093884.  Reminder to 
subject to come next visit without having injected yet.


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
In case of dose escalation:
-
Schedule additional safety visits 1 week (1 day) and 6 weeks (1 day) after dose 
escalation
Visit 7 (24 weeks 7 days after Visit 2) assessment of dose escalation
9.2.1.9
The subject’s eligibility for dose escalation will be assessed at this visit.  Therefore, subjects 
need to come to the site prior to the scheduled BAY 1093884 injection.
Visit windows of ±7 days (calculated from Visit 2) are allowed, but the next scheduled 
BAY 1093884 injection must be kept in mind to ensure subjects will not have more than 
8 days in between 2 injections of BAY 1093884.
The same procedures as at Visit 6 will be performed and data recorded.  Please refer to 
Section 9.2.1.8.  Please note difference in time window compared with Visit 6.
Every 12 weeks visit (7 days calculated from Visit 2)
9.2.1.10
The subject’s eligibility for dose escalation will be assessed at this visit.  Therefore, subjects 
need to come to the site prior to the scheduled BAY 1093884 injection.
Visit windows of ±7 days (calculated from Visit 2) are allowed, but the next scheduled 
BAY 1093884 injection must be kept in mind to ensure subjects will not have more than 
8 days in between 2 injections of BAY 1093884.
The same procedures as at Visit 6 will be performed and data recorded.  Please refer to 
Section 9.2.1.8.  Please note difference in time window compared with Visit 6.
Additional safety visits after dose escalation (if applicable)
9.2.1.11
This visit must be performed 1 week (1 day) and 6 weeks (1 day) after the previous visit, 
if the dose was escalated during the previous visit.
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG 

Physical examination (see Section 9.6.3.2) 

Vital signs (see Section 9.6.3.3)

Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
-
CBC, platelets, serum chemistry 
-
aTFPI-Ab
-
PD and exploratory biomarkers
-
PK sample


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
Start documented regular contact with the subject every 4 weeks to discuss adverse 
events, concomitant medication, EPD review and number of untreated bleeds

Plan next visit on day of scheduled injection with BAY 1093884.  Reminder to subject to 
come next visit without having injected yet.
Final visit or early termination visit
9.2.1.12
Planning of this visit depends on the time when the decision on the next step of the 
development program for BAY 1093884 will have been made (i.e., the visit time is 
independent of the previous visit date).  This visit will also be performed in subjects who 
prematurely terminate the study.
The following procedures will be performed and data recorded:

Recording of concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Physical examination (see Section 9.6.3.2) 

Vital signs (see Section 9.6.3.3)

HJHS (see Section 9.4.4)

Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
-
CBC, platelets, serum chemistry 
-
aTFPI-Ab
-
PD and exploratory biomarkers
-
PK sample

Return of all used and unused study medication 

Return EPD device

Plan Follow-up phone call 4 weeks (± 2 days) later
Follow-up phone call (4 weeks ± 2 days after “final or early 
9.2.1.13
termination visit”)
A phone call to the subject must be made to report adverse events and concomitant 
medication since final or early termination visit.  This includes occurrence and treatment of
bleeds, because the EPD device can no longer be used.
9.2.2
Visit description for PK–subjects
The following flow chart and visit descriptions apply to subjects who consented to
PK-subanalyses.
For details on pharmacokinetic/pharmacodynamics evaluations, please refer to Section 9.5.


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Note: For many visits, the same general assessments apply for PK subjects compared with 
non-PK subjects.  However, PK subjects must always come to site on the day of the 
scheduled injection without having injected yet for the first 12 weeks.  While for non-PK 
subjects this only applies for Visits 2 and 6.  Therefore, the visit windows for some visits are 
more stringent for PK subjects (see Table 9–4 and Table 9–5 for details).  From “Part B” 
onwards, the visits for PK and non-PK subjects are the same.


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Table 9–4
Tabular schedule of assessments (subjects participating in PK evaluations; Screening and Part A)
PK subjects
Screening
Part A
Visit Number
Visit 1
Visit 2.1
Visit 2.2
Visit 2.3
Visit 3.1
Visit 4
Visit 5
Phone call
Visit Name
Screening
Eligibility 
check
Start of 
treatment & PK 
day 0
PK day 1
PK day 4
Week 1 & PK 
day 7
Week 3
Week 6
Week 9
Time
≤6 wks before
V2
2-3 wks 
before V2
≤6 wks after V1
24 h after 
dosing at 
V2.1
96 h after 
dosing at 
V2.1
1 wk (168 h) 
after dosing at 
V2.1
3 wks ± 1 d 
after V2.1
6 wks ± 1 
d after 
V2.1
3 wks ± 2 d 
after V5
Procedures
Obtain informed consent 
X
Eligibility check 
X
X a
X a
Demographic data 
X
Med., disease and surgical history
X
Medication history
X
Physical examination
X
X m
X n
X
X
Vital signs
X
X b
X
X
X n
X
X
Blood sampling
X f,g,h
X g,i,k,m,n
X k
X k
X g,i,k,n
X g,i,l,n
X g,i,l,n
Adverse events
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
EPD device: training and dispense
X
EPD device: review
X
X
X
X
X
X
X
Remind subject of wash-out from pre-study 
product before next visit
X
Subject to come to site considering wash-out 
from pre-study product 
X
X
Body weight
X
X
12-lead ECG 
X
X
X
X
X
X
Confirm eligibility in IWRS to trigger first 
shipment of study drug
X
HJHS
X
Administration of study drug
X
Dispense study drug for home infusions
X
Plan next visit on day of scheduled injection 
with BAY 1093884. Reminder to subjects to 
come next visit un-injected. 
X
X
X
X
X
Subject to come un-injected
X
X
X
Abbreviations: d = day, ECG = Electrocardiogram, EPD = Electronic patient diary, HJHS = Hemophilia Joint Health Score, IWRS = Interactive web responding system, PK = Pharmacokinetic, wk = 
week, V = visit


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Table 9–5
Tabular schedule of assessments (subjects participating in PK evaluations; Part B through end of study)
PK subjects (continued)
Part A (continued)
Start of Part B
to End of Study
Study Part Independent Visits
Visit Number
Visit 6.1
Visit 6.2
Visit 6.3
Visit 6.4
Visit 7 and
every 12 weeks after Visit 7
Additional 
safety visits
Final visit or
Follow-Up 
Phone call
Visit Name
PK day 0
PK day 1
PK day 4
Week 12 & PK 
day 7
Week 24 onwards
if dose 
escalated
Early 
Termination 
visit
Time
11 wks ± 1 
d after 
V2.1
24 h after 
dosing at 
V6.1
96 h after 
dosing at 
V6.1
12 wks ± 1 d after 
V2.1. 1 wk /168 h 
after dosing at 
V6.1
24 wks ± 7 d after V 2.1 o
Every 12 wks ± 7 d after V2 o
1 wk ± 1 d and 
6 wks ± 1 d 
after previous 
visit
4 wks ± 2 d 
after 
Final/Early 
termination 
visit
Procedures
Physical examination
X n
X n
X n
X
X
Vital signs
X n
X
X
X b
X b
X
X
Body weight
X
X
12-lead ECG
X
X
X
X
X
X
Blood sampling
X g,i,k,n
X k
X k
X g,i,k,n
X g,i,j,n
X g,i,j
X g,i,j
Adverse events
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
EPD device: training and dispense
EPD device: review
X
X
X
X
X
X
X
EPD device: return
X
HJHS
X
Administration of study drug
X
X c
X c
Dispense study drug for home infusions
X
X
Return used and unused vials of study drug
X
X
X
Plan next visit on day of scheduled injection 
with BAY 1093884. Reminder to subjects to 
come next visit un-injected
X
X d
X d
X
Subject to come un-injected
X
X
X
Decision on dose escalation versus maintain 
current dose
X
X
Start 4-weekly contact with subjects
X d
X d
X
Schedule additional safety visits 1 week ± 1 d 
and 6 weeks ± 1 d after dose escalation
X e
X e


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a
Confirmation of eligibility including check of laboratory test results 
b
To be performed before and 30-60 minutes after study drug administration 
c
If the subject meets the dose-escalation criteria, the subject will receive the next higher dose; to be done under medical supervision 
d
If subject maintains current dose 
e
If subject is escalated to higher dose 
f
Only in subjects who consented to the optional pharmacogenetic research project: Blood sampling for pharmacogenetics (PgX).  Once consent is obtained, the sample may be taken at 
any time point during the study.
g
Blood sampling for CBC, platelets, serum chemistry 
h
Blood sampling for FVIII/FIX level and FVIII/FIX inhibitor level 
i
Blood sampling for aTFPI-Ab 
j
Blood sampling for PK, PD and exploratory biomarkers
k
Blood sampling for PK, PD and exploratory biomarkers as per PK schedule: pre-dose, and 4 h, 24 h, 96 h, 168 h post-dose 
l
Blood sampling for PK, PD and exploratory biomarkers prior to injection of study drug 
m
Blood sampling for LDL
n
To be performed prior to study drug administration 
o
Visit windows of ±7 days (calculated from Visit 2) are allowed, but the next scheduled BAY 1093884 injection must be kept in mind to ensure subjects will not have more than 8 days in 
between 2 injections of BAY 1093884. 


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Visit 1 – Screening visit
9.2.2.1
Please refer to “Visit 1 – Screening visit” for non–PK subjects (Section 9.2.1.1).  The same 
assessments apply.
Eligibility check (2-3 weeks prior to Visit 2)
9.2.2.2
Please refer to “Eligibility check” for non–PK subjects (Section 9.2.1.2).  The same 
assessments apply.
Visit 2.1 – Start of BAY 1093884 treatment at the respective dose 
9.2.2.3
(≤6 weeks after Visit 1) and 1st PK day 0
This visit should take place within 6 weeks of Screening visit.  The wash-out times for FVIII, 
FIX products and FEIBA as listed in Section 7.1.1 (Table 7–2) must be observed prior to the 
first injection of BAY 1093884.
The following procedures will be performed and data recorded:

Confirmation of eligibility including check of laboratory test results

Concomitant medications

Adverse events (see Section 9.6.1)

Review of EPD entries 

Local 12-lead ECG 

Body weight 

HJHS (see Section 9.4.4)

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o CBC, platelets, serum chemistry 
o aTFPI-Ab
o PD and exploratory biomarkers
o PK sample: pre-dose
o Blood sampling for LDL

Administration of study drug

Procedures 30-60 minutes after administration of study drug:
-
Vital signs

Procedures 4 h after administration of study drug:


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-
Blood sampling for PK/PD (incl. exploratory biomarkers; see Section 9.5): 4 h 
post-dose

Dispense study drug for home injections for 12 weeks
Visit 2.2 – 1st PK Day 1 (24 h)
9.2.2.4
This visit should take place 24 h after the recorded injection time at Visit 2.1.
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Vital signs (see Section 9.6.3.3)

Blood sampling for PK/PD  (incl. exploratory biomarkers; see Section 9.5): 24 h 
post-dose
Visit 2.3 – 1st PK Day 4 (96 h)
9.2.2.5
This visit should take place 96 h after the recorded injection time at Visit 2.1.
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Vital signs (see Section 9.6.3.3)

Blood sampling for PK/PD  (incl. exploratory biomarkers; see Section 9.5): 96 h 
post-dose

Reminder to the subject to come next visit without having injected yet.
Visit 3.1 – 1st PK Day 7 (168 h)
9.2.2.6
This visit should take place 168 h after the recorded injection time at Visit 2.1.
Subjects need to come to the site prior to the scheduled BAY 1093884 injection to take the 
168 h PK/PD sample before the next regular scheduled injection. 
The following procedures will be performed and data recorded: 

Concomitant medications  

Adverse events (see Section 9.6.1)


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
Review of EPD data

Local 12-lead ECG

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o Complete blood count (CBC), platelets, serum chemistry 
o Antibody against aTFPI (aTFPI-Ab)
o Blood sampling for PD and exploratory biomarkers
o PK sampling 

Plan next visit on day of scheduled injection of BAY 1093884.  Reminder to the subject 
to come next visit without having injected yet.

Administration of study drug either at the site or at home.  Infusion data to be 
documented in the EPD.
Visit 4 (3 weeks 1 day after Visit 2)
9.2.2.7
Note: PK subjects need to come to the site prior to the scheduled BAY 1093884 injection.
This visit should take place 3 weeks 1 day after Visit 2.1 (Start of treatment).
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o Complete blood count (CBC), platelets, serum chemistry 
o Antibody against aTFPI (aTFPI-Ab)
o Blood sampling for PD and exploratory biomarkers
o PK sampling 

Plan next visit on day of scheduled injection of BAY 1093884.  Reminder to the subject 
to come next visit without having injected yet.


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
Administration of study drug either at the site or at home.  Infusion data to be 
documented in the EPD.
Visit 5 (6 weeks 1 day after Visit 2)
9.2.2.8
Note: PK subjects need to come to the site prior to the scheduled BAY 1093884 injection.
This visit should take place 6 weeks 1 day after Visit 2 (Start of treatment).
Please refer to Section 9.2.2.7 for procedures.  The same procedures apply:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o Complete blood count (CBC), platelets, serum chemistry 
o Antibody against aTFPI (aTFPI-Ab)
o Blood sampling for PD and exploratory biomarkers
o PK sampling 

Plan next visit on day of scheduled injection of BAY 1093884.  Reminder to the subject 
to come to the visit at Week 11 without having injected yet.

