A Multicenter Phase III Uncontrolled Open-label Trial to Evaluate Safety and Efficacy of BAY81-8973 in Children With Severe Hemophilia A Under Prophylaxis Therapy
Phase: PHASE3
Conditions: Haemophilia A
Sponsor: Bayer

 
Document Type: Study Protocol 
Official Title: 
A multicenter Phase III uncontrolled open-label trial to evaluate 
safety and efficacy of BAY 81-8973 in children with severe 
hemophilia A under prophylaxis therapy 
NCT Number: 
NCT01311648 
Document Date: 
01-FEB-2019 
 

Integrated Clinical Study Protocol
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A multi-center Phase III uncontrolled open-label trial to evaluate safety and 
efficacy of BAY 81-8973 in children with severe haemophilia A under 
prophylaxis therapy
This protocol version is an integration of the following documents/sections:

Original protocol, Version 1.4, dated 20 SEP 2010

Amendment 01 (described in Section 13.1)
forming integrated protocol Version 2.0, dated 31 MAR 2011

Amendment 03 (described in Section 13.2)
forming integrated protocol Version 3.0, dated 03 SEP 2012

Amendment 04 (described in Section 13.3)
forming integrated protocol Version 4.0, dated 08 APR 2014

Amendment 06 (described in Section 13.4)
forming integrated protocol Version 5.0, dated 19 FEB 2016

Amendment 07 (described in Section 13.5)
forming integrated protocol Version 6.0, dated 30 MAY 2017

Amendment 08 (described in section 13.6) 
forming integrated protocol version 7.0, dated 31 JAN 2019
Amendments not included in the consecutive numbering of amendments are local amendments 
which are not part of this integrated global protocol.

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Title page
Study title
A multi-center Phase III uncontrolled open-label trial to evaluate safety and efficacy of 
BAY 81-8973 in children with severe haemophilia A under prophylaxis therapy
Short title:  BAY 81-8973 pediatric safety and efficacy trial
Test drug:
BAY 81-8973 / octocog alfa 
Study purpose:
Safety and efficacy
Clinical study phase:
III
Date:
01 FEB 2019
EudraCT no.:
2010-021781-29
Version no.:
7.0
Study no.:
BAY 81-8973 / 13400   
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915,
Whippany NJ 07981-0915, US (as of Amd 7)
Sponsor’s medical expert:
Bayer 
Rua Cancioneiro de Évora, 255 – Prédio E1- 1º and
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) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD

01FEB2019 
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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the integrated clinical study protocol as presented. 
Name: 
 
(as of Amd 6) 
Role: 
Global Clinical Leader (GCL) 
(aso/Amd 7) 
Signature: 
----------· 
PPD
PPD

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Signature of the investigator
The signatory agrees to the content of the integrated clinical study protocol as presented.
Name:
Date:
Signature:

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Synopsis
Title
A multicenter Phase III uncontrolled open-label trial to evaluate safety and 
efficacy of BAY 81-8973 in children with severe hemophilia A under 
prophylaxis therapy
Short title
BAY 81-8973 pediatric safety and efficacy trial
Clinical study phase
III
Study objective(s)
Primary objective

To demonstrate the safety and efficacy of treatment with BAY 81-
8973 for prophylaxis and breakthrough bleeds in children with 
severe hemophilia A 
Secondary objectives

To assess the safety and efficacy (as of Amendment 1 [Amd 1])
of BAY 81-8973 during surgeries 

To assess incremental recovery of BAY 81-8973 (as of Amd 1)

To characterize pharmacokinetics in a subset of a minimum of 
6 previously treated patients (PTPs), previously untreated 
patients (PUPs), or Minimally Treated Patients (MTPs) (as of 
Amd 6) if parents’ consent (participation for pharmacokinetic 
(PK) sampling is optional). (as of Amd 3)
Test drug(s)
BAY 81-8973
Name of active ingredient
Octocog alfa; full-length, unmodified plasma protein-free, recombinant 
factor VIII (rFVIII)  
Dose(s)
Part A:
PTPs: 25 -50 International Units (IU)/kilogram (kg) (rounded to nearest 
size vial); prophylaxis with at least 2 infusions per week and treatment for 
breakthrough bleeds (as of Amd 1)
Part B: 
PUPs/MTPs 15-50 IU/kg; prophylaxis with at least 1 infusion per week 
and treatment for bleeds (as of Amds 1 and 6)
Route of administration
Intravenous
Duration of treatment
6 months and/or >50 exposure days (ED). (as of Amd 1)
Optional extension study for at least 100 cumulative ED) 
Reference drug(s)
None
Indication
Hemophilia A
Diagnosis and main criteria for
inclusion
Severe hemophilia A (< 1% Factor VIII concentration [FVIII:C]), 
Part A: male, age 0-12 years, > 50 ED (as of Amd 1), no inhibitor history, 
no other bleeding disorder
Part B: male, PUPs, no prior exposure to factor VIII (FVIII) concentrate 
(as of Amds 1 and 6) or MTPs who do not have more than 3 EDs with 
any FVIII concentrate and no current evidence of inhibitor antibody (as 
of Amd 6)
Study design
Multicenter, open label, single treatment arm, uncontrolled

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Methodology
Part A (as of Amd 1):
The study consists of 6-months of treatment in PTPs with BAY 81-8973 for 
prophylaxis and treatment of breakthrough bleeding events to achieve at 
least 50 ED. All subjects will be evaluated for inhibitor development and 
incremental recovery at Baseline, Months 1, 2, and 6.  Enrollment in the 
study will be staggered, with subjects age 6-12 years entering first, 
followed by subjects <6 years. (as of Amd 3)
Part B (as of Amds 1 and 6):
PUPs/MTPs will be treated with BAY 81-8973 for all bleeding events and 
are required to start prophylaxis.  Treatment will continue until at least 
50 ED.  Screening and baseline visits may be combined for PUPs.  
Subjects will be tested for inhibitors every 3-5 ED up to 20 ED and again 
at 50 ED.  Incremental recovery will be measured at Baseline, 20 ED, 
and 50 ED. 
Pharmacokinetics (PK) samples will be collected in a subset of subjects at 
pre-infusion and then 20-30 minutes, 4 hours (h), and 24 h post infusion.  
Participation in the PK portion of the study is voluntary and requires 
specific consent. (as of Amd 1)
In both Part A and Part B, all infusions and bleeding events will be 
documented in an electronic patient diary (EPD) throughout the study. 
(as of Amd 1)
Optional extension study (as of Amd 1):
Subjects in both Part A and B will be offered participation in an optional 
extension study to continue treatment with BAY 81-8973, to accumulate 
at least 100 ED.  During the extension study, visits to the treatment center 
will take place every 6 months. (as of Amds 1 and 6)
The study is designed according the requirements defined in the European 
“Note for Guidance on the clinical investigation of recombinant FVIII and 
FIX products” CPMP/BPWG/1561/99.
Type of control
None
Number of subjects
Part A:
Total Number (N) = 50 PTPs
age group 6-12 years:  N=25
age group <6 years:    N=25
Part B:
N= at least 25 PUPs, plus approximately an additional 25 PUPs/MTPs
(as of Amds 3, 6 and 7)
age group <6 years
Total = approximately 100 (includes both Part A and B) (as of Amds 1, 3
and 7)
Primary variable
Response to treatment in relation to number of bleeding events and 
response to treatment of bleeds 
Plan for statistical analysis
Descriptive statistics

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Protocol Amendment Summary of Changes Table
The changes in this table have been implemented as part of global amendment 8.
Section number 
and name
Description of change
Brief rationale
Title page
Section 3 
Investigators and 
other study 
participants
Medical Expert contact information 
update
Contact information for Medical expert 
has been updated
Synopsis
Section 5.1.1 
Inclusion criteria
Change in the definition of MTP from 3 
injections to 3 Exposure days
Clarification that MTPs do not have 
more than 3 EDs with any FVIII 
concentrate, as number of injections 
and exposure days are not necessarily 
identical. 
Section 4 study 
design 
Addition that screening can continue 
whilst first cohort completes 20 ED
Protocol Amd 7 introduced a staggered 
enrollment and treatment approach to 
limit the entry of patients into the study 
until safety data related to inhibitor 
development during the first 20 EDs 
could be assessed in the next 10 
subjects treated (first cohort).
Safety evaluation of the first 5 patients 
in this first cohort shows that inhibitor 
development is within the expected 
range.   
The intention of this change in Amd 8  
is to allow identification and screening 
of subjects while the safety evaluation 
in the first cohort of 10 subjects is 
completed. 
Amd 8 also clarifies that patients may 
receive treatment other than BAY 81-
8973 during the screening interval if 
medically indicated. If there are no 
safety concerns identified in the first
cohort the patients may start treatment 
with study drug provided they still meet 
the protocol definition of MTP.
Screening therefore can continue to 
ensure continued enrollment in the 
study.
Section 4 Study 
design
Section 6.1.1 
Regular 
Participation in the extension study is 
continued only until 100 ED are 
reached.
Kovaltry is now marketed, and 
therefore the extension study is offered 
until 100 ED and not until marketing 
authorization.

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Section number 
and name
Description of change
Brief rationale
prophylaxis
Section 6.8 Post-
study therapy
Section 7.1.1 
Tabulated 
overview
Section 7.1.2 
Timing of 
assessments
Section 7.1.2.10 
Extension – final 
visit
Section 6.1.5 
Immune tolerance 
induction
Immune tolerance induction should be 
continued until the inhibitor is eradicated 
successfully, or until failure, for 
approximately 18 months. Treatment 
beyond 18 months requires approval 
from the sponsor and the coordinating 
investigator.
In accordance with the 
recommendation of the data monitoring 
committee, in cases where subjects 
have a clinical response with ITI, if 
deemed clinically necessary, ITI can be 
continued beyond 18 months following 
discussion with the sponsor and 
coordinating investigator.
Section 8.5 
Planned interim 
analyses
An additional analysis that will be 
performed when all PUPs/MTPs have 
completed part B was added.
An additional analysis was added for 
when all PUPs/MTPs have completed 
part B.
In addition, editorial and administrative changes have been made throughout the document.
Table of contents
Title page................................................................................................................................... 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of the investigator ................................................................................................... 4
Synopsis..................................................................................................................................... 5
Protocol Amendment Summary of Changes Table............................................................... 7
Table of contents....................................................................................................................... 8
Table of Tables ....................................................................................................................... 13
List of abbreviations............................................................................................................... 14
1.
Introduction..................................................................................................................... 17
2.
Study objectives............................................................................................................... 19
3.
Investigators and other study participants................................................................... 19

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4.
Study design..................................................................................................................... 20
5.
Study population ............................................................................................................. 22
5.1
Eligibility ....................................................................................................................... 22
5.1.1
Inclusion criteria......................................................................................................... 22
5.1.2
Exclusion criteria........................................................................................................ 23
5.2
Withdrawal of subjects from study................................................................................ 24
5.2.1
Withdrawal ................................................................................................................. 24
5.2.2
Replacement ............................................................................................................... 25
5.3
Subject identification ..................................................................................................... 25
6.
Treatments....................................................................................................................... 25
6.1
Treatments to be administered....................................................................................... 25
6.1.1
Regular prophylaxis.................................................................................................... 25
6.1.2
Breakthrough bleeds and surgeries............................................................................. 27
6.1.3
Missed infusions due to difficult venous access or family travel................................ 27
6.1.4
Optional pharmacokinetic measurements................................................................... 27
6.1.5
Immune tolerance induction....................................................................................... 27
6.2
Identity of Investigational Medicinal Product ............................................................... 28
6.2.1
Manufacture................................................................................................................ 28
6.2.2
Supply and Packaging ................................................................................................ 29
6.2.3
Labeling...................................................................................................................... 29
6.2.4
Storage........................................................................................................................ 29
6.2.5
Instructions for Administration .................................................................................. 29
6.3
Treatment assignment.................................................................................................... 30
6.4
Dosage and administration............................................................................................. 30
6.5
Blinding ......................................................................................................................... 31
6.6
Drug logistics and accountability................................................................................... 31
6.7
Treatment compliance.................................................................................................... 31
6.8
Post-study therapy.......................................................................................................... 31
6.9
Prior and concomitant therapy....................................................................................... 32
7.
Procedures and variables ............................................................................................... 32
7.1
Schedule of procedures.................................................................................................. 32
7.1.1
Tabulated overview .................................................................................................... 32
7.1.2
Timing of assessments................................................................................................ 36
7.1.2.1
Visit 1 – Screening.................................................................................................. 36
7.1.2.2
Visit 2 – Baseline .................................................................................................... 37
7.1.2.3
Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B (as of Amd 1)............ 39
7.1.2.4
Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B (as of Amd 1).......... 39
7.1.2.5
Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (as of Amd 1)................................... 40
7.1.2.6
Visit 6 – Part B only; ED 20 (20 ED +/- 1) (as of Amd 1) ..................................... 41
7.1.2.7
Interim visit – Only for Part B (30-40 ED) (as of Amd 1) ...................................... 42
7.1.2.8
Final Visit (end of the main study and start of the optional extension study) ........ 42
7.1.2.9
Extension study visits – 6 months after completion of Part A or B; then every 6 
months (as of Amd 1) .............................................................................................. 44

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7.1.2.10
Extension final visit................................................................................................. 45
7.2
Population characteristics .............................................................................................. 45
7.2.1
Demographic .............................................................................................................. 45
7.2.2
Medical history........................................................................................................... 46
7.2.3
Disease history............................................................................................................ 46
7.3
Efficacy.......................................................................................................................... 46
7.3.1
Efficacy variables ....................................................................................................... 46
7.3.2
Efficacy procedures.................................................................................................... 47
7.3.2.1
Incremental recovery of Factor VIII (as of Amd 1)................................................. 47
7.3.2.2
Treatment logs / bleeding verification .................................................................... 47
7.4
Pharmacokinetics (optional – consent required) (as of Amd 1) .................................... 48
7.5
Safety ............................................................................................................................. 49
7.5.1
Adverse events............................................................................................................ 49
7.5.1.1
Definitions............................................................................................................... 49
7.5.1.2
Classifications for adverse event assessment.......................................................... 50
7.5.1.2.1
Seriousness........................................................................................................... 50
7.5.1.2.2
Intensity................................................................................................................ 51
7.5.1.2.3
Causal relationship............................................................................................... 51
7.5.1.2.4
Action taken with study treatment ....................................................................... 52
7.5.1.2.5
Other specific treatment(s) of adverse events...................................................... 52
7.5.1.2.6
Outcome............................................................................................................... 52
7.5.1.3
Assessments and documentation of adverse events ................................................ 52
7.5.1.4
Reporting of serious adverse events ........................................................................ 53
7.5.1.5
Expected adverse events.......................................................................................... 53
7.5.2
Pregnancies................................................................................................................. 54
7.5.3
Further safety.............................................................................................................. 54
7.5.3.1
Vital signs................................................................................................................ 54
7.5.3.2
Physical examination............................................................................................... 54
7.5.3.3
Standard safety laboratory....................................................................................... 54
7.5.3.4
Inhibitor testing ....................................................................................................... 54
7.6
Other procedures and variables...................................................................................... 55
7.6.1
Epitope mapping (as of Amd 4).................................................................................. 55
7.6.2
Biomarker investigation (pharmacogenetics) (recommended – consent required) (as 
of Amd 4 and Amd 7)................................................................................................... 56
7.7
Appropriateness of procedures / measurements ............................................................ 56
8.
Statistical methods and determination of sample size ................................................. 56
8.1
General considerations................................................................................................... 56
8.2
Analysis sets .................................................................................................................. 56
8.3
Variables ........................................................................................................................ 56
8.4
Statistical and analytical plans....................................................................................... 58
8.5
Planned interim analyses ............................................................................................... 58
8.6
Determination of sample size......................................................................................... 59
9.
Data handling and quality assurance............................................................................ 59
9.1
Data recording................................................................................................................ 59

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9.2
Data processing.............................................................................................................. 60
9.3
Audit and inspection ...................................................................................................... 60
9.4
Archiving ....................................................................................................................... 60
10. Premature termination of the study .............................................................................. 61
11. Ethical and legal aspects................................................................................................. 61
11.1
Ethical and legal conduct of the study........................................................................... 61
11.2
Subject information and consent.................................................................................... 62
11.3
Publication policy .......................................................................................................... 63
11.4
Compensation for health damage of subjects / insurance.............................................. 63
11.5
Confidentiality ............................................................................................................... 63
12. Reference list ................................................................................................................... 63
13. Protocol amendments...................................................................................................... 66
13.1
Amendment 1................................................................................................................. 66
13.1.1
Overview of changes .................................................................................................. 66
13.1.2
Changes to the protocol text:...................................................................................... 75
13.1.2.1
Change 1.................................................................................................................. 75
13.1.2.2
Change 2.................................................................................................................. 85
13.1.2.3
Change 3.................................................................................................................. 96
13.1.2.4
Change 4................................................................................................................ 116
13.1.2.5
Change 5................................................................................................................ 118
13.1.2.6
Change 6................................................................................................................ 129
13.1.2.7
Change 7................................................................................................................ 132
13.1.2.8
Change 8................................................................................................................ 132
13.1.2.9
Change 9................................................................................................................ 143
13.1.2.10 Change 10.............................................................................................................. 146
13.1.2.11 Change 11.............................................................................................................. 151
13.1.2.12 Change 12.............................................................................................................. 152
13.1.2.13 Change 13.............................................................................................................. 154
13.1.2.14 Change 14.............................................................................................................. 155
13.1.2.15 Change 15.............................................................................................................. 159
13.1.2.16 Change 16.............................................................................................................. 160
13.1.2.17 Change 17.............................................................................................................. 162
13.2
Amendment 3............................................................................................................... 170
13.2.1
Overview of changes ................................................................................................ 170
13.2.2
Changes to the protocol text:.................................................................................... 172
13.2.2.1
Change 1................................................................................................................ 173
13.2.2.2
Change 2................................................................................................................ 180
13.2.2.3
Change 3................................................................................................................ 182
13.2.2.4
Change 4................................................................................................................ 183
13.2.2.5
Change 5................................................................................................................ 183
13.2.2.6
Change 6................................................................................................................ 183
13.2.2.7
Change 7................................................................................................................ 184
13.2.2.8
Change 8................................................................................................................ 184

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13.2.2.9
Change 9................................................................................................................ 185
13.2.2.10 Change 10.............................................................................................................. 186
13.3
Amendment 4............................................................................................................... 188
13.3.1
Overview of changes ................................................................................................ 188
13.3.2
Changes to the protocol text:.................................................................................... 189
13.3.2.1
Change 1................................................................................................................ 189
13.3.2.2
Change 2................................................................................................................ 193
13.3.2.3
Change 3................................................................................................................ 193
13.3.2.4
Change 4............................................................................................................... 193
13.3.2.5
Change 5................................................................................................................ 194
13.3.2.6
Change 6............................................................................................................... 194
13.4
Amendment 6............................................................................................................... 196
13.4.1
Overview of changes ................................................................................................ 196
13.4.2
Changes to the protocol text:.................................................................................... 200
13.4.2.1
Change 1................................................................................................................ 200
13.4.2.2
Change 2................................................................................................................ 207
13.4.2.3
Change 3................................................................................................................ 208
13.4.2.4
Change 4................................................................................................................ 211
13.4.2.5
Change 5................................................................................................................ 211
13.4.2.6
Change 6................................................................................................................ 211
13.4.2.7
Change 7................................................................................................................ 213
13.4.2.8
Change 8................................................................................................................ 225
13.4.2.9
Change 9................................................................................................................ 225
13.4.2.10 Change 10.............................................................................................................. 226
13.4.2.11 Change 11.............................................................................................................. 226
13.4.2.12 Change 12.............................................................................................................. 227
13.4.2.13 Change 13.............................................................................................................. 228
13.5
Amendment 7............................................................................................................... 230
13.5.1
Overview of changes ................................................................................................ 230
13.5.2
Changes to the protocol text:.................................................................................... 232
13.5.2.1
Change 1................................................................................................................ 232
13.5.2.2
Change 2................................................................................................................ 233
13.5.2.3
Change 3................................................................................................................ 235
13.5.2.4
Change 4................................................................................................................ 236
13.5.2.5
Change 5................................................................................................................ 242
13.5.2.6
Change 6................................................................................................................ 243
13.6
Amendment 8............................................................................................................... 252
14. Appendices..................................................................................................................... 253
14.1
Instruction for use of study medication ....................................................................... 253
14.1.1
Presentation of vials with Bio-SET reconstitution cap............................................. 253
14.1.2
Presentation of vial and vial adapter (as of Amd 6)................................................. 255
14.2
Standard of Care .......................................................................................................... 257
14.3
Healthcare Resources Utilization Questionnaire ......................................................... 258
14.4
Blood draws in subjects weighing less than 10 kg (as of Amd 1)................................ 260

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14.5
Laboratory evaluation for suspected inhibitor (as of Amd 1) ..................................... 261
Table of Tables
Table 7–1a: Schedule of evaluations (Part A – PTPs; >50 ED)............................................... 33
Table 7–2b: Schedule of evaluations (Part B – PUPs/MTPs).................................................. 34

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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase (also known as SGPT, qv)
Amd 1
Amendment 1 (as of Amd 1)
Amd 3
Amendment 3 (as of Amd 3)
Amd 4
Amendment 4 (as of Amd 4)
Amd 6
Amendment 6 (as of Amd 6)
Amd 7
Amendment 7 (as of Amd 7)
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate aminotransferase (also known as SGOT, qv)
AUC
Area under the curve
BMI
Body mass index
BU
Bethesda Unit
°C
Degrees centigrade
Ca
Calcium
CBC
Complete blood count
CHMP/BPWP
Committee for Medicinal Products for Human Use/Blood Products 
Working Party
Cl
Chloride
CL
Clearance
Cmax
Maximum concentration
CO
Bicarbonate
CPMP/BPWG
Committee for Proprietary Medicinal Products/Blood Products Working 
Group
CRF
Case Report Form (either paper or electronic)
CRO
Clinical research organization
CSP
Clinical Study Protocol
DD
Day
dL
Deciliter
DMC
Data Monitoring Committee (as of Amd 1)
EC
Ethics Committee
ECG
Electrocardiogram
ED
Exposure day(s)
eg
Exempli gratia, for example
EMA/PDCO
European Medicines Agency/Paediatric Committee
EMEA
European Agency for the Evaluation of Medicinal Products
ePRO
Electronic patient reported outcome
EP USP
European and US Pharmacopeia
EPD
Electronic Patient Diary (as of Amd 1)
EU
European Union
FDA
Food and Drug Administration
FVIII
Human coagulation factor VIII 
FVIII:C
Factor VIII concentration

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FIX
Factor nine
GCL
Global Clinical Leader
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HSP-70
Heat Shock Protein 70
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
ICU
Intensive care unit
lbs
Pounds
i.e.
Id est, that is
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITI
Immune Tolerance Induction 
ITT
Intent-to-treat
IU
International Units
IV
Intravenous
IVIG
Intravenous Immunoglobulin
IVRS
Interactive voice randomization system
h
Hour
HLA
Human leukocyte antigen
K
Potassium
kg
Kilogram
Kogenate FS
Kogenate Formulated with Sucrose
X-linked
A gene on the X chromosome 
LDH
Lactate dehydrogenase
LETE
Less than expected therapeutic effect
MD
Medical Director/Doctor
MedDRA
Medical Dictionary for Regulatory Affairs
min
Minute
mL
Milliliter
MM
Month
mm3
Cubic millimeter
MRT
Mean Residence Time
MTP
Minimally treated patient,  ≤3ED (as of Amd 6)
N
Number
Na
Sodium
NC
North Carolina
NSAIDs
Non-steroidal anti-inflammatory drugs
PICU
Pediatric intensive care unit
PID
Patient identification
PK
Pharmacokinetic
PTP
Previously treated patient
PUP
Previously untreated patient
QA
Quality assurance

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RAVE
Data base for electronic case report form (as of Amd 1)
rFVIII
Recombinant factor VIII
SAE
Serious Adverse Event
SE
Sweden
SNP
Single nucleotide polymorphisms (as of Amd 4)
SPM
Study Procedure Manual
SUSAR
Serious unexpected suspected adverse reaction (as of Amd 1)
t1/2
Half-life
TOSCA
Toolbox for System Configuration and Administration
USA
United States of America
YYYY
Year
WHO
World Health Organization

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1.
Introduction
Background
Hemophilia A is an X-linked (gene on the X Chromosome) congenital bleeding disorder with 
a frequency of 1 in 10,000 births caused by a deficiency of functional coagulation factor VIII 
(FVIII). Individuals with severe hemophilia A (<1% functional FVIII) experience frequent 
bleedings and recurrent spontaneous bleeds into the soft tissue and joints, leading to joint 
damage and severe disability with major effects on physical, psychosocial, quality of life, and
financial condition of the hemophilia subjects. Many studies have shown that, even at high 
doses, on-demand therapy is not effective in preventing arthropathy(1, 2) Observations that 
subjects with moderate hemophilia (FVIII >0.01-0.05 IU/milliliter [mL]) rarely develop 
chronic arthropathy are the rationale for prophylactic treatment of severe hemophilia(3). Based 
on these observations, there is a widely accepted hypothesis that maintaining the factor VIII
activity above 1% with prophylactic therapy may prevent bleeding and ultimately arthropathy 
in subjects with severe hemophilia. This observation was shown by the Swedish(4-6), British(7), 
and German(8) observational studies, as well as the international orthopedic outcome study(2)
and the comparison of different treatment regimens in France, The Netherlands, and 
Sweden(9). The advantage of prophylactic therapy was further confirmed by a prospective, 
randomized controlled study that compared the joint outcome between on-demand and 
prophylactic regimen in young children. The data confirmed that children on prophylaxis had 
significant less joint damage than on-demand treated children at the age of 6 years(10).
Recombinant coagulation Factor VIII (rFVIII) is a mainstay in the treatment of subjects with 
hemophilia A.  Bayer HealthCare has produced two rFVIII products, KOGENATE®
(introduced in 1993) and its sucrose-formulated successor Kogenate® FS (KOGENATE®
Bayer in Europe), which together have an excellent safety and efficacy profile demonstrated 
in clinical trials and in the normal clinical setting.(11-14)  In the 20 years since clinical testing 
for these products began, more than 8 billion IU have been infused.
Recombinant FVIII is one of the largest and most complicated human therapeutic proteins 
manufactured.  In the last 2 decades, major advances in production techniques have included 
the development of large-scale continuous perfusion fermentation technology and an assay to 
evaluate the presence of blood-borne prion pathogens.  More recently, Bayer has implemented 
advances in biological manufacturing that have simplified the process and have achieved a 
more consistent rFVIII product.  
Enhancement of the viability of the expression cell line during fermentation through co-
expression of the human heat-shock protein 70 (HSP-70) has permitted the generation of an 
improved rFVIII manufacturing process for BAY 81-8973(15).  HSP-70 has the dual effect of 
inhibiting apoptosis, and thereby the release of intracellular proteases that could damage 
FVIII molecules, and serving as a chaperone molecule that increases the proper folding of the 
FVIII protein, thereby reducing protein aggregation.  
Other significant changes to rFVIII manufacturing have been introduced.  BAY 81-8973 has 
the same amino acid composition as Kogenate® FS/Bayer. (as of Amendment 1 [Amd 1]) 
Compared to its predecessors, BAY 81-8973 has more complete sialic acid capping of N-

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terminal glycan groups on the molecular surface, a post-translational modification step that is 
critical to the activity and stability of some mammalian proteins.  Although pathogen 
contamination of a recombinant protein product is a theoretical possibility, the BAY 81-8973 
purification process achieves a greater level of viral clearance than the current process 
through the addition of a new viral filtration step.  Overall, the complexity of the rFVIII 
manufacturing process has been substantially simplified for BAY 81-8973 compared to its 
predecessor products.  This allows for a faster production time that may also reduce the 
buildup of aggregation and breakdown products, which may be linked to suboptimal yields of 
rFVIII products.  In addition, any human or animal additives have been eliminated from the 
fermentation process. The result of the technological innovations implemented for 
BAY 81-8973 is the production of a full-length unmodified rFVIII product that more 
consistently reflects the conformation and glycan structure of the native human FVIII protein
Based on PK data from 26 subjects who received a single 50 IU/Kg dose of BAY 81-8973 
and Kogenate FS (Kogenate formulated with Sucrose) in a cross over fashion, it has been 
demonstrated that BAY 81-8973 is non-inferior to Kogenate® FS/Bayer. (as of Amd 1)
Rationale of the study
The study is planned to demonstrate safety and efficacy of BAY 81-8973 for prophylaxis 
therapy and treatment of breakthrough bleeds in children with severe hemophilia A. 
The overall clinical program consists of 3 safety and efficacy studies, one study in subjects 
≥12 years of age (adults and adolescents) including two pharmacokinetic evaluations 
(baseline and month 6), one study in adults and adolescents ≥ 12 years of age comparing 
on-demand and prophylaxis treatment, and the present study in children from 0-12 years.  The 
first study in adults and adolescents is ongoing and has completed enrollment. (as of Amd 1)
The comparative pharmacokinetic study of BAY 81-8973 and Kogenate FS/Bayer has been 
completed and non-inferiority to the licensed product Kogenate FS/Bayer was demonstrated.  
The demonstration of safety in at least 20 adolescents and adults who received a minimum 
of 50 ED was a necessary requirement to open this study to enrollment of children 12 years 
of age and younger. (as of Amd 1)
Benefit-risk assessment
The investigational product is an unmodified recombinant human FVIII produced by a well 
characterized cell line and similar to the predecessor product with an excellent safety and 
efficacy profile based on 20 years clinical experience. 
All subjects will receive a replacement therapy at the highest level of standard of care. For 
previously untreated patients (PUPs), and minimally treated patients (MTPs) (as of 
Amendment 6 [Amd 6]), there is a well-known risk for inhibitor development during the first 
20 exposure days (ED) with any FVIII product which decreases with increasing exposure. 
Further details can be found in the Investigator’s Brochure, which contains comprehensive 
information on the study drug.