Administration of study drug either at the site or at home.  Infusion data to be 
documented in the EPD.
Phone call (3 weeks 2 days after Visit 5)
9.2.2.9
Please refer to “Phone call 3 weeks after V5” for non–PK subjects (Section 9.2.1.7).  The 
same assessments apply.
Visit 6.1 (11 weeks 1 day after Visit 2) 2nd PK Day 0
9.2.2.10
Note: PK subjects need to come to the site prior to the scheduled BAY 1093884 injection.
The following procedures will be performed and data recorded 11 weeks ± 1 day after Visit 
2:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data


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
Local 12-lead ECG

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2) 
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o CBC, platelets, serum chemistry 
o aTFPI-Ab
o PD parameters and exploratory biomarkers
o PK sample: pre-dose

Administration of study drug

Procedures 30-60 minutes after administration of study drug:
-
Vital signs

Procedures 4 h after administration of study drug:
-
Blood sampling for PK/PD (incl. exploratory biomarkers; see Section 9.5): 4 h 
post dose
Visit 6.2 – 2nd PK Day 1 (24 h)
9.2.2.11
This visit should take place 24 h after the recorded injection time at Visit 6.1.
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Vital signs (see Section 9.6.3.3)

Blood sampling for PK/PD  (incl. exploratory biomarkers; see Section 9.5): 24 h 
post-dose
Visit 6.3 – 2nd PK Day 4 (96 h)
9.2.2.12
This visit should take place 96 h after the recorded injection time at Visit 6.1.
The following procedures will be performed and data recorded:

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data


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
Local 12-lead ECG

Vital signs (see Section 9.6.3.3)

Blood sampling for PK/PD  (incl. exploratory biomarkers; see Section 9.5): 96 h 
post-dose

Reminder for the subjects to come uninjected to the next visit, because next visit is 
PK Day 7
Visit 6.4 – 2nd PK Day 7 (168 h) and assessment of dose escalation
9.2.2.13
This visit should take place 168 h after the recorded injection time at Visit 6.1.
Subjects need to come to the site prior to the scheduled BAY 1093884 injection to take the 
168 h PK/PD sample before the next regular scheduled injection.  The subject’s eligibility for 
dose escalation will be assessed at this visit. 
The following procedures will be performed and data recorded: 

Concomitant medications  

Adverse events (see Section 9.6.1)

Review of EPD data

Local 12-lead ECG

Body weight 

Procedures before administration of study drug
-
Physical examination (see Section 9.6.3.2)
-
Vital signs (see Section 9.6.3.3)
-
Blood samples for laboratory tests (see Sections 9.6.3.1 and 9.5.2): 
o Complete blood count (CBC), platelets, serum chemistry 
o Antibody against aTFPI (aTFPI-Ab)
o Blood sampling for PD and exploratory biomarkers
o PK sampling 

The decision as to whether the subject will stay on the current dose or if escalation is 
required (does not apply for subjects in Cohort 3 on Z dose; refer to Section 7.1.1 for 
dose escalation criteria)

Administration of study drug
-
If the subject meets dose-escalation criteria, and the DMC has approved the next 
higher dose, the subject will receive the next higher dose under medical supervision.
-
If the subject does not meet dose-escalation criteria or the DMC has not approved 
the next higher dose, the subject will receive their current dose; this does not 
necessarily need to be injected under medical supervision.


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
Procedures 30-60 minutes after administration of study drug (if the dose was escalated)
-
Vital signs (see Section 9.6.3.3)

Return of all used and unused study medication from the last visit

Dispensation of new study medication for next 12 weeks

In case of dose maintenance:
-
Start documented regular 4-weekly (phone) contact with the subject to discuss 
adverse events, concomitant medication, EPD review and number of untreated 
bleeds.
-
Plan next visit on day of scheduled injection with BAY 1093884.  Reminder to 
subject to come next visit without having injected yet.

In case of dose escalation:
-
Schedule additional safety visits 1 week (1 day) and 6 weeks (1 day) after dose 
escalation.
Visit 7 (24 weeks 7 days after Visit 2) assessment of dose escalation
9.2.2.14
The subject’s eligibility for dose escalation will be assessed at this visit.  Therefore, subjects 
need to come to the site prior to the scheduled BAY 1093884 injection.
Visit windows of ±7 days (calculated from Visit 2) are allowed, but the next scheduled 
BAY 1093884 injection must be kept in mind to ensure subjects will not have more than 
8 days in between 2 injections of BAY 1093884.
The same procedures as at Visit 6 for non-PK subjects will be performed and data recorded.  
Please refer to Section 9.2.1.9.  Please note difference in time window compared with Visit 6.
Every 12 week visit (7 days calculated from Visit 2)
9.2.2.15
The subject’s eligibility for dose escalation will be assessed at this visit.  Therefore, subjects 
need to come to the site prior to the scheduled BAY 1093884 injection.
Visit windows of ±7 days (calculated from Visit 2) are allowed, but the next scheduled 
BAY 1093884 injection must be kept in mind to ensure subjects will not have more than 
8 days in between 2 injections of BAY 1093884.
The same procedures as at Visit 6 for non-PK subjects will be performed and data recorded.  
Please refer to Section 9.2.1.10.  Please note difference in time window compared with 
Visit 6.
Additional safety visits after dose escalation (if applicable)
9.2.2.16
Please refer to “Additional safety visits after dose escalation” for non–PK subjects (Section 
9.2.1.11).  The same assessments apply.


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Final visit or Early Termination visit
9.2.2.17
Please refer to the “Final visit” for non-PK subjects (see Section 9.2.1.12).  The same 
procedures apply.
Follow-up phone call (4 weeks ± 2 days after “final or early 
9.2.2.18
termination visit”)
Please refer to the “Follow-up phone call” for non-PK subjects (see Section 9.2.1.13).  The 
same procedures apply.
Population characteristics
9.3
9.3.1
Demographic
The following demographic characteristics will be collected:

Year of birth

Age at Informed Consent

Sex

Race (as allowed by local regulation)

Ethnicity (as allowed by local regulation)

Height

Weight
9.3.2
Medical history
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
9.3.3
Disease history
The following baseline characteristics will be collected in addition: 

Date of hemophilia diagnosis

Start of therapy

Current FVIII or FIX products (product, dose and frequency of administration)

Current by-passing agents product(s), dose and frequency of administration)

Number of exposure days


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
Type of FVIII of FIX gene mutation (from history)

Family history

FVIII or FIX level and type of assay

Family and personal history of past inhibitor formation

Current inhibitor level

Current ITI status

Current treatment product and regimen

Number and type of bleeds in the past 6 months

Presence and location of target joints
9.3.4
Medication history
Medication history to be collected and recorded at Screening and will include prior and 
current FVIII/FIX products and bypassing agents used for hemophilia treatment as well as a 
history of other prior and current medications.
The details for all medications recorded in the eCRF should include:

Medication trade name and dose

Reason for medication

Start date and end date or if ongoing
Additional information regarding dates of vaccinations will be collected with emphasis on 
most recent vaccinations (prior 12 months).
9.3.5
Pharmacogenetic testing - optional
All subjects will be invited to participate in a voluntary research project involving genetic 
analyses of a blood sample.
The purpose of the genetic analysis is the evaluation of polymorphism of TFPI, but also of
other genes involved in blood coagulation in different hemophilia subjects with different 
genetic background.
Approval for pharmacogenetic sampling must be obtained.  A separate informed consent 
form (ICF) will be provided.  Subjects will be asked to participate in the optional 
pharmacogenetics.  If subjects elect to participate, a blood sample will be collected.  Once 
consent is obtained, the sample may be taken at any time point during the study.  Samples 
will be prepared and labeled according to laboratory specifications.  Details of the sample 
collection and shipment procedures will be explained in the laboratory manual. 
A subject does not need to agree to participate in the pharmacogenetic research project to be 
enrolled in the study.


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Efficacy
9.4
 
 
 
 
 
9.4.1
Electronic patient diary (EPD)
Treatment logs are commonly used for hemophilia subjects for documentation of their home 
treatment.  Home treatment and bleeding information are the key variables evaluated in this 
study.  Study specific treatment logs will be provided in national language.  The preferred 
system for this study will be EPD devices since they are interactive, allow for real time data 
transmission, record-stamp date and time of fulfillment, and facilitate the clarification of data 
with the site and during the data cleaning process.  Subjects or their caregivers will be 
provided with EPDs for the whole study.  At Screening visit, subjects and caregivers will be 
trained in the use of the device.  These logs will be used to collect the treatment data and 
bleeds by the caregivers or subjects, and the data will be verified for accuracy and completion 
by the investigator or delegate during regularly scheduled interactions with the subject or 
caregiver.  Thus, the EPD will be considered the source for these data.
For each self-administered injection of study drug, information must be recorded on the EPD
as follows:
Each injection of BAY 1093884
!
Date and time [24 hour clock]
!
Individual vial number (bar code scan from vial label)
!
Number of vials used
!
Volume in mL that was injected 
Injections of study drug as part of protocol-mandated visits and procedures will be recorded 
on the respective CRF pages.
All bleeding episodes (regardless if treated or not, or treated at home or under medical 
supervision) as well as the potential treatment with pre-study hemophilia drugs will be 
recorded in the EPD:
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Bleeding episode (onset)

Date and time [24 hour clock] of onset

Type of bleed [spontaneous, non-spontaneous/non-traumatic, traumatic]

Location [joint, muscle, skin or mucosa, internal, other; body map]

Intensity [mild, moderate, severe; according to subject’s own judgment]

Treated [yes/no]; 
if “yes”:
Date and time [24 hour clock]
Product class used
Number of injections, doses
9.4.2
Dose of pre-study hemophilia medication administered and number of 
injections needed to stop a bleeding event
The subjects will document dose of pre-study hemophilia medication used and the number of 
injections needed to stop a bleeding event.  Subjects assess the cessation of their own 
bleeding episode based on their long-term experience of coping with bleeds since childhood.  
The investigator and clinical staff will review the subject EPD to check for the dose used and 
the number of injections applied (including the date, time, and the severity of all bleeding 
events).
9.4.3
Assessment of adequacy of hemostasis during minor surgical 
interventions
Pre-study medication used for minor surgery will be recorded on the CRF.  The doses 
administered and the frequency of any treatment will be collected.
The investigator, surgeon, or interventionalist will be asked to compare estimated blood loss 
from experience with non-hemophilic subjects undergoing comparable procedures, and assess 
intraoperative efficacy at the end of the procedure (Table 9–6).  Post-surgical efficacy will be 
assessed at least 24 h after the end of the procedure by the investigator or surgical staff at 
drain removal, if required, and by the investigator or hematologist at discharge.


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Table 9–6
Criteria for the assessment of efficacy in minor surgery (5)
Excellent
Intra-operative and post-operative blood loss similar (within 10%) to the non-hemophilic 
patient.
!
No doses of FVIII/FIX/bypassing agents needed AND
!
Blood component transfusions required are similar to non-hemophilic patient
Good
Intra-operative and/or post-operative blood loss slightly increased over expectation for 
the non-hemophilic patient (between 10-25% of expected), but the difference is judged 
by the involved surgeon/anesthetist to be clinically insignificant.
!
No doses of FVIII/FIX/bypassing agents needed AND
!
Blood component transfusions required are similar to the non-hemophilic patient
Fair
Intra-operative and/or post-operative blood loss increased over expectation (25-50%) for 
the non-hemophilic patient and additional treatment is needed.
!
FVIII/FIX/bypassing agents needed OR
!
Increased blood component (within 2 fold) of the anticipated transfusion requirement
Poor/none
Significant intra-operative and/or post-operative blood loss that is substantially increased 
over expectation (>50%) for the non-hemophilic patient, requires intervention, and is not 
explained by a surgical/medical issue other than hemophilia
!
Unexpected hypotension or unexpected transfer to ICU due to bleeding OR
!
Substantially increased blood component (> 2 fold) of the anticipated transfusion 
requirement
Data on blood loss will be collected, as estimated at the time of surgery, change or drop in 
hemoglobin/hematocrit, the need for additional or other hemostatic medications, and the type 
and number of blood products transfused.  Hemostatic-related surgical complications will 
also be obtained including data on specific diagnostic evaluations needed (example: Imaging 
to follow size of a hematoma).
9.4.4
Hemophilia joint health score (HJHS)
 
 
The HJHS score will be evaluated at the start of treatment and the final visits.
The HJHS measures joint health in the domain of body structure and function (i.e., 
impairment) of the joints most commonly affected by bleeding in hemophilia: Elbows 
(left/right), knees (left/right), ankles (left/right).
Items to be assessed per joint: Swelling, duration (swelling), muscle atrophy, crepitus on 
motion, flexion loss, extension loss, joint pain, and strength.
The possible range per joint is 0-20 score points, where 0 denotes the best possible and 20 the 
worst joint status.  Thus, the sum for all 6 joints is 120 score points at maximum.  In addition, 
general gait is to be assessed: 0-4 score points.
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The HJHS total score is the sum of the 6 joint scores plus the score for general gait and 
ranges from 0 to 124 score points.
Pharmacokinetics/pharmacodynamics
9.5
9.5.1
Pharmacokinetics
Drug measurements
9.5.1.1
Blood samples for PK analyses of BAY 1093884 (anti-TFPI mAb) in plasma will be 
collected at the time points given in the study flow chart (see Table 9–1).
Plasma concentrations of BAY 1093884 will be measured using a validated ligand binding 
assay method.  Quality control (QC) and calibration samples will be analyzed concurrently 
with study samples.  The results of calibration, QC, and study samples will be reported in the 
bioanalytical report, which will be included in the clinical study report for this study.
Samples should be collected as close as possible to the nominal sample collection time.  The 
actual sampling time should be documented on the eCRF pages and actual sampling time will 
be used when calculating the pharmacokinetic parameters. Deviations from planned PK 
blood sampling times are not considered as protocol violations.  In the case of missing 
records of the actual sampling times, planned sampling times may be used for PK evaluation.
Information on the collection, processing, storage and shipment of biomarker samples will be 
provided in a separate document.
In case a subject bleeds during the period of dense sampling for PK, subject must treat the 
bleed and continue PK sampling with no modifications to the PK sampling schedule.
Pharmacokinetic evaluation
9.5.1.2
Non-compartmental analysis
PK parameters will be calculated using the model-independent compartment-free method 
according to the current Bayer guidelines using the PK software WinNonlin, version 5.3 or 
higher.  Based on the concentration time data, the following PK parameters will be 
calculated:
BAY 1093884 in plasma
Main PK parameters: 
AUC(0-tlast), AUC(0-tlast)/D, Cmax, Cmax/D
Additional parameters: Optionally AUC, AUC/D, t1/2, Vss, CL, MRT, Vz, %AUC(tlast-∞), 
points terminal may be estimated.  Normalization of AUC to dose 
and/or body weight may be performed.
For multiple dose administration, the following parameters may also be estimated in addition 
to the parameters listed as main PK parameters: 
After the first dose: 
AUC0-7d, AUC0-7d/D, Cmax, Cmax/D  
After the last dose: 
AUCτ,md, AUCτ,md/D, Cmax,md and Cmax,md/D, and accumulation ratios 
(RACmax, RAAUC)
Additional PK parameters may also be estimated.
In addition, data obtained from this study may be subject to PK modeling and simulation.


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Details of the model development and evaluation will be described in a separate Evaluation 
Plan and the results reported in a separate Evaluation Report.
9.5.2
Pharmacodynamics and biomarkers
Pharmacodynamic parameters will include:
!
PT, aPTT, D-dimer, fibrinogen, FV level (clotting assay), antithrombin activity, 
protein C activity, thrombin generation assay (TGA/CAT PPP), TFPI activity 
(chromogenic),  total (i.e., LDL-devoid and LDL-bound) TFPI concentration in 
plasma, FVIIa, dPT (dilute PT), prothrombin fragment 1 and prothrombin fragment 2 
(F1+2), thrombin-antithrombin complex (TAT)
Optional pharmacodynamic parameters (locally, if specific instrument is available):
!
Thrombelastometry/thrombelastography (ROTEM/TEG)
!
Thrombin generation assay (TGA/CAT PRP)
 
 
 
 
Procedures for processing, shipping and analysis of samples will be described in a separate 
manual.
Safety
9.6
Safety variables:
!
Incidences of drug-related AEs, SAEs, adverse events of special interest (AESIs), 
injection site reactions (ISRs) and clinically relevanta abnormal laboratory values. 
!
Incidences of binding and neutralizing antibodies against BAY 1093884
Safety measures will include:
! AEs/SAEs/AESIs and ISRs by
                                                
a “Clinically relevant” implies the presence of a clinical sign or symptom that requires medical action.
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o
Relationship to study drug
o
Severity
AEs leading to discontinuation of study drug 
Anti-TFPI antibodies (immunogenicity)
Clinical laboratory data including: 
o
CBC with differential count and platelets
o
Serum chemistry
Vital signs
Evaluation of concomitant medication
Physical examination
9.6.1
Adverse events
Please note:
Any bleeding event occurring during the study will not be documented as an AE, because this 
event is captured in the assessment of efficacy.  However, if the bleed requires hospitalization 
or fulfills another seriousness criterion, it must be reported as an SAE (see Section 9.6.1.3.1).
Please note:
Any thromboembolic or thrombotic microangiopathic event is an AESI and will be 
considered to be an SAE (see Section 9.6.1.4).  Any thromboembolic or thrombotic 
microangiopathic event will be sufficient to require a review of safety by the DMC (see 
Section 13.1.2).  Dosing will be suspended in the affected subject(s) until consultation with 
the DMC (see Section 9.6.1.7).
Definitions
9.6.1.1
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject
or clinical investigation subject after providing written informed consent for participation in 
the study.  Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product.


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In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal (e.g., physical examination findings, symptoms, diseases, laboratory, 
ECG).

Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded as 
medical history (e.g., seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject 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 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE, if 
at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 h
- The admission is pre-planned
(e.g., elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
- The admission is not associated with an AE 
(e.g., social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability/incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly/birth defect
f.
Is another serious or important medical event as judged by the investigator


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Classifications for adverse event assessment
9.6.1.2
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The severity or intensity of an AE should be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.  
If no exact matching code is available in NCI CTCAE version 5.0, the following guidance
should be used: 

CTCAE grade 1: Mild 

CTCAE grade 2: Moderate 

CTCAE grade 3: Severe and/or disabling AE

CTCAE grade 4: life-threatening and/or intervention needed

CTCAE grade 5: resulting in death (fatal) 
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation (e.g., mechanical bleeding at 
surgical site) 
or
2. Non-plausibility (e.g., the subject is struck by an automobile) when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of “yes” indicates that the AE is reasonably associated with the use of the 
study treatment.


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Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):  Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.
- Underlying, concomitant, intercurrent diseases:  
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have.
- Concomitant medication or treatment: 
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might have caused the event in question.
- Known response pattern for this class of drug: Clinical/preclinical
- The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.
- The assessment is not possible
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose not changed

Not applicable

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other


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9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
Assessment and documentation of adverse events
9.6.1.3
The investigator has to record all adverse events occurring in the period between the signing 
of the informed consent and the end of the follow-up phase on the respective CRF pages.
After the end of the follow-up phase, there is no requirement to actively collect AEs,
including deaths.  The type of information that should be assessed and recorded by the 
investigator for each AE is listed in Section 9.6.1.2.  
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For all serious adverse events (SAEs), the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.
9.6.1.3.1
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1.  Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant 
contact details, is summarized in the investigator site file.  This information will be updated 
as needed.
The investigator must report immediately (within 24 h of the investigator’s awareness) all 
SAEs and AESIs occurring during the observation period defined in Section 9.6.1.3 to the 
recipient detailed in the instructions for SAE reporting included in the Investigator File.  For 
this, an AE page in the CRF as well as the complementary pages provided in the Investigator 
File must be completed for each SAE.  
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs/IRBs
Notification of the IECs/IRBs about all relevant events (e.g., SAEs, suspected, unexpected,
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.


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Notification of the authorities
The processing and reporting of all relevant events (e.g., SAEs, suspected unexpected serious 
adverse reactions [SUSARs]) to the authorities will be done by the sponsor according to all 
applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g.,
SUSARs) according to all applicable regulations.
9.6.1.3.2
Expected adverse events
For this study, the applicable reference document is the current version of the investigator’s 
brochure (IB).
If relevant new safety information is identified, the information will be integrated into an 
update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
Adverse events of special safety interest
9.6.1.4
Thromboembolic and thrombotic microangiopathic (TMA) events
Subjects will be closely monitored for any signs of thromboembolic and TMA events (e.g., 
myocardial infarction, ischemic cerebrovascular accident, arterial thrombosis, deep vein
thrombosis, pulmonary embolism) after study drug administration and during the follow-up
visits.  If signs and symptoms of any thromboembolic event or signs of TMA are present 
during the study, the site physician will assess these symptoms/signs, order and review 
diagnostic procedures (ECG, ultrasound, computed tomography, magnetic resonance 
imaging, Doppler sonography, and blood tests, which include CBC, coagulation parameters, 
including D-dimer, platelets, and fibrinogen, TFPI, ATIII, and protein C etc.), as appropriate,
to confirm or refute the diagnosis.  If symptoms are suggestive of deep vein thrombosis, 
pulmonary embolism, or TMA, the guidelines for diagnosis and intervention will be 
followed.
Subjects will be provided with a subject alert card which includes a checklist of symptoms
and the advice to seek medical attention in case of occurrence of any symptoms (see separate
document).
Thromboembolic and TMA events are defined in this study as SAEs and must be documented 
accordingly on the corresponding AE pages of the eCRF and reported within 24 h of the 
investigator’s awareness as SAEs.
Hypersensitivity reactions
Hypersensitivity in this study is defined as AESI and must be documented on the 
corresponding adverse events of special safety interest pages of the eCRF and reported within 
24 h of the investigator’s awareness.  Non-serious hypersensitivity events should not 
automatically be upgraded by the reporting investigator to serious.


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If allergic or anaphylactic reactions occur, the injection will be stopped immediately and 
symptomatic treatment and therapy for hypersensitivity should be instituted, as appropriate.  
Subjects will be made aware that the potential occurrence of chest tightness, dizziness, mild 
hypotension, and nausea during or after the injection can constitute an early warning for 
hypersensitivity and anaphylactic reactions.  In such cases, the subject should immediately 
notify the investigator or the site staff of these symptoms.  In the event of shock, the current 
medical standards for shock treatment should be observed.
The first injection of every dose level will be administered under medical supervision.  
Subjects will be monitored at the site for about 1 h after study drug injection.
Reporting of medical device failuresb
9.6.1.5
The investigator must immediately report all non-approved medical device failures which 
could cause health damage, as well as any health damage that may be causally associated 
with a non-approved medical device failure.  For this reporting, the forms provided are to be 
used and sent to the designated recipient.
Dose-limiting toxicities
9.6.1.6
Dose-limiting toxicities (DLTs) are defined as any of the following events that are clearly 
unrelated to underlying disease and occurring at any dose level. 

Presence of any symptoms or signs of TE or TMA

Platelets <100 giga/L or fibrinogen <100 mg/dL at any visit 

Any grade ≥3 according to CTCAE criteria version 5.0 ( CTCAE criteria do not apply 
for toxicities related to underlying disease like aPTT) 

Grade ≥2 toxicities according to CTCAE criteria in case of symptoms of disseminated 
intravascular coagulation (DIC) or hemolysis
Adverse events requiring an ad hoc DMC meeting
9.6.1.7
Occurrence of any of the following events will require that an ad hoc meeting of the DMC 
take place.
1. Events resulting in suspension of treatment in the affected subject(s). 
a.
Occurrence of a single drug-related Serious Adverse Event (SAR), or two 
severe or clinically significant drug-related AEs
b. Subject experiencing a DLT as defined in Section 9.6.1.6
2. Events resulting in suspension of enrollment 
a.
Two subjects experiencing the same DLT as listed in Section 9.6.1.6
b. Death of a subject that is considered related to BAY 1093884 by the
investigator
                                                
b Only applicable for study sites located in Japan.


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9.6.2
Pregnancies
Not applicable in this male study population. 
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used.  The investigator should submit them 
within the same timelines as for an SAE.  
9.6.3
Further safety
Clinical laboratory assessments
9.6.3.1
Blood samples for clinically laboratory will be drawn at the time points specified Table 9–2
and Table 9–3for non-PK subjects, and Table 9–4 and Table 9–5 for PK subjects. 
All laboratory analyses will be performed at central laboratories.  Investigators will be 
provided with a laboratory manual containing instructions on how to collect and process 
samples, and will be provided with a copy of results for their subjects.
Remaining biological material may be used later for further safety analysis, if required. 
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g., clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
Standard safety laboratory
The following blood samples will be collected for laboratory analyses: 

CBC with differential:  Hemoglobin, hematocrit, platelets, leukocytes, neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes  

Serum chemistry:  Sodium [Na], potassium [K], bicarbonate [CO2], chloride [Cl], 
blood urea nitrogen [BUN], creatinine, alanine and aspartate aminotransferases [ALT, 
AST], total bilirubin, lactate dehydrogenase [LDH]

Fibrinogen
FVIII/FIX inhibitors
Antibody to FVIII/FIX (inhibitor) testing will be done according to the Nijmegen modified 
Bethesda assay.  A positive inhibitor test is defined with a threshold of ≥0.6 BU/mL at the 
central laboratory.
BAY 1093884 inhibitory antibodies (aTFPI-Ab)
If there is loss of efficacy (e.g., unexpected break-through bleeds):

Blood for central laboratory: Antibodies against BAY 1093884.


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Hypersensitivity reactions
If a hypersensitivity reaction is clinically suspected, the subject is to be managed according to 
local standard of care.  The investigator should immediately notify the sponsor. The 
following information and blood tests should be obtained within 7 days of the reported event.  
Confirmatory studies may be required.