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2.
Study objectives
Primary objective
The primary objective is to evaluate the safety and efficacy of the treatment with 
BAY 81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe
(as of Amd 1) hemophilia A. 
Secondary objectives
The secondary objectives are

To assess the safety and efficacy (as of Amd 1) of BAY 81-8973 during surgeries.

To assess incremental recovery of BAY 81-8973. (as of Amd 1)

To assess pharmacokinetic parameters in a subset of children. (PTPs and 
PUPs/MTPs -participation in pharmacokinetic [PK] sampling is voluntary and 
requires consent). (as of Amds 1, 3 and 6)
3.
Investigators and other study participants
Sponsor’s Medical Expert
Name: 
Title:    
Address:    Bayer 
Rua Cancioneiro de Évora, 255 – Prédio E1- 1º and
04708-010 São Paulo – SP -  Brasil
Tel: 
Coordinating Investigator for the Study
Name: 
Title:  
Address:
Skånes universitetssjukhus Malmö
Barn- och ungdomscentrum Ingång 108, plan 2
SE 205 02 Malmö, Sweden
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.
The principal investigator of each center must sign the protocol signature sheet before subject
recruitment may start at the respective center.  Likewise, all protocol amendments/integrated 
PPD
PPD
PPD
PPD
PPD

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protocols must be signed and dated by the principal investigator before coming into 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 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.
4.
Study design
Design overview
This is a phase-III multicenter, open-label uncontrolled study to demonstrate safety and 
efficacy of treatment with BAY 81-8973 for prophylaxis, breakthrough bleeds, and surgeries 
in children with severe hemophilia A. The study will be conducted worldwide.
The study is divided into two parts:  Part A will investigate a total of 50 PTPs up to 12 years 
of age.  Part B will include at least 25 PUPs, plus up to additional 25 PUPs/MTPs (as of 
Amd 6). All subjects will receive prophylactic administration of BAY 81-8973.  Subjects in 
Part A will be treated with 25-50 IU/kg at least 2 times per week, or more frequently as 
needed for prophylaxis.  
Treatment in Part B may begin with start of prophylaxis with 15-50 IU/kg (minimum dose 
250 IU) at least one day a week, or with the subject’s first bleeding event.  The study drug 
will be used both for treatment of bleeding events and prevention of bleeds and with 
surgical procedures. Individual subject dose decisions are at the discretion of the 
investigator. (as of Amds 1 and 3)
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in previous studies with 
BAY 81-8973.  PTPs age 6 to 12 years will begin enrollment first, followed by PTPs <6 years
(as of Amd 3).  Part B, for PUPs/MTPs (as of Amd 6) will begin enrollment after 20 children 
in Part A have had 50 ED. As of Amd 7, enrollment in Part B will be staggered. 10 patients 
will be enrolled, and will commence treatment for 20 ED. While safety assessment of the 
first cohort is ongoing, screening for the next sequence of 10 patients will continue. Treatment 
of next sequence/10 patients will start if no safety concerns are identified in the previous 
cohort following completion of 20 EDs. In the event patients would require FVIII treatment, 
they could still be eligible according to protocol definitions in case no more than 3 EDs of an 
alternative FVIII product has been administered.
Enrollment will be suspended if the inhibitor rate in the first cohort exceeds 50% following 
discussion with an independent Data Monitoring Committee (DMC). (as of Amd 7)
The total study duration (including screening period) per subject in Part A (as of Amd 1) will 
be approximately 6-8 months (as of Amd 1) during which the subjects will accumulate at least 
50 ED.  For Part B, subjects will continue in the study until achieving 50 ED.  

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Consequently the duration will vary depending upon the frequency of prophylactic infusion 
and number of bleeding events.  
All subjects in both Parts A and B (as of Amd 1) will be offered participation in an open-
label extension study for an additional 6-12 months to allow observations for (as of Amd 1) 
at least 100 ED. In countries where BAY 81-8973 is marketed under the proprietary name 
Kovaltry, the option to transition to marketed drug after completion of part B (50EDs) is
possible. Enrollment of PUPs/MTPs (as of Amd 6) in Part B and the extension study may 
continue after Part A and the extension study for PTPs have been completed. (as of Amd 1)
During the study, all subjects will receive treatment only with BAY 81-8973 for prophylaxis 
and treatment of bleeds.  In Part A, the (as of Amd 1) dosage range for prophylaxis 
treatment will be 25-50 IU/kg administered at least 2 times per week at the investigator’s 
discretion.  In Part B, PUPs/MTPs (as of Amd 6) may start at a lower dose at (as of Amd 1)
once per week schedule at the investigator’s discretion. (as of Amd 1)
The dosing for breakthrough bleeds will be dependent upon the bleeding location and
severity, and will be consistent with local (as of Amd 1) standards of care. Bleeding and 
treatment (as of Amd 1) information will be collected using an electronic patient (as of 
Amd 1) diary (EPD), which will be provided to the parents/caregivers. (as of Amd 1)
Incremental recovery and trough levels of BAY 81-8973 will be assessed in all subjects. 
Suitable subjects will be given the opportunity to participate in the pharmacokinetic (PK) 
evaluation (as of Amd 3).  Participation is optional, and requires consent.  PK parameters 
(maximum concentration [Cmax], half-life, area under curve [AUC], Mean Residence Time 
[MRT] and clearance) may be assessed using a sparse sampling schedule.
In the event that any subject acquires an inhibitor to FVIII, Immune Tolerance Induction 
(ITI) will be offered. The subject may receive BAY 81-8973 up to 200 IU/kg daily or 
100 IU/kg twice a day for 18 months.  Treatment will be at the discretion of the treating 
physician, although the detailed treatment plan should be agreed with the Coordinating 
Investigator (as of Amd 7).  Subject commences on ITI therapy will be followed up within 
the extension study.  Data on treatment, FVIII measurements, and inhibitor levels will be 
collected. (as of Amds 1 and 6)
Primary variable
Annualized number of total bleeds (sum of spontaneous bleeds and trauma bleeds) within 
48 hours (h) after a prophylactic infusion. (as of Amd 1)
Justification of the design
The study is designed according the requirements defined in the European “Note for Guidance 
on the clinical investigation of recombinant FVIII and FIX products” CPMP/BPWG/1561/99 
and taking into account the revised draft version of this guideline 
CHMP/BPWP/144533/09(16) (Committee for Proprietary Medicinal Products/Blood Products 

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Working Group; Committee for Medicinal Products for Human Use/Blood Products Working 
Party).
End of study
For each participating European Union (EU) country, the end of the study according to the 
EU Clinical Trial Directive will be reached when the last visit of the last subject (including 
subjects in the extension study) for all centers in the respective country has occurred. 
The end of the study as a whole will be reached as soon as the end of the study according to 
the above definition has been reached in all participating countries (EU and non-EU).
The primary completion date for this study according to the Food and Drug Administration 
(FDA) Amendment Act is specified in a separate document (not part of this Clinical Study 
Protocol [CSP]).
5.
Study population
5.1
Eligibility
5.1.1
Inclusion criteria
In order to be included in the study, subjects must have (as of Amd 1) all of the following 
criteria upon evaluation at the Screening or Baseline visit:
Part A (as of Amd 1)
1. Male, age ≤ 12 years.  Enrollment will begin with subjects 6-12 years before it is opened 
to all age groups. (as of Amd 1, Amd 3)
2. Severe hemophilia A defined as < 1% FVIII concentration (FVIII:C) based on 
documented prior testing (as of Amd 1) or screening laboratory (Amd 3)
3. ≥50 ED with any FVIII concentrate (as of Amd 1, Amd 3)
4. No current evidence of inhibitor antibody measured using the Nijmegen-modified 
Bethesda assay [<0.6 Bethesda units (BU)/mL] within 2-3 weeks of last FVIII (as of 
Amd 1) administration. PTPs (as of Amd 1) may not receive FVIII within 48 h prior to 
the collection of samples for inhibitor testing at the Screening visit. (as of Amd 1)
5. No history of FVIII inhibitor formation. Documentation of negative result in medical 
records required. [Subjects with a maximum historical titer of 1.0 BU on no more than 1 
occasion with the classical Bethesda assay but at least 3 successive negative (<0.6 BU) 
results thereafter are eligible.] 
6. Willingness and ability of subjects and/or parents to complete training in the use of the 
electronic patient diary (EPD) and to document infusions (as of Amd 1) during the study.
7. Written informed consent by parent/legal representative. Assent should be sought from 
subjects if appropriate

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
Part B (PUPs/MTPs): Enrollment s may start after safety is evaluated in 20 children
in Part A with 50 ED (as of Amds 1 and 6).
1.  Male, <6 years (as of Amd 3)
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or 
confirmed on (as of Amd 1, Amd 3) screening laboratory
3a.  PUPs: No previous exposure to any FVIII product (as of Amd 1)
3b. MTPs: Have no more than 3 EDs with any FVIII product and who have no current 
evidence of inhibitor antibody measured centrally using the Nijmegen-modified Bethesda 
assay [<0.2 Bethesda units (BU)/mL] at screening, with confirmation using local laboratory 
testing at baseline (<0.6 Bethesda unit [BU/mL]) (as of Amd 7). MTPs may not receive 
FVIII within 48 h prior to the collection of samples for inhibitor testing at the Screening
and Baseline visits. (as of Amd 6 and Amd 7)
3c. MTPs: No history of FVIII inhibitor formation. (as of Amd 6)
4. PUPs may be included if they will receive their first FVIII dose with BAY 81-8973 for 
treatment of first bleeds and agree to start prophylaxis as part of their care. (as of Amd 1). 
MTPs may be included if they agree to start prophylaxis as part of their care (as of Amd 6)
5.  Willingness and ability of parents to complete training in the use of the EPD and to 
document all treatment during the study. (as of Amd 1)
6.  Written informed consent by parent/legal representative. (as of Amd 1).
5.1.2
Exclusion criteria
Subjects who meet any of the following criteria at Screening or Baseline visits will be 
excluded from participating in the study:
Parts A and B
1. Any individual with another bleeding disorder (as of Amd 1) that is different from 
Hemophilia A (eg, von Willebrand disease, Hemophilia B)
2. Any individual with thrombocytopenia (platelet count < 100 000/mm3) 
3. Creatinine > 2x upper limit of normal or Aspartate aminotransferase (AST)/Alanine 
aminotransferase (ALT) > 5x upper limit of normal (as of Amd 1)
4. Any individual without a negative inhibitor testing at screening (except for PUPs) (as of 
Amd 3)
5. Any individual who is receiving chemotherapy, immune modulatory drugs (Intravenous 
immunoglobulin [IVIG], cyclosporine, chronic use of oral or i.v. corticosteroids), has 
received another investigational FVIII product within the last month, or received another 
experimental drug within the last 3 months. (as of Amd 1, Amd 3)
6. Any individual who requires any pre-medication to tolerate FVIII treatment (as of 
Amd 1) (eg, antihistamines)

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7. Any individual who is unwilling to comply with study visits or other protocol 
requirements, for example (eg. prophylaxis treatment) or is not suitable for participation in 
this study for any reason, according to the Investigator’s judgment. (as of Amd 1)
8. Known hypersensitivity to active substance, mouse, or hamster protein.
9. Previous participation in  this study
Part B only (PUPs/MTPs [as of Amd 6]):
10. First treatment with BAY 81-8973 for high risk bleeding situations (eg, surgery, 
intracranial bleed), or requiring intensive or prolonged treatment. (as of Amd 1)
11. Unable to tolerate volume of blood draws required for study participation (See 
Section 14.4). (as of Amd 1)
5.2
Withdrawal of subjects from study
5.2.1
Withdrawal
Subjects must be withdrawn from the study for any of the (as of Amd 1) following reasons:

At their own request or at the request of their parent/legal representative (as of 
Amd 1)

At any time during the study and without giving reasons a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being

A positive inhibitor result at Screening or Baseline visits (as of Amd 1). Evidence of 
inhibitor formation in MTPs prior to starting treatment with study drug (defined as 
≥0.2 BU/mL by central laboratory testing at screening, and/or ≥0.6 BU/mL by local 
laboratory testing at baseline) (as of Amd 7).
(Some text deleted as of Amd 1)

At the request of the sponsor

If, in the judgment of the investigator or the sponsor, the subject is not compliant with 
the protocol.
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been administered at least one dose of study drug
A subject who, for any reason (eg failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see above) is regarded a “screening 
failure”.

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In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in 
the subject's medical records.
Details for the premature termination of the study as a whole (or components thereof, 
eg, centers) are provided in Section 10.
5.2.2
Replacement
Subjects who are withdrawn after start of treatment will not be replaced. Subjects who are 
withdrawn due to failure to meet screening criteria, or who have (as of Amd 1) a positive 
inhibitor result at screening/baseline will be replaced.
5.3
Subject identification
Subjects will be identified by a unique patient identification (PID) number with 9 digits. The 
first 5 digits will identify the country and study site, the last 4 digits are assigned to the 
subject of the specific site in increasing order.
6.
Treatments
6.1
Treatments to be administered
6.1.1
Regular prophylaxis
Test drug:
BAY 81-8973 
Dosage:
25-50 International Unit (IU)/kg; ≥ 2 times per week in PTPs, 
15-50 International Unit (IU)/kg; ≥ 1 time per week in 
PUPs/MTPs. (as of Amds 1 and 6). Recommendations for 
starting prophylaxis in PUPs/MTPs are described below. (as of 
Amd 7)
(Smallest size vial is 250 IU, which may be used for initial treatment of PUPs/MTPs of any 
weight) (as of Amds 1 and 6)
Route of administration:
Manual intravenous (IV) infusion over 1 – 15 minutes (as of 
Amd 4) according to total volume (as of Amd 1)
Note: PTPs will continue their previous treatment up to 48 h before the first dose of 
BAY 81-8973 (as of Amd 3).
Duration:
Part A: 6 months and at least 50 ED 
Part B: 50 ED 
Extension study: at least 100 cumulative ED in subjects 
participating in the optional extension study

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(Enrollment of PUPs/MTPs may continue after PTPs have completed participation in 
Part A and the extension study) (as of Amds 1 and 6)
Effective prophylaxis requires replacement therapy in order to maintain FVIII activity in the
blood above 1%. Based on the kinetics, optimal prophylactic treatment requires infusion at 
least 3 times a week. As FVIII clearance is higher in children than in adults, the optimal 
infusion schedule for children may require treatment as frequently as every other day.  
Frequent injections may be difficult for small children and their caregivers.  Consequently,
the benefit for each individual child must be evaluated against this burden, particularly in 
very young children for whom venous access may be difficult. (as of Amd 1)
Recent studies have demonstrated that the timing of the first exposures to FVIII may be 
critical for the tolerance of the drug. The CANAL study showed that early intensive 
treatment such as that required for surgery or severe bleeds increased the risk for inhibitor 
development, whereas regular prophylaxis was associated with a lower risk (17). This 
observation was subsequently supported by studies demonstrating lower inhibitor rates in 
boys treated with low dose early prophylaxis in treatment centers in Germany (18). (as of 
Amd 1)
Taking into account these observations, the following is recommended for PUPs/MTPs 
participating in Part B (as of Amds 1 and 6):
Treatment recommendations (as of Amd 7) 

Treatment can be initiated with an on-demand regimen. Prophylaxis should begin after 
a minimal number of on-demand FVIII exposures with BAY 81-8973 (no more than 2-
3 bleeding events) or when the child is large enough to tolerate weekly infusion. (as of 
Amd 1 and 6)

Alternatively, prophylaxis can be started directly with a once-a-week schedule low dose 
of 250 IU (15-25 IU/kg); the starting dose may be tailored to the subject’s weight or 
demonstrated bleeding tendency. (as of Amd 1 and 6)

Increase frequency of infusion or dose as needed for breakthrough bleeding, increased 
physical activity, or weight gain. (as of Amd 1)

Avoid starting prophylaxis during febrile illness or other identified inflammatory 
events. (as of Amd 1)

Avoid surgery or need for high dose intensive treatment lasting more than 4 days 
during the first 20 ED. (as of Amd 1)

Do not give FVIII as prophylaxis for vaccinations. (as of Amd 1)
After treatment with BAY 81-8973 begins (as of Amd 1), inhibitor testing every 3-5 ED is 
required (as of Amd 1) until 20 ED are accumulated or in case of non-response to treatment
(Section 14.5) (as of Amd 1)

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6.1.2
Breakthrough bleeds and surgeries
BAY 81-8973 will be used for the treatment of breakthrough bleeds. The dosage will be at the 
discretion of the investigator.  For PUPs/MTPs in Part B, see Section 6.1.1. (as of Amds 1 
and 6)
For any surgery that may occur during the course of the study, BAY 81-8973 should be used. 
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide varying instructions based 
upon the type of surgical procedure to be undertaken.  For PUPs /MTPs in Part B (as of 
Amds 1 and 6), surgery is not allowed as first treatment and should be avoided, when 
possible, during the first 20 ED. (as of Amd 1)
If the study site routinely takes pharmacokinetic (PK) measurements prior to surgical 
procedures, these results may be used to fulfill the optional PK, provided that consent is 
given in advance, the subject undergoes a 48 hour washout, sampling is obtained at the 
designated time points, and samples are sent to the central laboratory for evaluation. (as of 
Amds 1 and 3)
In case of severe or potentially life threatening bleeding events, or the need for unplanned 
or emergency surgery, the subject should be managed following local standard of care, 
using readily available factor products. (as of Amd 1)
6.1.3
Missed infusions due to difficult venous access or family travel
During the trial, it is expected that all reasonable attempts will be made to ensure that 
subjects will comply with and adhere to their designated prophylaxis infusion schedule with 
few interruptions.  However, there may be situations when problems related to difficult 
venous access, or travel to locations where appropriate support for infusions is not 
available, may necessitate a brief hiatus in the treatment schedule.  Parents should inform 
the investigator of all such situations, and the reason documented in the medical record.   
Prolonged or repeated breaks in the prophylaxis schedule should be avoided, and could 
result in the subject being removed from the study. (as of Amd 1)
6.1.4
Optional pharmacokinetic measurements
Test drug:
BAY 81-8973 
Dosage:
50 IU/kg as a single IV infusion, at least 48 h after any previous 
treatment with FVIII. (as of Amd 1)
Suitable subjects will be given the opportunity to participate in the PK sub-study, either 
during the main study, or during the extension period (as of Amd 3).
6.1.5
Immune tolerance induction
If a subject develops an inhibitor, ITI should be considered. Clinically relevant inhibitor 
development is defined as the occurrence of at least 2 positive inhibitor titers combined with 

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a decreased recovery (as of Amd 3).  Subject commences on ITI therapy will be followed up 
within the extension study.  All treatments, FVIII measurements, and inhibitor levels will 
be documented. (as of Amds 1 and 6).
Test drug:
BAY 81-8973 
Dosage:
Up to 200 IU/kg per day as initial dose, either once a day or 100 
IU/kg twice a day at the investigator’s discretion until the inhibitor 
is eradicated successfully, or until failure, for  approximately 
18 months. Treatment beyond 18 months requires approval from 
the sponsor and the coordinating investigator. The detailed 
treatment plan should be agreed with the Coordinating 
Investigator. (as of Amd 1)  Details on ITI therapy should be 
documented.  Technical guidance on how to document this 
information will be provided in the study manual. (as of Amd 4)
The following criteria are applied for success:
1. no detectable inhibitor based on Nijmegen assay (< 0.6 BU)
2. normal recovery (> 66% of predicted)
3. normal half-life (≥ 6 h)
Failure is defined as no response (< 20% decrease in the inhibitor level) within a 6 months 
period in the absence of any infection. (some text deleted as of Amd 1)
6.2
Identity of Investigational Medicinal Product
6.2.1
Manufacture
The study drug, BAY 81-8973 is a rFVIII product (formulated in sucrose) containing full 
length unmodified rFVIII protein.
The BAY 81-8973 manufacturing process has been significantly improved from the current 
Kogenate® FS/Bayer manufacturing process. Key BAY 81-8973 manufacturing 
improvements include: removal of all human and animal derived raw materials from the cell 
culture fermentation and purification process, introduction of a new higher producing cell 
bank, new isolation technology, an optimized and simplified purification process, and the 
addition of a robust viral nanofiltration step.
The rFVIII molecule itself is comparable to the current Kogenate® FS/Bayer molecule, with 
some overall differences, such as reduced high molecular weight proteins.  The molecule is 
highly glycosylated, with increased levels of highly branched glycans and more consistently 
high sialylation of terminal galactose residues. For further details see Investigator Brochure. 
(some text deleted as of Amd 1)
The rFVIII is stabilized in a final formulation using sodium chloride, calcium chloride, 
histidine, glycine, sucrose, and polysorbate-80. The product contains no preservatives.

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6.2.2
Supply and Packaging 
BAY 81-8973 will be supplied lyophilized in glass vials.  Study vials may contain 250 IU, 
500 IU or 1000 IU of FVIII activity.  The nominal potency of the drug, as determined by 
chromogenic assay, will be indicated on the labels of each vial unit pack.  The medication is 
manufactured at Bayer HealthCare in Berkeley, California, United States. The vials of 
BAY 81-8973 will be packaged together with a pre-filled syringe of the appropriate amount 
of sterile water for injection, European and US Pharmacopeia (EP) (USP), for reconstitution.  
For BAY 81-8973, the volume of the solvent is 2.5 mL for all vial sizes. The BAY 81-8973 
vials will also be supplied with the following medical devices to facilitate the treatment (as of 
Amd 1): infusion set with filter and needle protection, plunger rod, and 10 mL sterile syringe.  
For preparing reconstitution, BAY 81-8973 will be provided in either of two presentations:
1. Vial with BIO-SET reconstitution cap:  See Section 14.1.1 for Instructions for Use. 
Before infusion, the product should be filtered using the infusion set provided or 
another approved filtration device (as of Amds 3 and 6). 
2. Vial and vial adapter: (see section 14.1.2 for Instructions for Use). (as of Amd 6).
6.2.3
Labeling
Each vial will be labeled with the nominal amount of FVIII activity in International Units (IU) 
based on chromogenic assay determination according to EU Pharmacopeia.  One IU, as 
defined by the World Health Organization (WHO) Standard for Blood Coagulation 
Factor VIII, human, is approximately equal to the level of FVIII activity found in 1.0 mL of 
fresh pooled human plasma.  
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.
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 ware 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 study file.
6.2.4
Storage
BAY 81-8973 must be stored under refrigeration (2°C to 8°C).  Freezing should be avoided.  
Reconstituted concentrate must be infused immediately after reconstitution.
Parents/caregivers will be provided with detailed instructions for proper storage of the study 
medication.
6.2.5
Instructions for Administration
Before reconstitution of rFVIII, allow the water for injection to reach room temperature, then 
reconstitute the study drug and administer immediately.  Once reconstituted, the preparation 

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should not be refrigerated or frozen.  Detailed information about reconstitution can be found 
in Appendix 14.1.
The rate of administration can be adapted to the response of the individual subject.  
Experience with Kogenate® FS/Bayer indicates that a dose may be administered over a period 
of 1 to 15 minutes. For PK and recovery studies, the entire dose should be administered over a 
5-minute period depending on the total volume. (some text deleted as of Amd 1)
Parents/caregivers will receive training and detailed information regarding the administration 
of the study medication. (as of Amd 1)
6.3
Treatment assignment
All subjects will be assigned to one single treatment arm.
6.4
Dosage and administration
The dose selections for this study are based on the recommended dosage for Kogenate®
FS/Bayer.6  The study medication, BAY 81-8973, has been shown to have similar biological 
activity to Kogenate® FS/Bayer, which is currently approved in more than 50 countries for the 
treatment of hemophilia A. 
In Part A of this study (as of Amd 1), subjects will receive prophylaxis treatment with 
BAY 81-8973 at least 2 times weekly with a dose of 25-50 IU/kg at the choice of the 
investigator and according to local standards and previous treatment.  The dose should be
rounded to the appropriate vial size.  In Part B, prophylaxis may be started with a low dose, 
once a week treatment schedule.  The recommended dose is 15-50 IU/kg, (minimum 250 
IU) (as of Amd 6).  For all subjects, the (as of Amd 1) frequency as well as the dose may be 
adapted to the individual needs up to daily if needed to accommodate for the subject’s 
activities or sports participation. (as of Amd 1)
Any bleeding events occurring in subjects receiving prophylactic care will be treated 
according to the local standard of care and severity of the bleed. (as of Amd 1)
Subjects will be injected by parents/caregivers at home, at a facility near the subject’s home, 
homecare nurse (as of Amd 1), or by the investigator/delegate during the study visits.  
Children may also self-infuse, if under the supervision of a responsible adult to ensure 
adherence to the prescribed treatment regimen. (as of Amd 1)
For the optional PK study, each subject will receive an exact dose of 50 IU/kg of 
BAY 81-8973.  The dose will be prepared by a pharmacist or nurse at the study site.   This 
dose is expected to increase the plasma level of FVIII to approximately 80-100% FVIII 
activity. (as of Amd 1)
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14.1).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide instructions based upon 
the type of surgical procedure to be undertaken. (some text deleted as of Amd 1)

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6.5
Blinding
Not applicable. This is an open-label study.
6.6
Drug logistics and accountability
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 study file; the site-relevant 
elements of this information will be available in the investigator site file.  The responsible site 
personnel will confirm receipt of study drug in writing (some text deleted as of Amd 1) and 
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.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
6.7
Treatment compliance
Parents/caregivers will be provided with an EPD for the whole study (for details see Section 
7.3.2.2). These logs will be used to collecting the treatment (as of Amd 1) data and bleeding 
episodes.  The subject/parent/caregiver will interact with the Investigator or delegate weekly 
to verify and complete the EPD entries, and monthly during the extension study. (as of 
Amd 1)
Data on the EPD will be transmitted after each treatment is entered.  The (as of Amd 1) 
EPD will be used to assess the subject’s compliance with the prophylaxis treatment schedule 
and with the recording of treatments and bleeding events, and assist in study (as of Amd 1) 
medication inventory.  See Section 6.1.3 for discussion of missed treatments. (as of Amd 1)
Participation in the study may be terminated at the sponsor's discretion if a subject fails to 
comply with the above protocol requirements. (as of Amd 1)
Empty vials of study medication must be returned to the study center at each study visit.  At 
the end of the study, all used and unused study drug vials will be counted and collected by 
the sponsor’s representative (as of Amd 1) for final drug accountability. 
6.8
Post-study therapy
At the end of the study, all participants who have completed Part A or B (as of Amd 1) will 
be offered participation in an extension study.  Participation in the extension study will allow 
(as of Amd 1) continuation of treatment for at least 100 ED.  The extension (as of Amd 1) 
study requires continued documentation of infusions, bleeding events, monthly interaction 
with the treatment center, and visits every 6 months for inhibitor testing and recovery 
measurements. (as of Amds 1 and 6)