Time and dose of last BAY 1093884 injection

Number of BAY 1093884 injections

Infused/injected product for the treatment of bleeds (if applicable)

Blood for central laboratory: CBC, antibodies against BAY 1093884, and 
immunoglobulins.
If the above samples cannot be obtained, collection of local samples stored at the site may be 
requested for testing in the central laboratory.  In the event of a confirmed hypersensitivity 
event, the subject should be removed from the trial, and subsequent treatment options should 
be discussed. 
Thromboembolic and thrombotic microangiopathic events
Blood for central laboratory: CBC, coagulation parameters, including D-dimer, platelets, and 
fibrinogen, TFPI, ATIII, and protein C, LDH
Physical examination
9.6.3.2
The physical examination (by means of inspection, palpation, and auscultation) will be 
performed by a physician at the study site, and must at least cover the organs of the 
cardiovascular, respiratory, and abdominal systems.  Orientating tests of neurological 
function will be included. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1).
Vital signs
9.6.3.3
Systolic and diastolic blood pressure, heart rate, respiratory rate and body temperature will be 
recorded (after resting for at least 5 minutes) before and within 30-60 minutes after the end of 
injection of the study medication that are given under medical supervision.
Electrocardiogram
9.6.3.4
ECGs will be conducted to assess safety at Visits 2 through 7, Every 12 Weeks Visit, and at 
any Additional Safety Visits.
Other procedures and variables
9.7
Contraception
It has been shown that there is no target-related specific transport mechanism for 
BAY 1093884 into semen or from semen into the conceptus.  Following administration to a 
male subject, BAY 1093884 would not be bioavailable via seminal delivery to the developing 
conceptus of an untreated partner.  Therefore, no method of contraception is needed.


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Appropriateness of procedures/measurements
9.8
The majority of the safety parameters, as well as the methods to measure them, are 
recognized clinical assays, and are reliable, accurate and relevant.  The safety evaluation for 
BAY 1093884 will be based on clinical and laboratory assessments including coagulation and 
immunological tests as well as on reported AEs.
10.
Statistical methods and determination of sample size
General considerations
10.1
All data (efficacy, safety, PK/ PD, and demographic data) will be listed and study summary 
tables will be provided where appropriate.  Variables measured on metrical scales will be 
summarized using descriptive statistics that will include the number of non-missing 
observations, the arithmetic mean, the sample standard deviation, the median, the minimum 
and maximum, as well as the first and third quartiles.  Frequency tables will be provided for 
variables measured on ordinal or nominal scales.  Tables will display the number and 
percentage of subjects falling within a particular category.
Data will be displayed by dose cohort and by study medication actually received during the 
respective study parts and their visits.
Data will be displayed by period of time.  This includes:

Part A: The first 12 weeks of treatment of each subject.

Part B: The additional 12-week periods of treatment after Part A.  Each subject will be 
analyzed in the dose cohort he was assigned to (data of dose escalated subjects will be 
not included).
In general, data will be displayed as measured at each scheduled time point, individual values 
will be presented in listings.
Statistical analysis will be performed using SAS; the version used will be specified in the 
statistical analysis plan (SAP).
Analysis sets
10.2
The statistical analysis sets are defined as follows:
Safety set (SAF)
All subjects with at least one intake of study drug.  Safety 
analyses will use treatments actually received (in case where 
this differs from assignment to treatment).
Per protocol set (PPS)
All SAF subjects who completed Part A and Part B of the study 
with no major protocol deviations.
PK set 
All subjects with evaluable PK profiles will be included.
Subjects who were assigned to treatment but did not receive study medication will not be 
included in the SAF.  As the number of these excluded subjects is anticipated to be 
negligible, if at all any exist in this design, an “all assigned treatment analysis set” will not be 
generated.


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Subjects who do not belong to SAF will not be included into statistical considerations.  These 
subjects are classified as ‘listing only set’ (LOS).  Number of screening failures and dropouts 
will be tabulated.
Demographics and other baseline characteristics will be analyzed based on the SAF and PPS. 
The primary analysis population for the safety analysis will be the SAF.  The efficacy 
analyses will be based on the PPS and sensitivity analyses will be based on the SAF as
appropriate.
Variables and planned statistical analyses
10.3
The primary endpoint is safety as defined by the frequency of drug-related AEs, SAEs, 
AESIs and clinically relevantc abnormal laboratory values.
Another safety endpoint will be the frequency of binding and neutralizing antibodies against 
BAY 1093884. 
The measures used for the assessment of the safety of BAY 1093884 are listed in Section 9.6.
efficacy variables are listed in Section 9.4.  Other efficacy variables may be 
defined in the statistical analysis plan (SAP).
Pharmacokinetic parameters are listed in Section 9.5.1.
Pharmacodynamic parameters are listed in Section 9.5.2.
Subgroups
Subgroups will be defined by type of hemophilia (A or B), presence of inhibitors, previous 
prophylaxis or OD treatment, age group, race and region.  Further subgroups will be defined,
if appropriate.
10.3.1
Baseline
Demographic characteristics, including age, weight, height and ethnicity will be presented for 
all subjects exposed to BAY 1093884 in the form of summary statistics.  The presentation 
will also be given for subgroups.  Other baseline characteristics, including laboratory findings 
and vital signs, will be handled similarly.
10.3.2
Extent of exposure
Extent of exposure to the study and reference drug (rescue medication, pre-study medication), 
including injection characteristics, will be summarized for all subjects receiving any amount 
of drug.
10.3.3
Analysis of efficacy
no multiplicity adjustment 
will be done for the evaluation of the different dose levels.
                                                
c “Clinically relevant” implies the presence of a clinical sign or symptom that requires medical action.
CCI
CCI


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All endpoints will be summarized by descriptive statistics.  For selected efficacy variables 
90% confidence intervals will be given. 
The efficacy analyses will be based on both Part A and Part B.  The proportion of responders 
will be estimated together with 90% confidence intervals based on exact method (Clopper-
Pearson).  For the analysis on each 12-week Part B period, only subjects who were not 
escalated are taken into account.  It should be noted that this kind of analysis must be 
interpreted carefully, as the restriction is based on post-baseline events.  Further efficacy 
analyses will include all bleeding data available at the time when Cohort 3 will have 
completed Part B of the study.
Further details will be clarified in the SAP.
Missing data
If the details of a bleed are missing (e.g., type of bleed spontaneous, non-spontaneous/non-
traumatic or traumatic), the bleed will be counted for all bleeds, but not for the corresponding 
subgroup of bleeds. 
Each subject’s bleeding period start and stop date will be needed to allocate the bleedings to 
the respective period.  If dates for bleeds and injections of rescue medication are both missing 
then these bleeds cannot be counted.  If the bleed date is missing, but the injection date is 
available, injection date will be used.  Otherwise, imputation rules will be specified in the 
statistical analysis plan or the analysis datasets specification document. 
A detailed missing data-handling plan will be provided in the statistical analysis plan.
10.3.4
Analysis of PK/PD parameters
All PK analyses will be based on the PK set.  Descriptive statistics for PK data will be 
presented as n, geometric mean, geometric standard deviation, geometric coefficient of 
variation, arithmetic mean, standard deviation (SD), median, minimum, and maximum.  The 
changes in PK parameters across the dose range studied may be assessed by comparisons of 
the above variables at each dose level.  BAY 1093884 plasma concentrations will be plotted 
as a function of time for each subject according to dose.  Plots of summary data for each dose 
(geometric mean and arithmetic mean plasma concentrations at each time point) will also be 
presented on both linear and logarithmic scales.  BAY 1093884 plasma levels may also be 
plotted to evaluate the correlation of plasma levels with safety and other endpoints.
PD parameters will be analyzed descriptively and with statistical models where appropriate.
10.3.5
Analysis of safety
The safety profile will be analyzed using the SAF population and safety data collected during 
Part A.  Vital signs, AEs, and laboratory data will be analyzed by descriptive statistics, such 
as summary statistics and frequency tables.  All AEs will be tabulated according to the 
affected system organ class and preferred term, as coded by the medical dictionary for 
regulatory affairs (MedDRA).
Further safety analyses will include all safety data available at the time when Cohort 3 will 
have completed Part A and Part B of the study.  For each subject, safety variables will be 


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analyzed by study part and the respective visits and by dose actually received, both by dose 
cohort and by study medication actually received during the respective interval.  This 
includes safety analyses by dose last received. 
The evaluation of safety data and the version of MedDRA used for coding will be detailed in 
the SAP.
Determination of sample size
10.4
no formal 
determination of sample size was done.
Considering that this is a Phase 2 study for a rare disease, a sample size of 24 is a reasonable 
number to evaluate the safety of a multiple escalating dose of a new drug.  Having the safety 
data of 8 subjects per cohort, a firm clinical understanding of the drug can be obtained 
(4 subjects per cohort have been evaluated for the single dose escalation in the first-in-man 
study).  All safety parameters will be analyzed by descriptive statistics only, no hypothesis 
tests will be performed.  The same holds true for the efficacy analysis.  Therefore, no sample 
size calculation applies for this study
 
 
Planned interim analyses
10.5
After all subjects still participating in the study have completed Part A and at least one 12-
week Part B period (primary completion) of the study, all dose levels will be assessed 
including clinical safety, routine safety laboratory, hemostasis and thrombosis markers as per 
PK/PD assessment and clinical efficacy.
For safety, AEs will be assessed for all subjects per dose level.  In case of comparable clinical 
safety, the routine lab findings will be evaluated.  In case of comparable clinical and 
laboratory safety, thrombosis and hemostasis markers will determine safety evaluation.
For efficacy, the number of subjects without spontaneous bleeds requiring treatment in 
addition to BAY 1093884 will be assessed; all other efficacy variables will be assessed for 
the dose levels observed. 
11.
Data handling and quality assurance
Data recording
11.1
The data collection tools for this study will be an eCRF; a validated electronic data capture 
system called RAVE, and an EPD (see Section 9.4.1) will be used.  Subject data necessary 
for analysis and reporting will be entered/transmitted into a validated database or data system 
(CIE/LSH; SAS).  
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide.  RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies.  RAVE allows for the application of 
CCI
CCI


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software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel.  Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study.  Data queries 
resulting from the application of the software logic are resolved by the site personnel.  The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual 
Private Network.
All access to the RAVE system is through a password-protected security system that is part 
of the RAVE software.  All internal Bayer and external investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer's clinical studies.  Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry 
can proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made, and the date and 
time it was made.  This information is available both at the investigator’s site and at Bayer.  
Data entries made in the RAVE EDC screens are supported by source documents maintained 
for all subjects enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation.  A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with 
the site to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site. EPD data will be considered source documentation.
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (subject number; year of birth/age; sex; if applicable,
race/ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit.  
These data will be transferred to the respective database.


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For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:

All information related to the SAE such as: 
- The SAE itself
- Concomitant medication
- Medical history
- Other information needed for SAE complementary page
Monitoring
11.2
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
Data processing
11.3
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on CRF as well as for data from other 
sources (e.g., IWRS, laboratory, ECG).
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used.
Missing data 
11.4
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF). 
Audit and inspection
11.5
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or 
a designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 


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performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues.  Audits and inspections may occur at any 
time during or after completion of the study.
Archiving
11.6
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
At the end of the study, sites will receive their EPD data electronically for archiving.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
- Safety findings from this study (e.g., SAEs)
- Results of any interim analysis
- Results of parallel clinical studies
- Results of parallel animal studies 
(e.g., toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.


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For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final 
decision on the closure must be in writing.

All affected institutions (e.g., IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification for destruction is given by the sponsor.

In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 6.3.1.
13.
Ethical and legal aspects
Investigators and other study personnel
13.1
13.1.1
Investigators
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; 
an abbreviated version with personnel relevant for the centers will be available in each 
center’s investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, ethics committee, sponsor) 
before subject recruitment may start at the respective center.  Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before taking effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
13.1.2
External bodies
In this study, there will be a Steering Committee (SC) and a Data Monitoring Committee 
(DMC).
Steering Committee (SC)
The SC will consist of external key experts in the field of hemophilia.  It will advise on all 
scientific aspects on the study.


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A separate SC Charter will describe roles and responsibilities as well as the cooperation with 
the sponsor in detail.
Data Monitoring Committee (DMC)
The primary role of the DMC is the regular review of the safety data and provision of 
recommendations for dose escalation to the next dose level. 
The DMC will consist of a chair and members who have recognized expertise in clinical 
trials and in the field of hemophilia as well as biostatistics.  They are not members of the SC
or involved as investigators or otherwise in the trial. 
A separate DMC Charter will describe roles and responsibilities of the committee in detail.
The DMC will review key safety data throughout the study, including the extension part, and 
may issue recommendations on:
Dose opening
Based on safety evaluation of the first 6 subjects after the first 6 weeks of treatment at each 
dose cohort, DMC will recommend escalation to the next dose level.  This also includes the 
evaluation of the 6 subjects on the Z dose and the subsequent advice on proceeding with the 
extension part.
Dose escalation
Subjects are allowed to escalate to the next dose only after DMC has opened that dose.  
Subjects from dose X can only escalate to dose Y and cannot escalate directly to dose Z, even 
if the z dose has already been opened by the DMC.
Adverse events review
If any of the events listed in Section 9.6.1.7 occurs, an ad hoc DMC meeting will be held.
Funding and financial disclosure
13.2
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
Ethical and legal conduct of the study
13.3
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 


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Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and forwarded to the sponsor.  Upon request, the responsible unit 
(e.g., IEC/IRB, head of the study center/medical institution) must supply the sponsor with a 
list of the IEC/IRB members involved in the vote, and a statement confirming that the 
IEC/IRB is organized and operating according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor 
may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As 
soon as possible, the implemented deviation or change, the reasons for it and if appropriate 
the proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/ sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
Subject information and consent
13.4
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject/legal representative or proxy consenter (if the subject is 
under legal protection), prior to his entry into the study (i.e., before any examinations and 
procedures associated with the selection for the study are performed or any study-specific 
data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each subject/legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  

The subject’s consent covers end-of-study examinations as specified in the visit 
descriptions in Section 9.2 to be conducted after withdrawal of consent.  