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After completion of the extension study, or if the subjects or their parents/caregivers are not 
willing to participate in the extension study, treatment with study drug will end.  Subsequent
(as of Amd 1 ) treatment will be mutually agreed upon by the parents/caregivers and the 
investigator.
6.9
Prior and concomitant therapy
BAY 81-8973 will be used as the sole FVIII source.  Pre-medications to tolerate treatment 
with BAY 81-8973 are not allowed.  Use of topical anesthetics prior to venipuncture is 
permitted.  (as of Amd 1).  Note: PTPs will continue their previous treatment up to 48 h 
before the first dose of BAY 81-8973 (as of Amd 3).
All medications and blood products required by the subject during the study will be listed in 
the CRF.  No other experimental drugs may be taken during the subject's participation in this 
study. 
No immunosuppressive/immunomodulatory drugs may be taken during the subject’s 
participation in the study.  If such therapy is deemed necessary for the subject’s welfare, or 
due to pre-existing illness, the situation should be discussed with the Sponsor before 
enrollment.  Medications which cause a bleeding diathesis (for example, Aspirin® or 
acetylsalicylic acid) are contraindicated in any individual with hemophilia and should be 
avoided, except as specifically prescribed by a treating physician. Use of non-steroidal anti-
inflammatory drugs, COX-2 inhibitors, or brief courses of corticosteroids to treat pain or 
acute synovitis, or inhaled or topical steroid medications (as for the treatment of asthma or 
eczema) are allowed. (as of Amd 1)
All concurrent prescription and non-prescription medications including over-the-counter and 
alternative preparations (including herbal remedies, vitamins, and health food supplements) 
will be recorded in the CRF (as of Amd 1) at screening and throughout the treatment and 
follow-up periods. 
7.
Procedures and variables
7.1
Schedule of procedures
7.1.1
Tabulated overview

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Table 7–1a: Schedule of evaluations (Part A – PTPs; >50 ED)
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week) (as 
of Amd 1)
Visit 4 
Month 2
(+/- 1 week) 
(as of 
Amd 1)
Final visit 
Month 6
(Minimum 50 
ED [as of 
Amd 1])
Extension 
Visit every 
6 months e
Extension
Final Visit  e
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
FVIII baseline level and inhibitor (one stage) (Amd 3) 
X
FVIII level pre infusion and inhibitor (as of Amd 1)
X
X
X
X
X
X
Recovery (20-30 min after infusion) c (as of Amd 1)
X
X
X
X
X f(Amd 6)
X (Amd 6)
Pharmacokinetics (optional)
-----------------------    X b ------------------------------------------------
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Electronic patient diary (EPD) documentation
      continuously       
Healthcare Resources Utilization Questionnaire (as of 
Amd 1)
X (as of 
Amd 1)
       monthly     
Interaction between subject/parent and investigator
     weekly                
  monthly 
Concomitant medication 
X
         continuously       
a.
Complete Blood Count (CBC), Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to be 
entered into CRF
c. 
Measured at least 48 h after last dose of FVIII (as of Amd 1)
d
Weekly contact during Part A, monthly during extension and 1-2 weeks after last study visit extension 
e.
For the regular Extension Visit every 6 months, a window of ±2 weeks is allowed.  The Extension Final Visit should take place no later than 2 weeks after 100 ED is 
achieved or until market authorization is obtained. (as of Amd 4)
f.
At the first extension visit 6 months after the start of the extension and at any time in case of  inhibitor development (as of Amd 6)

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Table 7–2b: Schedule of evaluations (Part B – PUPs/MTPs)
Assessments and procedures 
Main study
Optional extension 
study
Visit 1 
Screening
k
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
(PUPs only)
(as of Amd 6)
Visit 3 
ED ~5
(as of 
Amd 6)
Visit 4
ED 
~10
(as of 
Amd 6)
Visit 5 
ED 
~15
(as of 
Amd 6)
Visit 6 
ED 
~20
(as of 
Amd 6)
Interim
Visit
30-40 
ED
(as of 
Amd 1)
Final 
Visit
or
50 ED 
f
Extension 
Visit
every 
6 months f
Extension
Final Visit f
Informed consent
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X (Amd 7)
X (Amd 7)
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) 
(Amd 3)
X h (Amd 6) Xh (Amd 7)
X
FVIII level before infusion and inhibitor c (Amd 1)
X
X
X
X
X
X j
X
Epitope mapping (inhibitor positive patients) (Amd 4)
   X e 
Recovery (20-30 min after infusion) (Amd 1)
X
X
X
X
X j
(Amd 6)
X
(Amd 6)
Pharmacokinetics (optional) (Amd 3)
    X d 
Biomarker investigation (recommended) (Amd 4
and Amd 7)
    X g 
Infusion of study drug (Amd 1)
   continuously in accordance with the prophylaxis regimen  
Electronic patient diary (EPD) documentation
            continuously             
Healthcare Resources Utilization 
Questionnaire(Amd 1)
X (Amd 1)
       monthly      
Interaction between subject/parent and investigator
        weekly                        
  monthly  
Concomitant medication
X
          continuously        
For footnotes please see next page

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a
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c
Measured at least 48 h after last dose of FVIII
d
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to be entered 
into CRF
e
Epitope mapping to be performed in combination with confirmatory retest for inhibitory antibodies (as of Amd 4)
f
The Final Visit can be performed as soon as a minimum of 50 ED is achieved, but no later than 2 weeks after achieving 50 ED.  For the regular Extension Visit (performed 
every 6 months), a window of ±2 weeks is allowed. The Extension Final Visit should take place no later than 2 weeks after 100 ED is achieved 
g
The recommended biomarker investigation (pharmacogenetics) requires a separate signed informed consent (as of Amd 7). The single blood sample for this analysis can be 
taken at any visit except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional blood draw  (as of Amd 4)
h
Inhibitor to be evaluated at screening (central laboratory testing), and at baseline (central and local laboratory testing), in MTPs only (ie, unnecessary to evaluate in PUPs) 
(as of Amd 6, include retention sample for inhibitor assessment by ELISA for MTPs). Study drug administration should start upon availability of result from local laboratory
testing. (as of Amd 6 and Amd 7)
j
At the first extension visit 6 months after the start of the extension, and at any time in case of inhibitor development (as of Amd 6)
k
In case of MTPs, the screening visit should only take place after a washout period of at least 48 hours following any previous treatment with any FVIII replacement product 
(as of Amd 6).  

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7.1.2
  Timing of assessments
The main study consists of a Screening period followed by at least 50 ED per subject.  The 
Screening and Baseline visits may be combined to one visit for PUPs.  There is no 
minimum interval between the Screening and Baseline visits for PUPs/MTPs (as of Amd 6) 
or PTPs.  For PTPs, no longer than 8 weeks should pass between Screening and Baseline 
visits. (as of Amd 1)
In Part A, PTPs, a minimum of 50 ED will be accumulated during a 6 month treatment 
period.  Visits are scheduled at Month 1, Month 2 and Month 6. (as of Amd 1)
In Part B, the treatment period will be extended until 50 ED have been accumulated.  The 
duration of Part B will vary and is dependent upon the frequency of prophylactic infusion 
and the number of bleeding events.  Blood sampling for inhibitor testing is required every 
3-5 ED up to 20 ED, and again at 50 ED.  As most subjects will begin prophylaxis 1x week, 
study visits during the first 20 ED are expected to occur monthly.  However, it is understood 
that bleeding events resulting in added doses, delayed start of prophylaxis after first bleeds, 
or missed infusions due to difficult i.v. access may result in some variation in the number of 
ED a subject has obtained at each visit or the exact interval between visits.  Likewise, those 
subjects who receive more frequent infusions may require study visits more often than once 
a month. (as of Amd 1)
After completing Part A or B, all (as of Amd 1) subjects will be offered continued treatment 
in an extension study until a total number of at least 100 ED per subject are accumulated.  
Participation will require (as of Amd 1) additional visits every 6 months. 
7.1.2.1
Visit 1 – Screening
At the screening visit, the following procedures and assessments will be performed:

Obtain written informed consent from the parents/legal representative. Assent should 
be (as of Amd 1) obtained from subjects, depending on their age and intellectual status 
or according to local practice. (as of Amd 1)
Note: No Screening procedures may be performed unless written informed consent 
(and assent, if applicable) has been obtained. (see Section 11.2)

Assignment (as of Amd 1) of a unique PID number (see Section 5.3)

Eligibility check
No subject may receive treatment with study drug (as of Amd 1) unless all inclusion 
and exclusion criteria are met (as of Amd 1) as given in Section 5.1. Confirmation of 
selection criteria may be based on medical records, but laboratory test results must 
confirm eligibility.  The severity of hemophilia may be based on documented FVIII 
level at diagnosis. (as of Amd 1)

Recording of demographic data, medical and surgical history, and any adverse events 
(AEs) occurring after signing of informed consent. (as of Amd 3)

Recording of prior and concomitant medication and Healthcare Resources Utilization 
Questionnaire. (Appendix 14.3). (as of Amd 1)

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
Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.  Blood pressure may be deferred if appropriate cuff size or equipment is 
not available. (as of Amd 1)

Physical examination including measurement of body height/length and weight

Blood samples for laboratory tests: 
o
Complete blood count (CBC)
o
Serum chemistry (sodium [Na], potassium [K], bicarbonate [CO], chloride 
[Cl], creatinine, alanine and aspartate aminotransferases [ALT, AST], total 
bilirubin.  (See Section 14.4 for children <10 kg) (as of Amd 1)

FVIII:C level for PUPs and MTPs, inhibitor testing (not required for PUPs but 
required for MTPs incl. a retention sample for ELISA) (as of Amds 1 and 6)

Training on and dispensing (as of Amd 1) of the EPD.  Note: the EPD may be given 
to the subjects to take home at any time between Screening and Baseline, but no 
entries are to be made before the first injection at Baseline (as of Amd 3).
In case of MTPs, the screening visit should only take place after a washout period of at 
least 48 h following any previous treatment with any FVIII replacement product (as of Amd 
6).
7.1.2.2
Visit 2 – Baseline
This visit will serve as the Baseline visit. It will include the first administration of study drug. 
For subjects in Part A (PTPs)  (as of Amd 1), the Baseline visit should take place within 
8 weeks after Screening visit and at least 48 h after last FVIII administration. 
For PUPs, the Baseline visit (as of Amd 1) may be combined with the Screening visit if all 
selection criteria can be confirmed based on medical records. The first dose of BAY 81-8973
may be for treatment of a bleed.  First treatment should not occur during high risk 
situations, surgery, or bleeds requiring prolonged or intensive treatment (see Section 6.1.1). 
(as of Amd 1 and Amd 7)
This visit should start with the following assessments:
Confirmation of eligibility including check of laboratory test results.
Note: Eligible subjects (except PUPs) must be inhibitor negative at Baseline. MTPs 
must be inhibitor negative as evaluated via central laboratory testing at Screening 
visit (as of Amd 6). A confirmatory inhibitor test must be taken at Baseline visit.  
Results from local laboratory testing must be negative (<0.6 BU/mL ) prior to 
administration of study drug. (as of Amd 7)
The following activities will be performed (as of Amd 7):

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment). (as of Amd 1)

Measurement of body height/length (as of Amd 1) and weight

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
Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before infusion.  (Blood pressure may be deferred if appropriate cuff 
size or equipment is not available). (as of Amd 1)

Update of concomitant medication and Healthcare Resources Utilization 
Questionnaire (as of Amd 1). (Appendix 14.3) 

HSP-70 antibodies (in children > 7kg) (as of Amd 1)

Infusion of the first dose of study drug or dispensation of study drug for on-demand 
treatment in Part B (as of Amd 6).
Note:  For subjects in Part B (PUPs/MTPs), first exposure to study drug may be either 
for treatment of an uncomplicated bleed or for start of prophylaxis.  Inhibitor testing is 
mandatory every 3-5 ED until 20 ED are accumulated.  See discussion on treatment of 
PUPs/MTPs in Section 6.1.1. (as of Amds 1 and 6)

Vital signs (Heart rate, temperature, blood pressure) after infusion. (as of Amd 1)

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion. (as of Amd 1) (Only for subjects who start prophylaxis at Baseline, for 
others, recovery should be done when prophylaxis is started [as of Amd 6].) 

Optional PK: Additional blood samples at 4 h and 24 h post infusion (can also be 
performed at a later visit; obtained only once during study.)
Note to investigators: In compliance with European Medicines Agency (EMA) 
guidance and for subject safety, no more than 1% blood volume may be obtained at 
any one visit, and no more than 3% may be taken in one month (see Section 14.4).  
If additional PK samples are taken, the total volume of blood drawn in 24 h will be 
too high for infants weighing less than 9 kg, who must therefore be excluded from 
the PK sub-study.  (as of Amd 1, Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening, ideally at Visit 3 or whenever the subject’s body 
weight/condition is suitable for an additional blood draw (as of Amds 4 and 6). 
Additional informed consent is required. (as of Amd 7)

Documentation of AEs

Check of understanding of EPD use.  Repeat training on the device if required. (as 
of Amd 1)

Instruction on the prophylaxis regimen to be administered to the subject
Begin regular weekly contact between parents and the site to check the EPD documentation 
until next clinic visit.  Contacts should be documented in the medical record. (as of Amd 1)

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7.1.2.3
Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B (as of Amd 1)
The following procedures and assessments will be performed:

Check of EPD entries and bleeding history.  Collect information on AEs, update of 
concomitant medication and completion of Healthcare Resources Utilization 
Questionnaire. (Appendix 14.3).  (as of Amd 1 and Amd 3)

Measurement of body height/length (as of Amd 1) and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and 
body temperature.   (Blood pressure may be deferred if appropriate cuff size or 
equipment is not available). (as of Amd 1)

Blood sample for inhibitor testing and determination of FVIII:C trough levels (≥ 48 
h after last FVIII treatment). (as of Amd 1)

Infusion of study drug (Part A only) (as of Amd 1)

Vital signs after infusion, if given (as of Amd 1)

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion (Part A only) (as of Amd 1)

Optional PK: Additional blood samples at 4 h and 24 h post infusion, for Part B 
subjects also at 20-30 min after end of infusion (can also be performed at a later 
visit; obtained only once during study.)
Note to investigators: In compliance with EMA guidance and for subject safety, no 
more than 1% blood volume may be obtained at any one visit, and no more than 3% 
may be taken in one month (see Section 14.4).  If additional PK samples are taken, 
the total volume of blood drawn in 24 h will be too high for infants weighing less 
than 9 kg, who must therefore be excluded from the PK sub-study.  (as of Amd 1, 
Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
Regular weekly contacts between parents and the site to check the EPD documentation 
until next clinic visit.
7.1.2.4
Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B (as of Amd 1)
The following procedures and assessments will be performed:

Measurement of body height/length (as of Amd 1) and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and 
body temperature.   (Blood pressure may be deferred if appropriate cuff size or 
equipment is not available). (as of Amd 1)

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
Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (as of Amd 1) (Appendix 14.3).  

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment) (as of Amd 1)

Infusion of study drug (Part A only) (as of Amd 1)

Vital signs after infusion, if given. (as of Amd 1)

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion. (Part A only) (as of Amd 1)

Optional PK: Additional blood samples at 4 h and 24 h post infusion, for Part B 
subjects also at 20-30 min after end of infusion (can also be performed at a later 
visit; obtained only once during study.)
Note to investigators: In compliance with EMA guidance and for subject safety, no 
more than 1% blood volume may be obtained at any one visit, and no more than 3% 
may be taken in one month (see Section 14.4).  If additional PK samples are taken, 
the total volume of blood drawn in 24 h will be too high for infants weighing less 
than 9 kg, who must therefore be excluded from the PK sub-study.  (as of Amd 1, 
Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)

Check of EPD entries (as of Amd 1) of interval treatment and bleeding history.
Regular weekly contacts between parents and the site (as of Amd 1) to check the EPD 
documentation until next clinic visit.
7.1.2.5
Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (as of Amd 1)
The following procedures and assessments will be performed:

Measurement of body height/length and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and 
body temperature.   (Blood pressure may be deferred if appropriate cuff size or 
equipment is not available).  

Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (Appendix 14.2).  

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment).

Check of EPD entries of interval treatment and bleeding history.

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
Optional PK: Additional blood samples at 4 h and 24 h post infusion, for Part B 
subjects also at 20-30 min after end of infusion (can also be performed at a later 
visit; obtained only once during study.)
Note to investigators: In compliance with EMA guidance and for subject safety, no 
more than 1% blood volume may be obtained at any one visit, and no more than 3% 
may be taken in one month (see Section 14.4).  If additional PK samples are taken, 
the total volume of blood drawn in 24 h will be too high for infants weighing less 
than 9 kg, who must therefore be excluded from the PK sub-study.  (as of Amd 1, 
Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
Regular weekly contact between parents and the site to check the EPD entries until next 
clinic visit. (as of Amd 1)
7.1.2.6
Visit 6 – Part B only; ED 20 (20 ED +/- 1) (as of Amd 1)
The following procedures and assessments will be performed:

Measurement of body height/length and weight (as of Amd 1)

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and 
body temperature.   (Blood pressure may be deferred if appropriate cuff size or 
equipment is not available).  (as of Amd 1)

Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (as of Amd 1) (Appendix 14.3).  

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII infusion). (as of Amd 1)

Infusion (as of Amd 1) of study drug.

Vital signs after infusion. (as of Amd 1)

Blood sample for the determination of recovery to be taken at 20-30 min after end of
infusion. (as of Amd 1)

Check of EPD entries (as of Amd 1) of interval treatment and bleeding history.

Optional PK: Additional blood samples at 4 h and 24 h post infusion, for Part B 
subjects also at 20-30 min after end of infusion (can also be performed at a later 
visit; obtained only once during study.)
Note to investigators: In compliance with EMA guidance and for subject safety, no 
more than 1% blood volume may be obtained at any one visit, and no more than 3% 
may be taken in one month (see Section 14.4).  If additional PK samples are taken, 
the total volume of blood drawn in 24 h will be too high for infants weighing less 

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than 9 kg, who must therefore be excluded from the PK sub-study.  (as of Amd 1, 
Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
Regular weekly contacts between parents and the site (as of Amd 1) to check the EPD 
documentation until next clinic visit.
7.1.2.7
Interim visit – Only for Part B (30-40 ED) (as of Amd 1)
Visit only required for PUPs and MTPs who have less than 40 ED, 6 months after the 
Baseline visit.  The intent is to have at least one scheduled visit between completion of 
20 ED and the expected date of accumulating 50 ED.  The primary purpose of the visit is to 
assess the well-being of the subject, ensure continued compliance with the treatment, and 
make any needed adjustments in dosage or infusion frequency based upon weight or 
bleeding events.
The following procedures and assessments will be performed:

Measurement of body height/length and weight

Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (Appendix 14.2).  

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and 
body temperature.  (Blood pressure may be deferred if appropriate cuff size or 
equipment is not available).  

Check of EPD entries of interval treatment and bleeding history.
Regular weekly contacts between parents and the site to check the EPD documentation 
until next clinic visit. (as of Amd 1)
7.1.2.8
Final Visit (end of the main study and start of the optional extension 
study) 
For subjects in Part A (as of Amd 1), this visit will take place 6 months after baseline and at 
least 50 ED were accumulated, or in case of early termination.
For PUPs and MTPs in Part B, this visit will take place after 50 ED with study medication 
are accumulated, or in the case of early termination (as of Amd 6).  It is expected 50 ED 
will be achieved for most subjects between 6 and12 months after start of prophylactic 
treatment. (as of Amd 1)
The following procedures and assessments will be performed:

Physical examination including measurement of body height/length (as of Amd 1) and 
weight

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
Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and 
body temperature.   (Blood pressure may be deferred if appropriate cuff size or 
equipment is not available). (as of Amd 1)

Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (Appendix 14.3). (as of Amd 1) 

Blood samples for laboratory tests: 
o
Complete blood count [CBC]
o
Serum chemistry (sodium [Na], potassium [K], bicarbonate [CO], chloride 
[Cl], creatinine, alanine and aspartate aminotransferases [ALT, AST], total 
bilirubin.  (See Section 14.4 for children <10 kg) (as of Amd 1)

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment). (as of Amd 1)

HSP-70 antibodies (in children > 7 kg). (as of Amd 1)

Infusion of study drug. (as of Amd 1)

Vital signs after infusion. (as of Amd 1)

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion. (as of Amd 1)

Optional PK: Additional blood samples at 4 h and 24 h post infusion, for Part B 
subjects also at 20-30 min after end of infusion (can also be performed at a later 
visit; obtained only once during study.)
Note to investigators: In compliance with EMA guidance and for subject safety, no 
more than 1% blood volume may be obtained at any one visit, and no more than 3% 
may be taken in one month (see Section 14.4).  If additional PK samples are taken, 
the total volume of blood drawn in 24 h will be too high for infants weighing less 
than 9 kg, who must therefore be excluded from the PK sub-study.  (as of Amd 1, 
Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)

Check of EPD entries of interval treatment and bleeding history.
For subjects not participating in the optional extension study:

Return of EPD  

Return of used and unused study vials (as of Amd 1) for final drug accountability

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
Follow-up phone call (1-2 weeks after end of treatment)
Call parents/caregiver via telephone and review any new AEs and changes in 
concomitant medication since the last study visit.
For subjects participating in the optional extension study:

Informed consent signed by parents/legal representative must be available.

Continuation of prophylaxis treatment 

Begin regular monthly contacts between parents and the site to check the EPD 
documentation until next clinic visit. (as of Amd 1)
7.1.2.9
Extension study visits – 6 months after completion of Part A or B; then 
every 6 months (as of Amd 1)
The following procedures and assessments will be performed:

Measurement of body height/length, weight, and vital signs (as of Amd 1 and 
Amd 7).

Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (Appendix 14.3). (as of Amd 1)

Check of EPD entries of (as of Amd 1) interval treatment and bleeding history

Blood sample for inhibitor testing and determination of FVIII:C trough level (>48 h 
after last FVIII treatment) (as of Amds 1).

Blood sample for recovery measurement to be collected only at the first extension
visit at 6 months. Blood sample to be taken at 20-30 min after end of infusion (as of 
Amd 6).

Optional PK: Additional blood samples at 20-30 min, 4 h and 24 h post infusion 
(can also be performed at a later visit; obtained only once during study.)
Note to investigators: In compliance with EMA guidance and for subject safety, no 
more than 1% blood volume may be obtained at any one visit, and no more than 3% 
may be taken in one month (see Section 14.4).  If additional PK samples are taken, 
the total volume of blood drawn in 24 h will be too high for infants weighing less 
than 9 kg, who must therefore be excluded from the PK sub-study.  (as of Amd 1, 
Amd 3)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)

Regular monthly contacts between parents and the site to check the EPD 
documentation, update information on AEs and concomitant medication, 
completion of Healthcare Resources Utilization Questionnaire before next clinic 
visit. (as of Amd 1, Amd 3)

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7.1.2.10
Extension final visit
This visit will take place at the end of the extension period, or in the event of early 
termination. (as of Amd 3)
The extension study will be continued (as of Amd 1) for at least 100 cumulative ED.
The final study visit must be performed at the time of switch to commercial drug.
The following procedures and assessments will be performed:

Measurement (as of Amd 1) of body height, weight, and vital signs (as of Amd 7)

Documentation of interval history including AEs and concomitant medication and 
Healthcare Resources Utilization Questionnaire (Appendix 14.3). (as of Amd 1)

Blood sample for inhibitor testing and determination of FVIII:C trough level (>48 h 
after last FVIII infusion) (as of Amd 1) 

Check of EPD entries (as of Amd 1) of interval treatment and bleeding history

Return of EPD

Return of used and unused study vials (as of Amd 1) for final drug accountability

Recovery measurement, blood sample to be taken at 20-30 min after end of infusion.
(as of Amd 6)

(Some text deleted as of Amd 1)

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
Follow-Up Phone Call (1-2 weeks after end of treatment)
Call parents/caregiver via telephone and review any new AEs since the last study visit.
7.2
Population characteristics
7.2.1
Demographic
Demographic characteristics to be recorded at Screening will include age and race. In 
addition, a complete physical examination including pulse, blood pressure, body temperature, 
height, weight, and a review of body systems will be performed and the results documented. 
If known, any gene mutation should be noted (as of Amd 3).

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7.2.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected:

Not pertaining to the study indication

Start before signing of the informed consent 

Considered relevant to the study.
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 7.5.1.1.
7.2.3
Disease history
Disease history to be recorded at Screening will include date of diagnosis, start of therapy, 
number of ED, family history, past inhibitor testing, current treatment regimen, FVIII level 
and type of assay, number of bleeds in the last 12 months, and presence of target joints.
7.3
Efficacy
7.3.1
Efficacy variables
The primary variable is the annualized number of total bleeds (sum of spontaneous bleeds 
and traumatic bleeds) during prophylaxis that occurs within 48 h of the last prophylaxis 
infusion. Both joint and non-joint bleeding will be assessed. (as of Amd 1)  Additional 
efficacy parameters include:

Subject/parents’ assessment of the response to treatment of bleeding events, which is 
assessed as excellent, good, moderate or poor. (as of Amd 1)

Annualized number of total bleeds (sum of spontaneous and trauma bleeds) (as of 
Amd 1) during prophylaxis treatment

Assessment of adequacy of hemostasis (as of Amd 1) during surgical interventions

Number of infusions for the treatment of a bleed

Consumption of FVIII
The main surrogate efficacy parameter is the recovery of FVIII after infusion. (as of Amd 1)
If an infusion is given to control a bleed at the same location within 72 hours of the 
previous dose for a bleed at that site, it is to be considered a follow-up infusion and not 
treatment of a new bleed, unless both bleeds are skin/mucosa bleeds (as of Amd 3).
The complete list of variables to be analyzed for this study will be provided in the Statistical 
Analysis Plan.

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7.3.2
Efficacy procedures
7.3.2.1
Incremental recovery of Factor VIII (as of Amd 1)
Samples for FVIII trough levels will be collected in the clinic before the next planned 
prophylactic infusion as scheduled. Recoveries should be performed in conjunction with 
planned prophylaxis infusions, using the subject’s usual dose (exception, during optional 
PK). Infusions given at study visits will not be recorded in the EPD, but in the site patient 
records, which will be the source document and will be used to enter this information in the 
CRF. (as of Amd 1)
Levels of BAY 81-8973 will be determined in a central laboratory with the chromogenic 
method. (as of Amd 1)
FVIII trough levels will be determined in the blood samples collected before the scheduled
BAY 81-8973 infusions at Baseline, Month 1, Month 2, and Month 6 (or final visit) in Part 
A; or at Baseline, ED 20, and final visit (ED 50) in Part B. The measurement should be 
performed at least 48 h after last infusion of BAY 81-8973. (as of Amd 1)
Incremental recovery at 20-30 min after end of infusions (as of Amd 1) will be determined 
at Baseline, Month 1, 2, Month 6 (or final visit), 1st extension visit and final extension visit
(as of Amd 6). Incremental recovery should only be measured when the subject is not actively 
bleeding. The exact sampling times before and after infusion (as of Amd 1) have to be 
documented in the CRF.
A determination of recovery should also be performed with the confirmatory inhibitor test
(as of Amd 7).
7.3.2.2
Treatment logs / bleeding verification
Treatment (as of Amd 1) logs are commonly used for hemophilia subjects for documentation 
of their home treatment. Home treatment and bleeding frequency are key variables evaluated 
in this study.  Study specific 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 also the data cleaning process.
Subjects/parents/caregivers will be provided with EPDs for the whole study. At Screening and 
Baseline visits, subjects and parents/caregivers will be trained in the use of the device. These 
logs will be used to collect the treatment (as of Amd 1) data and bleeding episodes by the 
parents/caregivers or subjects, and interact on a regularly scheduled (as of Amd 1) basis with 
the investigator or delegate to verify and complete the data on (as of Amd 1) the EPD. Thus, 
the EPD will be considered the source for these data.
For each use of study medication including the infusions administered during a planned visit 
for evaluation of recovery, information must be recorded on the Treatment (as of Amd 1) 
Logs as follows:
1. Date and time
2. Lot numbers / number of vials administered

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3. Reason for treatment (as of Amd 1) (prophylaxis, spontaneous bleed first treatment, 
trauma bleed first treatment, follow-up treatment, surgery, other).  (If an infusion is 
given in response to a fall or identified trauma, such as may occur when a child has 
an uncomplicated blow to the head and there is no clinical sign or evidence of 
bleeding, the event should be recorded as prophylaxis.) (as of Amd 1)
If treatment is for a bleeding episode: site of bleeding, severity (severe, moderate, mild), and 
response to treatment (excellent, good, moderate, poor, too early to tell) are to be recorded.  
If ‘too early to tell’ is entered, the subject will be queried for a response the next time they 
use the device.  For guidance to the subject or their caregivers, the following definitions for 
response to treatment are suggested.  Individual subject responses may vary (as of Amd 1):

Excellent: Abrupt pain relief and /or improvement in signs of bleeding with no 
additional infusion administered (as of Amd 1)