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 

Subject material obtained before withdrawal may be used to generate subject-specific 
data after withdrawal (e.g., image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The subject has the right to object to the 
generation and processing of this post-withdrawal data.  The subject’s oral objection 
may be documented in the subject’s source data.
Each subject/legal representative or proxy consenter will have ample time and opportunity to 
ask questions.
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he enter the study.  Additionally, the 
investigator will personally sign and date the form.  The subject/legal representative or proxy 
consenter will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
For the optional pharmacogenetics testing, a separate informed consent will additionally be 
obtained according to the procedures described above.
1. If the subject is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the sponsor and 
the investigator).  This is to be documented by a signature from the informing 
physician as well as by a signature from the witness.
2. In emergency situations, when prior consent of the subject is not possible, the consent 
of the subject’s legal representative(s) or proxy consenter, if present, should be 
requested.  The subject should be informed about the study as soon as possible and his 
consent to continue the study should be requested.
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and/or the 
written informed consent form.  The investigator will inform the subject/legal representative 
or proxy consenter of changes in a timely manner and will ask the subject to confirm his 
participation in the study by signing the revised informed consent form.  Any revised written 


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informed consent form and written information must receive the IEC/IRB`s 
approval/favorable opinion in advance of use.
Publication policy and use of data
13.5
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.  
Compensation for health damage of subjects/insurance
13.6
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
Confidentiality
13.7
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF, and if the subject name appears on any other document (e.g., pathologist report), 
it must be obliterated before a copy of the document is supplied to the sponsor.  Study 
findings stored on a computer will be stored in accordance with local data protection laws.  
As part of the informed consent process, the subjects will be informed in writing that 
representatives of the sponsor, IEC/IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available 
for inspection will be handled in strictest confidence and in accordance with local data 
protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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14.
Reference list
1.
Berntorp E, Boulyjenkov V, Brettler D, Chandy M, Jones P, Lee C, et al. 
Modern treatment of haemophilia. Bull World Health Organ. 
1995;73(5):691-701.
2.
MASAC. MASAC Recommendation concerning prophylaxis. National 
Hemophilia Foundation. 2016;Document #241 (Replaces #179).
3.
Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' 
experience of prophylactic treatment in severe haemophilia A and B. J Intern 
Med. 1992;232(1):25-32.
4.
Oldenburg J, Dolan G, Lemm G. Haemophilia care then, now and in the 
future. Haemophilia : the official journal of the World Federation of 
Hemophilia. 2009;15 Suppl 1:2-7.
5.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, 
Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia : 
the official journal of the World Federation of Hemophilia. 2013;19(1):e1-
47.
6.
Berntorp E, Dolan G, Hay C, Linari S, Santagostino E, Tosetto A, et al. 
European retrospective study of real-life haemophilia treatment. 
Haemophilia : the official journal of the World Federation of Hemophilia. 
2017;23(1):105-14.
7.
Di Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A. Cost of 
care of haemophilia with inhibitors. Haemophilia : the official journal of the 
World Federation of Hemophilia. 2010;16(1):e190-201.
8.
Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan 
V, et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in 
Hemophilia A. N Engl J Med. 2016;374(21):2054-64.
9.
Brown TM, Lee WC, Joshi AV, Pashos CL. Health-related quality of life 
and productivity impact in haemophilia patients with inhibitors. 
Haemophilia. 2009;15(4):911-7.
10.
Darby SC, Keeling DM, Spooner RJ, Wan Kan S, Giangrande PL, Collins 
PW, et al. The incidence of factor VIII and factor IX inhibitors in the 
hemophilia population of the UK and their effect on subsequent mortality, 
1977-99. J Thromb Haemost. 2004;2(7):1047-54.
11.
Morfini M, Haya S, Tagariello G, Pollmann H, Quintana M, Siegmund B, et 
al. European study on orthopaedic status of haemophilia patients with 
inhibitors. Haemophilia : the official journal of the World Federation of 
Hemophilia. 2007;13(5):606-12.
12.
Tjonnfjord GE, Holme PA. Factor eight inhibitor bypass activity (FEIBA) in 
the management of bleeds in hemophilia patients with high-titer inhibitors. 
Vasc Health Risk Manag. 2007;3(4):527-31.


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13.
Allen G, Aledort L. Therapeutic decision-making in inhibitor patients. Am J 
Hematol. 2006;81(1):71-2.
14.
Ananyeva NM, Lee TK, Jain N, Shima M, Saenko EL. Inhibitors in 
hemophilia A: advances in elucidation of inhibitory mechanisms and in 
inhibitor management with bypassing agents. Semin Thromb Hemost. 
2009;35(8):735-51.
15.
HEMLIBRA. HEMLIBRA® (emicizumab-kxwh) injection, for 
subcutaneous use. US Prescribing Information. 2017.
16.
Welsch DJ, Novotny WF, Wun TC. Effect of lipoprotein-associated 
coagulation inhibitor (LACI) on thromboplastin-induced coagulation of 
normal and hemophiliac plasmas. Thrombosis research. 1991;64(2):213-22.
17.
Erhardtsen E, Ezban M, Madsen MT, Diness V, Glazer S, Hedner U, et al. 
Blocking of tissue factor pathway inhibitor (TFPI) shortens the bleeding 
time in rabbits with antibody induced haemophilia A. Blood coagulation & 
fibrinolysis : an international journal in haemostasis and thrombosis. 
1995;6(5):388-94.
18.
Hendrikx J, Haanen J, Voest EE, Schellens JHM, Huitema ADR, Beijnen 
JH. Fixed Dosing of Monoclonal Antibodies in Oncology. The oncologist. 
2017;22(10):1212-21.
19.
Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I,
et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe 
hemophilia A. Blood. 2014;123(3):317-25.
20.
Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et 
al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia 
B. N Engl J Med. 2013;369(24):2313-23.
21.
Ewing N, Escuriola-Ettingshausen C, Kreuz W. Prophylaxis with FEIBA in 
paediatric patients with haemophilia A and inhibitors. Haemophilia : the 
official journal of the World Federation of Hemophilia. 2015;21(3):358-64.


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15.
Protocol amendments
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 4
15.1
Integrated protocol Version 2.0, dated 26 JUN 2018
15.1.1
Overview of changes to the study
Table of main changes
Section # & Name
Description of Change
Brief Rationale
3  Introduction
Text describing the product 
updated to include most recent data 
from the ongoing First in Man 
Phase 1 study
Update of data available for BAY 
1093884
2  Synopsis
5  Study design
7.4.1  Selection of doses in the 
study
Dose escalation criteria and safety
rules between cohorts added in 
addition to those already described 
within cohorts/subjects
Present a more detailed version of 
the study design
2  Synopsis
5  Study design
7.1.1  Prophylaxis treatment with 
BAY 1093884
7.4.1  Selection of doses in the 
study
7.4.1.1  PK/PD criteria for dose 
recommendations
9.6.1.7  Adverse events requiring 
an ad hoc DMC meeting
13.1.2  External bodies
Text added providing further detail 
on the role and responsibilities of 
the DMC
Clearly describe the safety 
oversight and decision process of 
the DMC
5  Study design
Text added describing the rationale 
for fixed doses
Provide justification for change 
from weight-based doses to fixed 
doses
5  Study design
Communication plan added
Description of methods for 
communicating safety data and 
dose escalation decisions to 
investigator sites
6.3.2  Replacement
Text added stating that subjects 
may be replaced only if they have 
not withdrawn from the study for 
drug-related safety concerns
Clarification of description of when 
subjects may be replaced.


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Section # & Name
Description of Change
Brief Rationale
7.1.2  Treatment of bleeds
8.1  Prior and concomitant therapy 
(including treatment of bleeds)
Guidance added for use of 
bypassing agents to treat bleeds 
during treatment with BAY 
1093884
Intensity and location of trauma for 
which bleeding has not yet 
occurred must be considered by 
investigator prior to initiating 
preventative treatment with a 
replacement factor or bypassing 
agent.
7.1.3  Treatment of PK/PD 
assessments
8.2  Post-study therapy
9.1  Tabular schedules of 
evaluations
9.2.1.10  Every 12 weeks visit (± 7 
days calculated from Visit 2)
9.2.2.15  Every 12 weeks visit (± 7 
days calculated from Visit 2)
Every 24-week visit changed to 
frequency of every 12 weeks
Additional safety monitoring of 
subjects
7.2  Identity of study treatment
Dose strength changed from “100 
mg/mL” to “either 100 mg/mL or 
150 mg/mL”
Introduction of 150 mg/mL dose 
strength
7.4.1.1  PK/PD criteria for dose 
recommendations
Additional detail provided on the 
amount and type of safety, PK and 
PD data collected
Further describe the amount of 
safety, PK and PD data collected in 
order to open next dose cohort
9.2.1  Visit description for non-PK 
subjects
9.2.2  Visit description for PK 
subjects
Local ECG added at Visits 3 – 7 
and every 12 week visits
Additional safety monitoring
9.2.1.3  Visit 2 – Start of BAY 
1093884 treatment at the 
respective dose (≤6 weeks after 
Visit 1)
9.2.2.3  Visit 2.1 – Start of BAY 
1093884 treatment at the 
respective dose (≤ 6 weeks after 
Visit 1) and 1st PK day 0
LDL added to blood samples 
collected at Visit 2
Additional safety laboratory 
collection
9.6.1.2.2  Intensity
AE intensity should be graded 
according to NCI CTCAE version 
5.0
Updated guidance for the 
assessment of AEs
9.6.1.5  Reporting of medical 
device failures
Section added describing reporting 
of non-approved medical device 
failures
Guidance specific to Japan sites for 
reporting of non-approved medical 
device failures


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Section # & Name
Description of Change
Brief Rationale
9.6.1.6  Dose-limiting toxicities
Section added to define DLTs for 
the study
Additional safety guidance on the 
reporting of DLTs
9.6.3.1  Clinical laboratory 
assessments
Lactate dehydrogenase and 
fibrinogen added to standard safety 
laboratory analyses
Additional safety laboratory blood 
samples
9.6.3.1  Clinical laboratory 
assessments
Immunoglobulins will be collected 
for hypersensitivity reactions
Addition of immunoglobulins to 
blood tests collected for 
hypersensitivity reactions
9.6.3.1  Clinical laboratory 
assessments
LDH added to central laboratory 
tests for thromboembolic and 
thrombotic microangiopathic 
events
Additional safety laboratory 
collection
9.6.3.4  Electrocardiogram
Section added to note that ECGs 
will be performed at PK visits
Description of ECG safety 
assessment schedule
2  Synopsis
10.3  Variables and planned 
statistical analyses
Injection site reactions removed as 
separate endpoint, as these will be 
collected as part of regular AE 
reporting
Remove redundant endpoint of 
injection site reaction
12  Premature termination of the 
study
Note pertaining to DMC review of 
thromboembolic or thrombotic 
microangiopathic events removed, 
as this is now described in new 
section 9.6.1.7
Remove redundant DMC review 
text regarding thromboembolic or 
thrombotic microangiopathic 
events
Table of corrections and clarifications
Section # & Name
Description of Change
6.1  Inclusion criteria
Inclusion criteria 1 and 2 combined into one criterion, as subjects cannot 
satisfy both criteria. Content of criteria not changed.
2  Synopsis
6.2  Exclusion criteria
Exclusion criterion 12 text updated to clarify that patients receiving 
treatment with an investigational drug 3 months prior to the screening 
visit are excluded. 
6.3.1  Withdrawal
10.5  Planned interim analysis
Definition of completer updated to specify that at least one Part B 
segment must be completed by the subject.
7.1.1  Prophylaxis treatment with 
BAY 1093884
Frequency of administration updated from “once weekly” to “every 7 
days ± 1 day” for consistency with description of visit schedule.
8.1  Prior and concomitant therapy 
(including treatment of bleeds)
Wording simplified to state that no immunomodulatory drugs are allowed 
during the study.