Good:  Definite pain relief and/or improvement in signs of bleeding, but possibly 
requiring more than one infusion for complete resolution (as of Amd 1)

Moderate:  Probable or slight improvement in signs of bleeding, with at least one 
additional infusion for complete resolution (as of Amd 1)

Poor:  No improvement at all between infusions or condition worsens. (as of 
Amd 1)
7.4
Pharmacokinetics (optional – consent required) (as of Amd 1)
Participation in the PK evaluations is optional.  The minimal number of subjects in the 
optional PK is 6.  If consent/assent is obtained, PK will be assessed using the (as of Amd 1)
sampling time points specified in this protocol (as of Amd 1). The pharmacokinetics of the 
study drug in plasma can be determined at any time, and should be scheduled to coincide 
with a scheduled visit to measure incremental recovery, if possible (as of Amd 1).  There 
must be a washout of previous FVIII of at least 48 h before the first infusion (as of Amd 1) of 
study drug and the subject must have no signs or symptoms of an acute bleeding episode.  All 
samples will be processed in the central laboratory. (as of Amd 1)
Subjects will be administered a dose of 50 IU/kg. Blood samples will be obtained pre-
infusion (as of Amd 1) and at 20-30 min, 4 h, and 24 h (as of Amd 1) after the end of 
infusion (as of Amd 1) of study medication. FVIII levels will be determined by the 
chromogenic assay. Details of the blood sampling and processing procedures for all 
laboratory measurements will be provided in the Laboratory Manual, developed by the 
central laboratory (as of Amd 3), that accompanies this protocol.  A dose preparation 
worksheet will be provided in the Pharmacy manual (as of Amd 1).
Note to investigators: In compliance with EMA guidance and for patient safety, no more 
than 1% blood volume may be obtained at any one visit, and no more than 3% may be 
taken in one month (see Section 14.3).  If additional PK samples are taken, the total volume 
of blood drawn in 24 h will be too high for infants weighing less than 9 kg, who must 
therefore be excluded from the PK sub-study.  (as of Amd 3)

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Based on the plasma concentration time data the following pharmacokinetic parameters will 
be calculated:  Maximum concentration (Cmax), recovery, AUC, half-life (t1/2), MRT and 
clearance (CL). 
7.5
Safety
7.5.1
Adverse events
7.5.1.1
Definitions
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.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal, eg, physical examination findings, symptoms, diseases, laboratory values.

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 (eg, seasonal allergy without acute complaints, abnormal laboratory finding at 
screening).

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 (eg, allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs.
Note:  Any bleeding event occurring during the study will not be documented as an AE, 
because this event (as of Amd 1) is captured in the assessment of efficacy. However, if the 
bleed requires hospitalization, it must be reported as a Serious Adverse Event (SAE) (see 
Section 7.5.1.4).

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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 in subject 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 hours
- The admission is pre-planned 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
- The admission is not associated with an AE 
(eg, 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 medically important serious event as judged by the investigator.
Note: Any inhibitor development is considered an SAE.
7.5.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
7.5.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.5.1.1.

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7.5.1.2.2
Intensity
The intensity of an AE is classified according to the following categories, taking into account 
the possible range of the intensity of the event:
- Mild
- Moderate
- Severe
7.5.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 
CRF.
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 clear alternative explanation, eg, mechanical bleeding at surgical 
site.
or
2. Non-plausibility, eg, 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 there is a reasonable suspicion that the AE is associated 
with the use of the study treatment.
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 subjects response after re-challenge should be 
considered in the 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 

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examined to determine whether any of them may be suspected to cause the event in 
question.
- 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.
7.5.1.2.4
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 reduced
- Dose not changed
- Dose increased
- Not applicable
- Unknown
7.5.1.2.5
Other specific treatment(s) of adverse events
- None
- Remedial drug therapy
- Other
7.5.1.2.6
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
7.5.1.3
Assessments and documentation of adverse events
Subjects must be carefully monitored for AEs. All AEs occurring after signed informed 
consent was obtained must be fully recorded in the subject’s CRF.
Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality occurring after screening considered clinically relevant, eg, causing the subject to 

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withdraw from the study, requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an AE.  Each event should be 
described in detail along with start and stop dates, severity, relationship to investigational 
product, action taken, and outcome.
7.5.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 7.5.1.1.
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.
All SAEs occurring during the observation period defined in Section 7.5.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the recipient 
detailed in the manual.  An SAE form must also be completed within 24 hours of the 
investigator awareness and forwarded to the designated recipient.  Each SAE must be 
followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the Independent Ethic Committees (IECs) / Institutional Review Boards 
(IRBs)
Notification of the IECs / IRBs about all relevant events (eg, SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (eg, SAEs, 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 (eg, SUSARs) 
according to all applicable regulations.
7.5.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB).
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current 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.

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The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
7.5.2
Pregnancies
Not applicable in this pediatric male subject population.
7.5.3
Further safety
7.5.3.1
Vital signs
Systolic and diastolic blood pressure, heart rate, and body temperature will be measured at all 
visits.  Blood pressure may be deferred in infants if appropriate size cuff or equipment is 
not available. (as of Amd 1)
7.5.3.2
Physical examination
A complete physical examination including the measurement of body height, weight and 
temperature will be performed at the Screening visit and at the Month 6 (or final visit).  Body 
length will be measured instead of height, as age appropriate. (as of Amd 1)
At the other visits, and during the (as of Amd 1) optional extension study (every 6 months 
until switch to commercial drug), only the subject’s body height, temperature and weight will 
be measured.
7.5.3.3
Standard safety laboratory
The following blood (as of Amd 1) samples will be collected at Screening and Month 6 (or 
final visit): 

CBC with differential: erythrocytes, hemoglobin, hematocrit, platelets, leukocytes, 
neutrophils, eosinophils, basophils, monocytes, and lymphocytes  

Serum chemistry (electrolytes (sodium [Na], potassium [K], bicarbonate [CO], 
chloride [Cl], creatinine, alanine and aspartate aminotransferases [ALT, AST], total 
bilirubin) (as of Amd 1)
The following blood samples will be collected at Baseline and Month 6 (or final visit) (as of 
Amd 1): 

HSP-70 antibody (except in subjects <7kg) (as of Amd 1)
7.5.3.4
Inhibitor testing
Premise for inclusion requires confirmed diagnosis of severe hemophilia A (<1% FVIII) 
and documentation of a (as of Amd 1) negative test result of inhibitor at Baseline. 
Blood samples for FVIII inhibitor testing will be taken at Screening (PTPs and MTPs only), 
Baseline, at regularly scheduled intervals throughout the study, and at the (as of Amds 1
and 6) final visit. The premise for inclusion of PTPs and MTPs in this study is the availability 
of a negative inhibitor result (as of Amds 1 and 6) as measured in the blood sample at 
Screening and Baseline (as of Amd 7). A further sample will be taken at baseline before the 
first infusion (as of Amd 1). If the inhibitor testing result changes from negative at screening 

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to positive at baseline, before the first infusion (as of Amd 1) of study medication, the subject 
must be withdrawn from the trial.
In Part B, the requirement for a FVIII inhibitor testing before study entry (as of Amd 1) is 
not applicable for PUPs but is applicable for MTPs (as of Amd 6). The absence of inhibitors 
will be assessed using central laboratory testing at Screening (<0.2 BU/mL), with 
confirmation using local laboratory testing at Baseline (<0.6 BU/mL) (as of Amd 7). After 
treatment is started (as of Amd 1), PUPs/MTPs must be tested for inhibitor development 
every 3-5 ED until 20 ED are accumulated (as of Amd 6), and at the final visit (50 ED) (as of 
Amd 7). Afterwards, blood samples for inhibitor testing and determination of FVIII:C 
trough level (>48 h after last FVIII treatment) are to be taken:

every 6 months in the extension study until finalization of the study, and at the final 
visit (as of Amds 1 and 6).
The laboratory analyses will be performed at central laboratories. 
Investigators will be provided with a detailed laboratory manual and a copy of the individual 
results. Inhibitor testing will be done according to the Nijmegen modified Bethesda inhibitor 
assay at the central laboratory (as of Amd 1). A positive inhibitor testing is defined with a 
threshold of ≥ 0.6 BU in the central laboratory. Any positive test must be confirmed by a 
second plasma (as of Amd 1) sample and a determination of recovery should be performed. 
(as of Amd 6)
For any subject confirmed positive for inhibitors, epitope mapping will be performed (see 
Section 7.6.1 for details).  (as of Amd 4)
Remaining rest of the plasma samples collected at specified study visits could be used for 
immunology or additional coagulation analysis, or for clarification of any clinical or 
laboratory adverse event and in no case for genetic analyses. (as of Amd 6)
7.6
Other procedures and variables
7.6.1
Epitope mapping (as of Amd 4)
In the event a subject tested positive for inhibitor, additional blood, up to a maximum 
allowable as described in Table 14-4a, should be taken to confirm the result (retesting).  
If the result upon retesting is also positive, epitope mapping will be performed with the 
additional blood sample that was taken.  Details of sample collection and shipment 
procedures will be provided in the Laboratory Manual. (as of Amd 4)

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7.6.2
Biomarker investigation (pharmacogenetics) (recommended – consent 
required) (as of Amd 4 and Amd 7)
The purpose of this genetic analysis is to identify markers for risk of inhibitor development 
in subjects treated with BAY 81-8973.  The markers to be analyzed are type of FVIII gene 
mutation if not available, single nucleotide polymorphisms (SNPs) in immunoregulators 
(eg, IL 10), HLA genotype, and FVIII polymorphisms. This biomarker analysis is 
exploratory and will be analyzed for PUPs and MTPs only. (as of Amds 4 and 6)
A separate informed consent for pharmacogenetic sampling is required and participation is 
recommended.  (as of Amd 4 and Amd 7)
If a subject elects to participate, a blood sample can be collected at any visit except 
Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for 
an additional blood draw.  Samples will be prepared and labeled according to laboratory 
specifications.  Details of the sample collection and shipment procedures will be provided in 
the Laboratory Manual. (as of Amd 4)
A subject does not need to agree to participate in the pharmacogenetic sub-study to be 
enrolled in the main study. (as of Amd 4). However, as this analysis provides important 
information about inhibitor development, participation is the sub study is recommended. 
(as of Amd 7)
7.7
Appropriateness of procedures / measurements
All procedures / measurements are established and validated in this therapeutic area. The 
assessments closely follow the recommendations specified in CPMP/BPWG/1561/99.
8.
Statistical methods and determination of sample size
8.1
General considerations
Statistical analyses will be performed using SAS release 9.1 or higher (SAS Institute Inc., 
Cary, North Carolina [NC], United States of America [USA]).  The version used will be 
specified in the Statistical Analysis Plan. (As of Amd 1)
8.2
Analysis sets
Efficacy and safety data will be collected from all subjects who received study medication.  
The intent-to-treat (ITT) population will include all subjects randomized into the study who 
received study drug.  The per-protocol population will exclude subjects who are deemed 
invalid in the Validity Review Report.  Subjects from Part A and Part B will be summarized 
separately. (as of Amd 1)
8.3
Variables
Baseline

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Demographic characteristics, including age, weight, height and race as well as previous 
exposure to FVIII will be presented for all treated subjects, in the form of summary statistics.  
Other baseline characteristics, including laboratory findings and vital signs, will be handled 
similarly.   
Extent of Exposure
Extent of exposure to the study drug, including treatment (as of Amd 1) characteristics, will 
be documented in subject diaries and summarized for each subject receiving any amount of 
drug.
Safety
Safety data will be summarized for all subjects in the safety population.  Laboratory findings, 
AEs, concomitant medications, and medical history data will be provided in subject listings.
Laboratory values and vital signs will be summarized.  Individual listings of AEs [including 
AEs as reported, start, duration, severity, relation to study drug] will be provided.  The 
incidence of treatment-emergent AEs will be summarized using the Medical Dictionary for 
Regulatory Affairs (MedDRA). (some text deleted as of Amd 1)
Inhibitor development, as measured by Nijmegen assay, will be summarized by time point 
and presented in subject listings.  The purpose of the listing is to delineate the clinical 
factors which may be positively associated with development of the inhibitor. (as of Amd 1)
The frequency of subjects who develop positive inhibitor titers (Bethesda > 0.6 BU) and 
confirmed by repeat measurement (as of Amd 1) will be presented by time point. If the 
inhibitor value drops below 0.6 BU on repeat measure without intervention, the inhibitor 
will be determined as being transient.  We will classify inhibitor patients as being either low 
titer or high titer based upon persistence of an inhibitor >5 BU. (as of Amd 1)  The rate of 
inhibitor development associated with BAY 81-8973 will be determined.  Subjects with no 
inhibitors are required to have at least 50 ED to be counted in the denominator.  
Efficacy
Efficacy data will be summarized for all subjects in the intent-to-treat (as of Amd 1) (ITT)
population.  The primary efficacy variable will be the annualized number of total bleeds (sum 
of spontaneous bleeds and traumatic bleeds) (as of Amd 1) within 48 h after a prophylaxis 
infusion (as of Amd 1).  Other variables summarized will be the 
physician’s/subject’s/parents’ (as of Amd 1) assessment of the response to treatment of bleeds 
(excellent, good, moderate, poor) (as of Amd 1) and during surgeries.  The number of 
treatments required to control bleeds, the proportion (as of Amd 1) of prophylaxis infusions 
with less than expected therapeutic effect (LETE) (defined as a prophylaxis infusion followed 
by a bleed within 48 h), annualized number of total bleeds (sum of spontaneous bleeds and 
trauma bleeds) (as of Amd 1) during prophylaxis, FVIII usage and recovery will be 
summarized. A detailed Statistical Analysis Plan with be provided (as of Amd 1).
Pharmacokinetics / pharmacodynamics (Optional)

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For investigation of drug exposure and potential relationships to drug effects, selected 
subjects will participate in pharmacokinetic (PK) sampling. Any subject’s participation in PK 
sampling is voluntary and consent/assent is required (as of Amd 1).
Based on the known PK of FVIII in hemophilia subjects it is expected that a reduced (as of 
Amd 1) sampling strategy will be sufficient to calculate relevant pharmacokinetic parameters. 
Blood samples for population PK analyses will be collected according to a sampling schedule. 
Blood sampling for the determination of FVIII:C in plasma will be taken at baseline before
the infusion (pre-infusion) at 20-30 minutes, 4 h, and 24 h after end of infusion. Attempt 
should be made to collect the sample as close as possible to the times indicated above.  If 
there is a delay in collecting a sample, the sample should still be collected so that there are 
at least 3 samples post infusion.  In all cases the exact time of start and end of infusion and 
the time of actual sample collection should be noted in the CRF. (as of Amd 1)
A minimal number of 6 subjects is required. The following parameters will be calculated: 
Cmax, AUC, recovery, clearance, MRT and t ½ using non-compartmental methods.
8.4
Statistical and analytical plans
The data will be summarized using the software package SAS release 9.1 or higher (SAS 
Institute Inc., Cary, North Carolina [NC], United States of America [USA]).  All data will be 
listed and summary tables will be provided.  The number of data available and missing data, 
mean, standard deviation, and other summary statistics will be calculated for continuous data.  
Frequency tables will be generated for categorical data.  No formal statistical tests will be 
performed.  
8.5
Planned interim analyses
The main study has a duration of 6 months.  The 6-month data for PTPs (as of Amd 1) will be 
analyzed for regulatory purposes as an interim analysis.  An interim analysis will be 
performed for 25 PUPs after they will have completed in Part B (as of amd 6). An 
additional analysis will be performed when all PUPs/MTPs have completed part B. If 
required for regulatory purposes, Part B data will be described in an interim analysis if at 
least 5 PUPs have been recruited(as of Amd 3). The overall study will be closed after all
subjects in Parts A and B (as of Amd 1) have completed the extension trial and an additional 
analysis will include all data from the main trial and the extension part.
When safety has been assessed in 10-20 PTPs who have received at least 50 ED, enrollment 
will begin in Part B.  All subjects will have the option of continuing in the extension trial. 
The trial data will be reviewed periodically by an independent DMC.  The DMC will review 
certain safety and efficacy data sets as defined in the charter, as well as the planned interim 
analysis, and provide written reports to the sponsor.  The decision to open enrollment to 
each age group will be made following recommendation of the DMC. (as of Amd 1).