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Section # & Name
Description of Change
Table 9-2B
Table 9-3B
Part B and subsequent visits combined into one column, as procedures are 
identical at these visits
Table 9-2A
Table 9-2B
9.2.1.1  Visit 1 – Screening visit
Table 9-3A
Table 9-3B
9.3.5  Pharmacogenetic testing –
optional
Clarification that pharmacogenetic sample may be collected at any time 
point during the study once separate consent is obtained, not just Visit 1
9.4  Efficacy
 efficacy variable of primary interest clarified to note that the 
number of subjects in each 12-week Part B period, as opposed to Part B 
overall, will be observed
10.1  General considerations
10.3.3  Analysis of efficacy
Description of Part B clarified to note that there are multiple 12-week 
periods after Part A
10.3.3  Analysis of efficacy
Sentence added: “It should be noted that this kind of analysis must be 
interpreted carefully, as the restriction is based on post-baseline events.”
Typographical, grammatical, and other minor edits are not identified.
15.1.2
Changes to the protocol text
Changes to the protocol text are provided in a separate track changes version.
Amendment 5
15.2
Integrated protocol Version 3.0, dated 12 FEB 2019
15.2.1
Overview of changes to the study
Table of main changes
Section # and name
Description of change
Brief rationale
Table 9-1  Visit schedule overview
Table 9-2  Tabular schedule of 
assessments (subjects not 
participating in PK evaluations; 
Screening and Part A)
Table 9-3  Tabular schedule of 
assessments (subjects not 
participating in PK evaluations; 
Part B through end of study)
The visit schedule was updated to 
include an additional safety visit 6 
weeks (± 1 day) after dose 
escalation.  
This change will allow for 
additional safety monitoring of 
study subjects after escalation to a 
higher dose.
CCI


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Section 9.2.1.8  Visit 6 (12 weeks 
± 1 day after Visit 2) assessment 
of dose escalation
Section 9.2.1.11  Additional safety 
visits after dose escalation (if 
applicable)
Table 9-5  Tabular schedule of 
assessments (subjects 
participating in PK evaluations; 
Part B through end of study)
Section 9.2.2.13  Visit 6.4 – 2nd PK 
Day 7 (168 h) and assessment of 
dose escalation
Section 9.2.2.16  Additional safety 
visits after dose escalation (if 
applicable)
Section 2  Synopsis
Section 6.1  Inclusion criteria
Inclusion criterion 1 was modified 
to specify that subjects with 
inhibitors against FVIII or FIX 
also have undetectable FVIII or 
FIX levels.
DMC recommendation
Section 2  Synopsis
Section 6.2 Exclusion criteria
Exclusion criterion 10 was 
modified to more accurately 
describe advanced liver disease.
DMC recommendation
Table of corrections and clarifications
Section # & Name
Description of Change
3  Introduction
The portion of the section presenting information on the product was 
updated to refer the reader to the “current version of the IB” instead of 
version 3.
7.2  Identity of study treatment
Vial size was corrected from 2 mL to 10 mL.
The contents of the 150 mg/mL vial were corrected from 1.6 mL to 1.8 
mL of BAY 1093884. 
9.2.1.11  Additional safety visits 
after dose escalation (if 
applicable)
The ECG erroneously omitted in amendment 4 was added to the 
description of the additional safety visit.
9.2.2.9  Phone call (3 weeks ± 2 
days after Visit 5)
The time window of the phone call at Week 9 was corrected from ±1 day 
to ±2 days.
9.6.3.1  Clinical laboratory 
assessments
The unit of measure for FVIII/FIX testing was corrected from BU to 
BU/mL.
Typographical, grammatical, and other minor edits are not identified.


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15.2.2
Changes to the protocol text
Changes to the protocol text are provided in a separate track changes version.


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Version 4.0
Page: 94 of 96
16.
Appendices
Hemophilia Joint Health Score
16.1


Integrated Clinical Study Protocol
BAY 1093884 / 19580
05 APR 2019
Version 4.0
Page: 95 of 96
Subject ID#:. ______ _ 
Name of Physiotherapist: _______ _ 
Assessment# : 
Date: ------
Time: 
YYW I mm I dd 
Hemo1plliilia Joint Health Score 2.1 - Summan-- Scoire Sheet 
Swelling 
(swellina} 
Muscle Atrc:mhv 
Crepi~us on motion 
IFrexion Loss 
Extension Loss 
Joint Pain 
Strength 
Joint Total 
Sum of JointTotals 
Global Gait Soore 
Left El bow 
Right Elbow 
Dr.1: 
Dr.1: 
lJ NE 
O tt: 
+ 
Left !Knee 
Right Knee 
Lett All klle 
!Right Ankle 
O tt: 
INE = Non -Evalu:al>l.e 
(D rE included in Gail items) 
HJIH S Total Soore 
SwellingI 
O= N'oSY/efnoJ 
1 = Mild 
2 = Mbdera:e 
3 = Sarere 
IJuration 
0 = N'o swe.l!DJ 
er < 6, mooths 
1 = 6, mcnlhs 
M'11scle Atrophy 
O= N'ooe 
1 = Mild 
2= Se,rere 
JointPai11 
-
Orepirus on Motion 
O= None 
1= Mld 
2 = Sel/€!fe 
Fleidon loss 
= <5" 
1 = 5•·- 10'" 
2 = 
3 = > 20' 
Exte:11sion 1:oss 
{from h~~nsion) 
= <5" 
1 = -,. - 10'" 
2 = 1 1''- 2(],• 
3 = >20' 
O = N'o pain through acoue range of motion 
1 = N'o pain through a • e range; miy pain oo 
gen 
01re1pre-ssiie er pa'.pallbn 
2 = Pm lhrnv, adive r.K'IQe 
Stre:11gtil (llsillg The Daniels & Worthingham"s sca;le) 
~',Im aval3ble ROM 
0 = l-£dlds n,,51 po:sitioo "9 · 
ga'fli'/ ~lith ~
Lnl resistance ( ,gr. - ) 
1 = H'dlds n,,51 po:sitioo "9 · 
gaJ • ~lith moderate re~t317ce 
(llut breaks ~lith m.minal l'eSistance} ( 1T.4 ) 
2 = H'dlds n,,51 po:sitioo 
h minimal resistmce ( IT- 31-), 
er hotls test pooiioo agains1,gra'Llitj ( gr.3 } 
3 = l>ble l.o partially co~le1E ROM .against gravity ( IT .3-12+ ), 
er~ lo mc,-e 1hro19'1 ROM graiiity eliminated (gr.2), 
er througi 
ROM graiiity eliminated ( IT 2 -) 
= Trace ( gr.1)or no muscle oonca.alirn ( gr.O} 
E = Non-eval~e 
Global GaiIt (w.alking, st:afrs, running, hopping an 
leg) 
O= A'I 
arce~m
noonal llinrtts 
1 = Cne skill · not within normal lirrits 
2 = Two skills aie net WJhin normal limits 
3 = Three-~ 
arre not ~lithin normal limits 
= N'o skills are wlilhin norma limits 
fl/IE= N:m-eusl~e 
fr4OTlE: Th.ere ns an aooornpa11ying instrucilio 111 rnan.ua and worksh.eets that are required when adminis.teri11gI the HJHS 
General Comments: 
20 11-01-31 


Integrated Clinical Study Protocol
BAY 1093884 / 19580
05 APR 2019
Version 4.0
Page: 96 of 96
The HJHS is designed for use by physiotherapists. In order to maintain t he precision and va lidity of the tool 
(score), the developers of the tool strongly recommend that the tool be used by physiotherapists/healthcare 
professionals who have hemophilia-related expertise/experience and have been t rained in the use of cl inical 
measures, musculoskeletal assessment and specifically administration of the HJHS. 
It is essential for t he physiotherapist to possess the requ ired expertise and skills necessary to use 
anthropometric measures such as muscle testing-and range of mot ion / goniometry, as well as posture & gait 
assessment prior to performing the evaluation (HJHS). 

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
Multiple escalating dose study of BAY 1093884 in adults with 
hemophilia A or B with or without inhibitors 
NCT Number: 
NCT03597022 
Document Date: 
10-MAR-2020 
 




 
Additional Statistical Analysis Plan  
for abbreviated CSR 
 
 
Protocol No.: BAY 109-3884/19580 
Page: 2 of 3
 
Reference Number: RD-SOP-1119 
Supplement Version: 5 
Preamble  
This Statistical analyses plan is for the documentation of post-hoc analyses for publishing 
purposes.  
 
Table of Contents 
Title page ............................................................................................................................... 1 
1. 
Annualized Bleeding rates ............................................................................................ 3 
2. 
Individual Lab plot ....................................................................................................... 3 
3. 
PK/PD individual plots ................................................................................................. 3 
 
 
 


 
Additional Statistical Analysis Plan  
for abbreviated CSR 
 
 
Protocol No.: BAY 109-3884/19580 
Page: 3 of 3
 
Reference Number: RD-SOP-1119 
Supplement Version: 5 
1. 
Annualized Bleeding rates 
The number of bleeds and annalized bleeding rate is shown by treatment arm. The table 
differentiates the bleeds into all bleeds and spontenous bleeds. In addition, these bleeds are 
separated by treated and untreated bleeds. For the number of bleeds the 24 hours rule as well 
as the 72 hours rule as descriped in SAP sections 4.5.3 and 4.5.4 apply. Use SAS code from 
Kovaltry and/or Jivi as reference.  
The annualized bleeding rate is defined as  
ሺ# 𝑜𝑓 𝑏𝑙𝑒𝑒𝑑𝑠 𝑖𝑛 𝑑𝑎𝑡𝑎 𝑠𝑐𝑜𝑝𝑒 𝑡𝑖𝑚𝑒ሻ∙365.25
ሺ𝑙𝑎𝑠𝑡 𝑑𝑎𝑡𝑒 𝑖𝑛 𝑑𝑎𝑡𝑎 𝑠𝑐𝑜𝑝𝑒െ𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑡𝑒 𝑖𝑛 𝑑𝑎𝑡𝑎 𝑠𝑐𝑜𝑝𝑒൅1ሻ 
The following data scopes will be analysed: 
 Bleeds in 6 months before randomization. The last date of data scope is the day of 
randomization, the irst date in data scope is 6 months before, i.e. the time in the data 
scope is fixed at 183 days. This bleeds will be shown by dose initially received. 
 Dose initially given: First date in that data scope is defined as first intake of the study 
treatment. Last date is the date of the intake of any study drug. Show bleeds for 
combined Part A and Part B (whole study time), as well es for Part A (last date is the 
end of Part A in this case) and Part B (first date is the start of Part B in this case). 
 Dose actually given: show for the dose actually given the annualized bleeding rates in 
Part B  - for patients that get escaled in Part B the last date in the data scope for a 
specific dose is the day the escalation into the higher dose group. For these patients the 
first day is the new dose group is the first date of the data scope for Part B and that 
escalated dose group is the day of the escalation. 
Subgroup analyses will be performed by previous treatment. 
2. 
Individual Lab plot 
Show table CLIPS LB1C and figure CLIPS LB-F2 for available laboratory parameter and 
subjects. 
3. 
PK/PD individual plots 
Show figure CLIPS PK-F2 for available PK/PD parameter. 
 
 




 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 2 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
Table of Contents 
 
Title page ............................................................................................................................... 1 
Abbreviations ........................................................................................................................ 3 
1. 
Introduction ................................................................................................................... 3 
2. 
Study Objectives ............................................................................................................ 6 
3. 
Study Design .................................................................................................................. 6 
4. 
General Statistical Considerations .............................................................................. 9 
4.1 
General Principles ........................................................................................................ 9 
4.2 
Handling of Dropouts .................................................................................................. 9 
4.3 
Handling of Missing Data .......................................................................................... 10 
4.4 
Interim Analyses and Data Monitoring ..................................................................... 10 
4.5 
Data Rules .................................................................................................................. 10 
4.5.1 
Baseline values ....................................................................................................... 10 
4.5.2 
Annualized bleed rate ............................................................................................. 11 
4.5.3 
24 hours rule ........................................................................................................... 11 
4.5.4 
72 hours rule ........................................................................................................... 11 
4.6 
Blind Review ............................................................................................................. 12 
5. 
Analysis Sets ................................................................................................................ 12 
5.1 
Assignment of analysis sets ....................................................................................... 12 
6. 
Statistical Methodology .............................................................................................. 12 
6.1 
Population characteristics .......................................................................................... 13 
6.1.1 
Demography and baseline characteristics ............................................................... 13 
6.1.2 
Medical history ....................................................................................................... 13 
6.1.3 
Disease history ........................................................................................................ 13 
6.1.4 
Medication history .................................................................................................. 14 
6.2 
Efficacy ...................................................................................................................... 14 
6.2.1 
Additional analyses................................................................................................. 15 
6.2.2 
Subgroup analysis ................................................................................................... 15 
6.3 
Pharmacokinetics/pharmacodynamics ....................................................................... 16 
6.4 
Safety ......................................................................................................................... 16 
6.4.1 
Adverse events ........................................................................................................ 16 
6.4.2 
Vital signs ............................................................................................................... 17 
6.4.3 
Laboratory parameter ............................................................................................. 17 
6.4.4 
Subgroup analysis ................................................................................................... 18 
6.4.5 
Pregnancies ............................................................................................................. 18 
7. 
Document history and changes in the planned statistical analysis ......................... 18 
8. 
References .................................................................................................................... 18 
9. 
Appendix ...................................................................................................................... 18 
9.1 
Determination of sample size .................................................................................... 18 
 
 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 3 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
Abbreviations 
 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CRF 
Case report form 
DIR 
Dose initially recived  
DMC 
Data Monitoring Committee 
eCRF 
Electronic case report form 
EU 
European Union 
FIX 
Factor IX 
FVIIa 
Activated factor VII 
FVIII 
Factor VIII 
FX 
Factor X 
FXa 
Activated factor X 
IgG2 
Immunoglobulin G2 
ISR 
Injection site reaction 
ITI 
Immune tolerance induction 
IV 
Intravenous 
LOS 
Listing only set 
mAb 
Monoclonal antibody 
MedDRA 
Medical dictionary for regulatory activities 
OD 
On demand 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
SAE 
Serious adverse event 
SAF 
Safety (set) 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
TF 
Tissue factor 
TFPI 
Tissue factor pathway inhibitor 
US 
United States (of America) 
 
1. 
Introduction 
This SAP is based on Study Protocol version 2.0 (dated 26 JUN 2018). 
Background 
Hemophilia A and B are genetic bleeding disorders caused by the deficiency of Factor VIII 
(FVIII) or Factor IX (FIX), respectively.  Persons with mild hemophilia (6% – 49% Factor 
level) may have excessive bleeding following dental procedures, injury or surgery, while 
moderate (1% to 5% factor activity) and severe (< 1% factor activity) hemophilia are typically 
characterized by more frequent and severe bleeding complications.  Persons with severe 
hemophilia may experience not only bleeding after injury, trauma or surgery, but also 
spontaneous bleeding into joints, muscles and internal organs, including the brain.  Recurrent 
bleeding into joints results in chronic debilitation.   
The standard treatment for hemophilia A or B is replacement therapy, with intravenous (IV) 
administration of plasma-derived or recombinant FVIII or FIX, respectively.  Some subjects 
treat bleeding episodes as they occur (i.e., on-demand [OD] treatment), while others treat 
themselves prophylactically to prevent bleeding according to the recommendations from the 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 4 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
World Health Organization.  In recent years, prophylactic treatment has become the 
prevailing type of hemophilia treatment in most developed countries.  
The proven clinical benefits of prophylaxis have led to a shift in treatment paradigm from OD 
treatment to the use of prophylaxis in many countries. 
Better outcomes of prophylaxis versus OD treatment regimen are proven, but three major 
challenges characterize prophylactic treatment: the need for IV injections, the relatively high 
bleeding rate and the most significant treatment complication, the development of inhibitors. 
Despite frequent and painful IV injections (and the subsequent frequent need for central 
venous access devices in young children), subjects on prophylaxis still bleed, with a median 
annualized bleeding rate of up to 6 bleeds, thus, leaving a high unmet medical need for better 
protection. A higher level of protection is in some cases achievable only by increasing the 
burden of treatment (more frequent injections), to reduce the clotting factor fluctuations that 
characterize replacement factors treatment (presence of peaks and troughs).  
Effective treatment options are significantly lower if inhibitory antibodies against the FVIII or 
FIX (inhibitors) develop.  The inhibitors interfere with the infused factor concentrates 
rendering them ineffective and requiring the use of more costly and less effective alternative 
hemostatic agents, defined as “bypassing agents”.  The incidence of new FVIII inhibitors in 
subjects with severe FVIII deficiency is up to 45%.  Inhibitor development is currently the 
most significant treatment complication seen in subjects with hemophilia.  While 
improvements in hemostatic agents for subjects with inhibitors have resulted in decreased 
mortality, inhibitors are still associated with significant morbidity, including a higher rate of 
bleeding complications, increased disability, and a decreased quality of life. 
As such, these bypassing agents are effective in most cases, but neither agent is universally 
effective and there is no prophylaxis option for subjects with hemophilia B and inhibitors, as 
NovoSeven is not licensed for prophylaxis in EU and US.   
HEMLIBRA (emicizumab-kxwh) is currently approved in the US for subcutaneous routine 
prophylaxis in hemophilia A subjects with inhibitors, however, mimicking the action of 
activated FVIII (FVIIIa), it does not provide a steady state protection (variable rates of 
fluctuation with potential low levels at the end of the injection interval). Additionally, it 
carries a black box warning of thrombotic microangiopathy and thromboembolism when used 
with aPCC/FEIBA for the treatment of breakthrough bleeds. 
There is currently no treatment available to provide constant protection against bleeding 
episodes, to lower burden of treatment, and to avoid risk of FVIII/FIX inhibitor development 
for the entire hemophilia population, regardless of the FVIII or FIX deficiency status or the 
presence of FVIII or FIX inhibitors. 
BAY 1093884 may address all these unmet needs, representing a valid treatment option for 
all subjects with hemophilia.  
The coagulation cascade and the role of tissue factor pathway inhibitor (TFPI) 
In the cell-based model, the coagulation is initiated (the Initiation Phase) by the formation of 
a complex between the tissue factor (TF), exposed on the surface of fibroblasts as result of 
vessel injury, and activated factor VII (FVIIa), normally present in the circulating blood. The 
TF-FVIIa complex converts factor X (FX) in activated FX (FXa), which activates 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 5 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
prothrombin (FII) to thrombin (FIIa). In this Amplification Phase, due to this limited amount 
of thrombin, FVIII and FIX are activated and involved in the following Propagation Phase, 
where full thrombin generation takes place, enabling for clot formation. 
According to this model, the TF extrinsic pathway is the principal cellular initiator of normal 
blood coagulation in vivo, and the major regulator of hemostasis and thrombogenesis, with 
the intrinsic pathway playing an amplification role. 
In people with hemophilia, the TF initiated extrinsic coagulation pathway is intact, so a 
question may rise on why these people do bleed. The explanation is provided by the fact that 
the TF activity and the extrinsic pathway of blood coagulation are regulated by a specific and 
natural coagulation inhibitor: the tissue factor pathway inhibitor – TFPI.  
In healthy individuals TFPI maintains a normal hemostatic balance (it is in fact considered a 
natural anticoagulant) while in people with hemophilia it further reduces the already 
insufficient thrombin due to the lack of FVIII or FIX. 
Thus, the inhibition of TFPI through the administration of anti-TFPI antibodies 
(BAY 1093884) is expected to restore the hemostatic balance toward normal thrombin 
generation, and thus a potential mechanism to restore hemostasis in hemophilia subjects. 
The product 
BAY 1093884 is a human monoclonal IgG2 antibody with a novel mechanism of action based 
on blocking the function of endogenous TFPI.  
TFPI usually consists of 3 Kunitz domains (K1, K2, K3). The primary anticoagulant 
properties of TFPI are mediated through the K1 and K2 domains. BAY 1093884 binds to both 
K1 and K2 domains, blocking TFPI inhibition of key factors (FXa via K2, and FVIIa/TF 
complex via K1) in the tissue factor initiated coagulation pathway. K3 binds to Protein S, 
which is not directly inhibiting the protease function. 
BAY 1093884 has been optimized for affinity. The effect of neutralizing TFPI with BAY 
1093884 has been evaluated and demonstrated in several in vitro and in vivo studies, showing 
prolonged efficacy compared to current bypass therapies. As a monoclonal antibody (mAb), 
BAY 1093884 also offers the opportunity of subcutaneous (SC) administration, while other 
currently available hemophilia treatments have to be administered intravenously. 
The goal of TFPI inhibition is to restore normal levels of FXa, and thus correct the low levels 
of thrombin generated due to deficiency of either FVIII or FIX, independent of whether the 
deficiency results from ineffective production, or results from presence of inhibitory 
antibodies directed against either protein.  TFPI inhibition targets a normal regulatory protein, 
and consequently is not a pro-coagulant.  Thus, normal events that lead to initiation of 
coagulation at a site of injury are unaffected.  Additionally, TFPI inhibition does not interfere 
with downstream mechanisms that protect from or turn off thrombin generation, thus 
regulation of thrombin and fibrinolysis remain intact, with a consequent favorable safety 
profile. 
The overall nonclinical toxicology and safety profile of BAY 1093884 lends to support 
clinical studies with repeated administration of BAY 1093884 in subjects with hemophilia A 
or B with or without inhibitors.  
Further details can be found in the Clinical study protocol, which contains comprehensive 
information on the study drug. 




 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 7 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
patient experiences more than 2 bleeds during the first 12 weeks or more than 1 bleed at any 
12 weeks interval after the first 12 weeks of dosing at a particular dose level. The safety 
criteria to be assessed for this portion of the study (individual dose escalation after 12 weeks 
of dosing in that particular dose cohort) are provided later in this section. 
For each subject, the study is structured in three parts 
Part A. Each subject will be treated with the allocated dose of BAY 1093884 (X mg, Y mg or 
Z mg) for 12 weeks.  These first 12 weeks will allow for primary safety evaluations of each 
dose. 
Part B. Each subject will be treated for additional periods of 12 weeks in duration. After 
evaluation of the number of bleeds at the end of each 12-week period, subjects can be treated 
with the same dose or with the next higher opened dose level. The date when the last subject 
in Cohort 3 (Z dose) has completed Part B, will be the database cut-off date (i.e., primary 
completion date). 
Extension part. After completion of Part B of the Z dose cohort, and upon DMC evaluation 
of safety data from the first 6 patients for 6 weeks in the dose Z cohort, all subjects will be 
invited to continue the treatment in an extension part, at the end of their ongoing Part B 
period. During the extension, all subjects will be evaluated (number of bleeds) every 12 
weeks and escalated to the next higher opened dose, if dose escalation criteria are fulfilled (as 
per Part B). The extension part will continue, pending submission of safety and efficacy data 
to Health Authorities after 12 months from its start and every 12 months thereafter, until 
Marketing Authorization. 
Any bleeding event, which should occur during the study (including the extension part) and 
which requires additional control, will be treated with the subject’s pre-assigned treatment 
(by-passing agent or replacement factor) prescribed by the Investigator pre-study. 
Figure 1 shows a schematic overview of the study design. 
  
Figure 1 Design overview 
 
 
DMC = Data Monitoring Committee. 
Black boxes:  
Part A: Initial 12 weeks of treatment with BAY 1093884 (no escalation) 
Grey boxes:  
Part B: all subsequent groups of 12 weeks of treatment with BAY 1093884 (first 
escalation allowed) 
White boxes:  
Extension part with evaluations every 12 weeks (further escalations allowed) 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 8 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
Solid line arrows:  
Option for dose escalation, if the next higher dose is approved and the subject 
meets the escalation criterion (>2 bleeds in Part A).  
Dotted line arrows:  
Option for dose escalation, if the next higher dose is approved and the subject 
meets the escalation criterion (>1 bleed in 12 weeks). 
At least 24 adult subjects (≥18 years of age) will be enrolled.  If additional safety evaluation is 
needed, a maximum number of 40 subjects may be included. 
Eight (8) new distinct subjects are planned to be enrolled in each of the 3 dose cohorts.  
Opening of the new cohort will only enroll new subjects. These subjects will be treated 
prophylactically with the X Y or Z dose of BAY 1093884 once weekly for 12 weeks (part A).  
At least 1 inhibitor subject (any titer) and 2 PK subjects (willing to undergo full PK 
evaluations) will be enrolled in each cohort.  
All subjects of each cohort will continue on the dose assigned for Part A (12 weeks) to obtain 
safety data and also individual efficacy data.  
Individual subject dose escalation criteria in the dose finding part of the study:  
In this portion of the study, the objective is to identify the appropriate dose(s) for the Phase 3 
study. The dose selection for Phase 3 will be based on both the assessment of safety and 
evidence of efficacy based on individual bleeding control assessed over a 12 week period of 
dosing for each patient.  
Subjects will be evaluated for the number of bleeds occurring during each part of the study. In 
particular, only the bleeds recorded as “spontaneous” (not related to any trauma or activity) 
and requiring additional treatment will be considered for the dose escalation efficacy 
evaluation, and are defined below as “bleeds.”  
Evaluation at the end of Part A:  
Subjects who present ≤2 bleeds during Part A will start Part B and continue on the same 
weekly dose; otherwise (if presenting >2 bleeds) subjects will escalate to the next higher 
opened dose cohort.  
Evaluation at the end of every 12-week period of Part B and extension:  
Subjects who present ≤1 bleed in 12 weeks, during Part B, or during the extension part, will 
continue on the same weekly dose; otherwise (if presenting >1 bleed) subjects will escalate to 
the next higher opened dose cohort.  
Since dose Z is the highest dose, any subject on dose Z who meets the escalation criteria 
described above may withdraw from the study or may continue treatment to provide further 
safety and efficacy data. The decision on treatment continuation is at the subject’s and 
investigator’s discretion.  
The first injection of any new or escalated dose will be given under medical supervision.  
If a subject qualifies for dose escalation based on the number of bleeds, but the next higher 
dose cohort has not been opened, the subject should stay on the current dose and then escalate 
to the next higher dose only after it is opened.  
End of study 
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU). 
Primary completion 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 9 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
The primary completion event for this study is when the last subject in Cohort 3 has 
completed 24 weeks of treatment (end of Part B). 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA).  
All data (efficacy, safety, PK/ PD, and demographic data) will be listed and study summary 
tables will be provided where appropriate.  Variables measured on metrical scales will be 
summarized using descriptive statistics that will include: the number of non-missing 
observations, the arithmetic mean, the sample standard deviation, the median, the minimum 
and maximum, as well as the first and third quartiles where appropriate. Frequency tables will 
be provided for variables measured on ordinal or nominal scales. Tables will display the 
number and percentage of subjects falling within a particular category. 
Data will be displayed by dose cohort and by study medication actually received during the 
respective study parts and their visits. 
Data will be displayed by period of time. This includes: 
 Part A: The first 12 weeks of treatment of each subject. 
 Part B: The additional 12-week periods of treatment after Part A. Each subject will be 
analyzed in the dose cohort he was assigned to (data of dose escalated subjects will be 
not included). 
In general, data will be displayed as measured at each scheduled time point, individual values 
will be presented in listings. 
 
4.2 
Handling of Dropouts 
In this study, all efforts must be taken to engage patients to comply with all study procedures 
and to continue to be followed until the end of the study. 
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has received at least 1 dose of BAY 1093884. A subject is regarded a 
“screening failure” if he terminates the study for any reason (e.g., failure to satisfy the 
selection criteria) prior to the time point used for the definition of “dropout” .   
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject's medical records. 
The number of subjects who prematurely discontinue the study during the treatment phase or 
during the post-treatment observation phase for any reason, as well as the reasons for 
premature discontinuation of study, will be displayed by dose cohort and dose actually 
recived. Baseline characteristics will be displayed by premature discontinuation (yes/no) from 
study. 
Subjects who drop from the study after first administration of study treatment will be included 
in a listing in addition to the inclusion into the SAF. 


 
Statistical Analysis Plan 
 
 
Protocol No.: BAY 1093884 / 19580 
Page: 10 of 19
 
Reference Number: RD-OI-0119 
Supplement Version: 9.0 
4.3 
Handling of Missing Data 
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF).  
General rules 
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data: 
 Efficacy Variables 
If the details of a bleed are missing (e.g., type of bleed spontaneous, non-
spontaneous/non-traumatic or traumatic), the bleed will be counted for all categories 
of bleeds, but not for the corresponding subgroup of bleeds.  
Each subject’s bleeding period start date will be needed to allocate the bleedings to the 
respective period. If dates for bleeds and injections of rescue medication are both 
missing then these bleeds cannot be counted. If the bleed date is missing, but the 
injection date is available, injection date will be used. 
 AE Variables 
For the purpose of treatment-emergent flags, missing AE start day will be imputed as 
the 15th of the month. However, if the AE start day is missing, but the AE starts 
suring the same month or on the same day as the first dose, but the AE start time is 
missing, the AE start day (and time in the second case) will be taken from first dose 
start day (and time). If both day and month of AE start date are missing, day and 
month will be imputed as the date of the first dose. 
4.4 
Interim Analyses and Data Monitoring 
An independent Data Monitoring Committee will review safety data according to the DMC 
charter.  No alpha adjustment is required. No interim efficacy analysis is planned. 
After all subjects still participating in the study have completed Part A and at least one 12-
week Part B period (primary completion) of the study, all dose levels will be assessed 
including clinical safety, routine safety laboratory, hemostasis and thrombosis markers as per 
PK/PD assessment and clinical efficacy. 
4.5 
Data Rules 
All bleed and infusion data will be reported and imported into SAS.  If an infusion is given 
for a bleed and the bleed information is not provided, the infusion date will be used as the 
bleed date.  All bleeds include spontaneous bleeds and trauma. An untreated bleed is a bleed 
with no corresponding infusion for the bleed.  Bleeds occurring before start of treatment with 
study medication will not be counted.  Bleeds will be counted if at least one of the following 
information on bleed is available: parts of the date of bleed (as long as the information is 
sufficient that the bleed fits in the treatment period), given severity or response to treatment of 
bleed, type of bleed or information on treatment or reason for treatment.  
4.5.1 
Baseline values 
Baseline values for vital sign measures and laboratory values are planned to be taken at Visit 
2 before administration of study drug. If these values are not available, values taken before 
first administration of study drug will be considered (e.g., values taken on Visit 1). In case of 


 
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more than one available value before first administration of study drug, the non-missing value 
closest to Visit 2 will be taken. 
4.5.2 
Annualized bleed rate 
Regarding the definition on the annualized bleed rate (see section 6.2.1) the following 
datetime will be used: 
For annualized bleed rate for Part A, the first datetime of Part A will be the datetime of the 
first administration of study drug (Visit 2 – Start of BAY 1093884 treatment at the respective 
dose). The last datetime of Part A will be 1 minute before the datetime of the Visit 6 
administration of study drug (the first administration of study drug in Part B). For subjects 
who discontinue the study during Part A, the last datetime of Part A is the datetime of the 
later of last visit and last administration of study drug.   
For annualized bleed rate for each 12-week Part B period, the first datetime of the Part B 
period will be the datetime of the first administration of study drug in Part B (Visit 6) in case 
of first Part B period, or the datetime of the administration of study drug of Visit 7 or any 
subsequent 12-week visit. The last datetime of Part B will be 1 minute before the datetime of 
the administration of study drug of Visit 7 or the following subsequent 12-week visit. For 
subjects who discontinue the study during Part B, the last datetime of Part B is the datetime of 
the later of last visit and last administration of study drug.   
For annualized bleed rate for period on dose initially recived (DIR), the first datetime on DIR 
will be the datetime of the first administration of study drug (Visit 2 – Start of BAY 1093884 
treatment at the respective dose). The last datetime on DIR will be 1 minute before the 
datetime of the administration of the next higher dose of study drug (Visit 6 or Visit 7). For 
subjects who discontinue prior to administration of the next higher dose or never met the 
dose-escalation criteria, the last datetime on DIR is the datetime of the later of last visit and 
last administration of study drug.   
4.5.3 
24 hours rule 
Count no more than 1 bleed in a calendar day.  If there is more than 1 bleed in a calendar day, 
to determine the bleed that gets counted, give priority to treated bleeds, spontaneous or trauma 
bleeds, then joint bleeds.  Otherwise, count the first bleed in the day.  Severity and treatment 
response will come from this selected bleed.  Bleed site will be aggregated over all bleeds 
from that day.  Regardless of which bleed is selected, the time of the first bleed in the day will 
be used.  All other infusions in the day for treating bleeds will be considered follow-up 
infusions.   
If more than one prophylaxis injection is given on a calendar day, the data of all prophylaxis 
injection will be combined to one injection and the time will be taken from the first 
prophylaxis injection of that day. 
4.5.4 
72 hours rule 
Do not count a spontaneous joint/muscle bleed if it occurs within 72 hours of a bleed (or 
infusion for that bleed) at the same site.  For a bleed to be affected by this rule, all sites listed 
on the bleed must also be specified in the previous bleed.  If the current and previous bleeds 
are both skin/mucosa bleeds, this rule does not apply.  Such infusions for bleeds will be 
considered to be follow-up infusions.  


 
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Joint bleeds can occur in more that 1 joint site.  For each joint bleed, count all sites 
(combining left and right).  For the table showing the Joint Site frequency, sum counts over 
all sites. 
 
4.6 
Blind Review 
The results of the  final  data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the  review  of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP. 
 
5. 
Analysis Sets 
5.1 
Assignment of analysis sets 
Final decisions regarding the assignment of subjects to analysis sets will be made during the  
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis set(s) (see section 4.6). 
The statistical analysis sets are defined as follows: 
Safety analysis set (SAF) 
All subjects with at least one intake of study drug.  
Per protocol set (PPS) 
All SAF subjects who completed Part A and Part B of the study with no major protocol 
deviations. 
Pharmacokinetic Analysis Set (PK set) 
All SAF subjects with evaluable PK profiles. 
Subjects who were assigned to treatment but did not receive study medication will not be 
included in the SAF. As the number of these excluded subjects is anticipated to be negligible, 
if at all any exist in this design, an “all assigned treatment analysis set” will not be generated. 
Subjects who do not belong to SAF will not be included into statistical considerations. These 
subjects are classified as ‘listing only set’ (LOS). Number of screening failures and dropouts 
will be tabulated. 
6. 
Statistical Methodology 
The efficacy analyses will be based on the PPS and sensitivity analyses will be based on the 
SAF as appropriate. 
The primary analysis population for the safety analysis will be the SAF.  


 
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6.1 
Population characteristics 
6.1.1 
Demography and baseline characteristics  
Demographic and baseline data will be evaluated descriptively for the SAF as well as for the 
PPS and PK set, by treatment groups and overall. No statistical tests will be performed to 
compare these characteristics across treatment groups. 
Descriptive statistics (such as mean, standard deviation, median, quartiles, minimum and 
maximum) will be provided for continuous variables such as  
 age at Screening, 
 body weight, 
 body height. 
Counts and (appropriate) percentages will be provided for categorical variables such as 
 year of birth, 
 sex, 
 race/ethnicity. 
Reasons for exclusion from analysis populations will be summarized. 
6.1.2 
Medical history 
Medical history data will be evaluated by frequency tables, showing the number and 
percentage of subjects with medical history findings (i.e., previous diagnoses, diseases or 
surgeries) that started before signing of the informed consent and that are considered relevant 
for the subject’s study eligibility using MedDRA Primary System Organ Class / Prefered 
Term. 
6.1.3 
Disease history 
The following baseline characteristics of the disease history will be evaluated descriptively 
for the SAF as well as for the PPS, by treatment groups and overall in addition:  
 Date of hemophilia diagnosis 
 Start of therapy 
 Current FVIII or FIX products (product, dose and frequency of administration) 
 Current by-passing agents (product, dose and frequency of administration) 
 Number of exposure days 
 Type of FVIII of FIX gene mutation (from history) 
 Family history of hemophilia 
 FVIII or FIX level and type of assay 
 Family and personal history of past inhibitor formation 
 Current inhibitor level 
 Current ITI status 
 Number and type of bleeds in the past 6 months 






 
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6.3 
Pharmacokinetics/pharmacodynamics 
All PK analyses will be based on the PK set. 
Descriptive statistics for PK data will be presented as n, geometric mean, geometric standard 
deviation, geometric coefficient of variation, arithmetic mean, standard deviation (SD), 
median, minimum, and maximum.  
The changes in PK parameters across the dose range studied may be assessed by comparisons 
of the above variables at each dose level. BAY 1093884 plasma concentrations will be plotted 
as a function of time for each subject according to dose.  
Plots of summary data for each dose (geometric mean and arithmetic mean plasma 
concentrations at each time point) will also be presented on both linear and logarithmic scales. 
BAY 1093884 plasma levels may also be plotted to evaluate the correlation of plasma levels 
with safety and other endpoints.  
PD parameters will be analyzed descriptively and with statistical models as appropriate. 
 
6.4 
Safety 
In accordance with the primary objective of the study, which is the assessment of the safety 
and tolerability of multiple subcutaneous doses of BAY 1093884 in subjects with hemophilia 
A or B with or without inhibitors, the primary variables of the study are the following: 
 Incidences of drug-related AEs, SAEs, adverse events of special interest (AESIs), and 
clinically relevant abnormal laboratory values. 
Hypersensitivity reactions, thromboembolic and thrombotic microangiopathic events are 
defined as AESIs.  
In addition, the following safety variables are also of particular interest: 
 Incidences of injection site reactions (ISRs) 
 Incidences of binding and neutralizing antibodies against BAY 1093884 
6.4.1 
Adverse events 
The investigator has to record on the respective CRF pages all adverse events occurring in the 
period between the signing of the informed consent form and the end of the follow-up phase. 
The original terms used by investigators to report AEs via the CRFs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).   
For each AE, the number and percentage of subjects who experienced at least 1 occurrence of 
the given event will be tabulated according to the affected primary system organ class (SOC) 
and preferred term (PT) by dose cohort and dose actually recived. A total column will be 
included in all safety summaries.   
Frequency tables, showing an overall summary of number of subjects with drug-related AEs, 
SAEs and AESIs will be given, and will include the following information: 
 maximum intensity for any AE, 
 AE related deaths, 
 AE resulting in permanent discontinuation of study drug, 


 
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 treatment emergent AE. 
 
AEs will be considered treatment-emergent if they begin after the first administration of study 
drug and they do not start after more than 30 days after the last administration.  Determination 
of whether or not an event is treatment-emergent will be derived after the missing or 
incomplete AE start date is imputed.  Inhibitors will be defined as treatment-emergent if they 
develop after first study drug application.  Imputation rules for missing and incomplete AE 
start are described in section 4.3. 
The severity or intensity of an AE should be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. If no exact 
matching code is available in NCI CTCAE version 5.0, the following guidance should be 
used: 
 CTCAE grade 1: Mild 
 CTCAE grade 2: Moderate 
 CTCAE grade 3: Severe and/or disabling AE 
 CTCAE grade 4: life-threatening and/or intervention needed 
 CTCAE grade 5: resulting in death (fatal) 
A similar table showing overall summary information of AEs during screening will be given.  
In addition, frequency tables will summarize the number of subjects with injection site 
reactions. 
Similar to 6.2, frequency tables will summarize the number of subjects with 
 any event during Part A, 
 any event during each 12-week Part B period 
 any event during combination of these periods. 
This will also include tabulation by dose actually received. 
6.4.2 
Vital signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate and body 
temperature) obtained at Visit 1 (Screening), Visit 2 (before and 30-60 minutes after study 
drug administration), Visit 3, Visit 4, Visit 5, Visit 6 (before and 30-60 minutes after study 
drug administration), Visit 7 or any subsequent 12-week visit (before and 30-60 minutes after 
study drug administration) as well as during Final visit and Early termination visit will be 
displayed by means of descriptive statistics and change from baseline. 
6.4.3 
Laboratory parameter  
Only centrally analyzed blood samples will be considered for analysis. 
Central laboratory parameters at Visit 1 (Screening), Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, 
Visit 7 or any subsequent 12-week visit as well as during Final visit and Early termination 
visit will be displayed by means of descriptive statistics and change from baseline.  




 
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