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8.6
Determination of sample size
Sample size has been determined according to the requirements set forth by (as of Amd 1)
guideline CPMP/BPWG/1561/99 (Note for Guidance on the Clinical Investigation of 
Recombinant Factor VIII and Factor IX Products), and taking into account the revised draft 
version, CHMP/BPWP/144533/09. Age groups are in accordance with the International 
Conference on Harmonization (ICH)/CPMP guideline E11 (Clinical Investigation of 
Medicinal Products in the Pediatric Population(19)) and sample sizes have been confirmed 
on consultation with the European Medicines Agency Paediatric Committee [EMA/PDCO] 
on submission of the Pediatric Investigation Plan. (as of Amd 1)
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.  This study consists of two parts.  Part A (as of 
Amd 1) will include a total of 50 PTPs (as of Amd 1); 25 subjects age 6 – 12 years (as of 
Amd 3) and 25 subjects age <6 years. Part B will enroll at least 25, plus approximately an 
additional 25 PUPs/MTPs age <6 years. (as of Amd 3 and Amd 7) The total sample size will 
be approximately 100 subjects. (as of Amds 3, 6 and 7)
9.
Data handling and quality assurance
9.1
Data recording
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.  A source document is defined as the first place data are 
recorded; the CRF is not a source document. The site must ensure the existence of source 
documents. (as of Amd 1) A source document checklist will be used at the site to identify the 
source data for all data points collected and the monitor will work with the site to complete 
this.
The patient reported data may be entered directly into the EPD, for all other data source 
documentation must be available.  
Monitoring
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. (some text deleted as of Amd 1)
The sponsor/designee will monitor the site activity to verify that the:
Data are authentic, accurate and complete
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.

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The investigator and the head of the medical institution (where applicable) agree to allow the 
monitor direct access to all relevant documents.
9.2
Data processing
The data collection tool for this study will be a validated electronic system called RAVE.  
Subject data necessary for analysis and reporting will be entered/transmitted into a validated 
database or data system (eg, Toolbox for System Configuration and Administration 
[TOSCA]; SAS).  Clinical data management will be performed in accordance with applicable 
sponsor’s standards and data cleaning procedures.  This is applicable for data recorded on 
CRF as well as for data from other sources (eg, EPD, Interactive voice randomization system 
[IVRS], laboratory, electrocardiogram [ECG], electronic patient reported outcome [ePRO], 
adjudication committees).
For data coding (eg, AEs, medication), internationally recognized and accepted dictionaries 
will be used.
9.3
Audit and inspection
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 
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 Independent Ethics 
Committee (IEC)(s)/Institutional Review Board (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.
9.4
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Subject (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 
(eg, relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The investigator’s contract will contain all regulations relevant for the study center.

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10.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[eg, 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 (eg, SAEs)
- Results of any interim analysis
- Results of parallel clinical studies
- Results of parallel animal studies 
(on eg, toxicity, teratogenicity, carcinogenicity or reproduction toxicity).
If the study conduct (eg, recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the study within a reasonable 
time frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:
Closure should occur only after consultation between involved parties.
All affected institutions (eg, 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 given by the sponsor for destruction.
In case of a partial study closure, ongoing subjects, including those in post-study 
follow-up, must be treated (as of Amd 1) of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 5.2.1.
11.
Ethical and legal aspects
11.1
Ethical and legal conduct of the study
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 under the guiding principles detailed in the 
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 also forwarded to the Sponsor.  The responsible unit (eg, Ethic 
Committee [EC]/IRB, head of the study center/medical institution) must supply to the 

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Sponsor, upon request, a list of the EC/IRB members involved in the vote and a statement to 
confirm that the EC/IRB is organized and operates 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 study 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 10.
11.2
Subject information and consent
All relevant information on the study will be summarized in an integrated subject/parent 
information sheet and informed consent form provided by the sponsor or the study center.  A 
sample subject/parent 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 / parent / legal representative or proxy consenter (if the 
subject is under legal protection), prior to his/her 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.
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision.
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 
investigator and other information provider (if any) 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 subject’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.

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For minors, consent shall be given by the parents/legal representative. (as of Amd 1) The 
assent (as of Amd 1) of a minor shall also be requested where such a person is able to express 
his/her own will.  His/her refusal or the withdrawal of his/her consent may not be disregarded.
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/parents’ 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/her participation in the study by signing the revised informed consent form.  Any 
revised written informed consent form and written information must receive the IEC/IRB’s 
approval / favorable opinion in advance of use.
11.3
Publication policy
The sponsor is interested in the publication of the results of every study it performs.  
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.  
11.4
Compensation for health damage of subjects / insurance
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.
11.5
Confidentiality
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 (eg, 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.
12.
Reference list 
1.
Petrini P, Lindvall N, Egberg N, Blomback M. Prophylaxis with factor concentrates in 
preventing hemophilic arthropathy. Am J Pediatr Hematol Oncol. 1991;13(3):280-7.

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2.
Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic 
outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome 
Study Group. J Intern Med. 1994;236(4):391-9.
3.
Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of 
arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta 
Orthop Scand Suppl. 1965:Suppl 77:3-132.
4.
Lofqvist T, Nilsson IM, Berntorp E, Pettersson H. Haemophilia prophylaxis in young 
patients--a long-term follow-up. J Intern Med. 1997;241(5):395-400.
5.
Ljung RCR. Prophylactic treatment in Sweden--overtreatment or optimal model? 
Haemophilia. 1998;4(4):409-12.
6.
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.
7.
Liesner RJ, Khair K, Hann IM. The impact of prophyactic treatment on children with 
severe haemophilia. Br J Haematol. 1996;92(4):973-8.
8.
Kreuz W, Escuriola-Ettingshausen C, Funk M, Schmidt H, Kornhuber B. When should 
prophylactic treatment in patients with haemophilia A and B start?--The German 
experience. Haemophilia. 1998;4(4):413-7.
9.
van den Berg HM, Fischer K, van der Bom JG. Comparing outcomes of different 
treatment regimens for severe haemophilia. Haemophilia. 2003;9 Suppl 1:27-31.
10.
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. 
Prophylaxis versus episodic treatment to prevent joint disease in boys with severe 
hemophilia. The New England journal of medicine. 2007;357(6):535-44.
11.
Abshire TC, Brackmann HH, Scharrer I, Hoots K, Gazengel C, Powell JS, et al. 
Sucrose formulated recombinant human antihemophilic factor VIII is safe and 
efficacious for treatment of hemophilia A in home therapy--International Kogenate-FS 
Study Group. Thromb Haemost. 2000;83(6):811-6.
12.
Kreuz W, Gill JC, Rothschild C, Manco-Johnson MJ, Lusher JM, Kellermann E, et al. 
Full-length sucrose-formulated recombinant factor VIII for treatment of previously 
untreated or minimally treated young children with severe haemophilia A: results of an 
international clinical investigation. Thromb Haemost. 2005;93(3):457-67.
13.
Lusher J, Abildgaard C, Arkin S, Mannucci PM, Zimmermann R, Schwartz L, et al. 
Human recombinant DNA-derived antihemophilic factor in the treatment of 
previously untreated patients with hemophilia A: final report on a hallmark clinical 
investigation. Journal of thrombosis and haemostasis : JTH. 2004;2(4):574-83.
14.
Seremetis S, Lusher JM, Abildgaard CF, Kasper CK, Allred R, Hurst D. Human 
recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of 
haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE 
Study Group. Haemophilia. 1999;5(1):9-16.
15.
Konstantinov KB. Monitoring and control of the physiological state of cell cultures. 
Biotechnol Bioeng. 1996;52(2):271-89.
16.
EMEA. Note for guidance on the clinical investigation of recombinant factor VIII and 
IX products. CPMP/BPWP/1561/99. 2000.

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17.
Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of 
inhibitor development in previously untreated patients with hemophilia A: the 
CANAL cohort study. Blood. 2007;109(11):4648-54.
18.
Kurnik K, Bidlingmaier C, Engl W, Chehadeh H, Reipert B, Auerswald G. New early 
prophylaxis regimen that avoids immunological danger signals can reduce FVIII 
inhibitor development. Haemophilia. 2010;16(2):256-62. (as of Amd 1)
19.
ICH. ICH harmonised tripartite guideline: Clinical investigation of medicinal products 
in the pediatric population E11. 2000:1-12.

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13.
Protocol amendments
13.1
Amendment 1
Description of Amendment
Amendment 1 implements revisions and clarifications secondary to the recommendations of 
regulatory agencies and in response to specific questions and comments received from 
pediatric specialists and investigators.  These include provision of an improved explanation of 
the staggered enrollment by subject age, a more exact definition of the number of subjects to 
be enrolled into the study, clarification of the timing of start of prophylaxis in PUPs, and 
reduction of the number of blood draws and blood volumes required for study participation in 
all age groups.  The PK sampling scheme in Part A has been revised to reduce the burden on 
subjects and allows participation of all PTPs as PK measures may be required after start of 
study to make decisions regarding individualized dosing regimens.  The duration of study 
participation and timing of study visits and blood draws in Part B are further clarified since 
the time to accumulate 50 ED in PUPs may vary.  Important additions were made regarding 
the risk of inhibitor development, including instructions on possible methods to avoid their 
development, how to respond if an inhibitor occurs, clarification that such subjects will be 
offered an immune-tolerance regimen with BAY 81-8973using the study drug, and added 
detail on how inhibitors will be defined and evaluated. 
Updated information was added reflecting current clinical studies using BAY 81-8973. The 
chromogenic assay used to measure the potency of the investigational drug is mentioned, 
since this information may be important to investigators when picking the appropriate dosages 
for subjects.  Inclusion and exclusion criteria and measurements of vital signs were clarified 
to be more consistent with pediatric practice.  Finally, editorial changes, correction of 
typographical errors, and minor revisions of language were made to ensure clarity and 
consistency throughout the document.  As the terms injection and infusion were previously 
used interchangeably, infusion is now used preferentially.  
13.1.1
Overview of changes
Change 1:  Specification of the exact number of subjects to be enrolled and clarification of the 
time points in which each age group will be allowed to enter the study.
A total of 75 subjects will participate in study 13400, with 25 subjects enrolled in each age 
group.  A clarification that the sample size was defined by the requirements of European 
Agency for the Evaluation of Medicinal Product (EMEA) guidance and direct feedback by 
regulatory agencies has been added.  
It is now more clearly defined that the study consists of 2 parts, Part A for PTPs, and Part B 
for PUPs.  Part A opens only after 20 adolescents and adults in another study have been 
treated with at least 50 ED.   Part A will first enroll PTPs age >6-12 years, followed by PTPs 
age 0-6 years.  Part B for PUPs will not begin enrollment until after 20 subjects in Part A have 
received at least 50 ED.  As an external DMC has been formed to provide independent 

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assessment of the safety prior to opening the study to each age group, the existence of this 
committee and their role has been added to the protocol.
Sections affected include:

Synopsis – Duration of treatment

Synopsis – Methodology

Synopsis – Number of Subjects

Section 4, Study design

Section 7.1.1, Tabulated overview

Section 7.1.2, Timing of assessments

Section 8.5, Planned interim analyses

Section 8.6, Determination of sample size
Change 2:  Several changes have been introduced with the primary intent to reduce the burden 
on children incurred by recurrent blood draws or withdrawal of volumes which may be 
unsafe.  
The original protocol included the requirement for a plasma sample to be retained for repeat 
measurements of coagulation studies.  This sample was mistakenly referred to as a serum 
sample in several places in the protocol and its specific use was not well defined.  Reappraisal 
of procedures in the central laboratory and sample volumes resulted in the determination that 
storage of a plasma sample is not needed.  Consequently the retention sample has been 
removed.  An inconsistency was also identified in which a sample for HSP-70 antibody was 
required in the schedule of visits, but not in the text.  This has been clarified by removing the 
requirement for the sample to be drawn from the chart.  Another inconsistency specifying the 
required serum chemistry analytes to be measured was identified and corrected, as this could 
result in larger blood draw volumes than intended.  
Review of procedures in Part B for the PUPs identified potential confusion regarding blood 
draws required for mandatory inhibitor screening during the first 20 ED, as this could 
possibly occur on a day that is not a scheduled study visit.  To reduce the likelihood that more 
blood samples are obtained than needed, these procedures were clarified.  The blood volumes 
for required studies were reassessed and it was determined that the total might exceed safe 
levels in the smallest subjects.  The protocol has been revised to provide specific information 
on the blood volumes to be collected at each study visit and provides methods to modify the 
samples to be drawn in infants who weigh less than 10 kg.  In this population, HSP-70 
antibody measurements will be not be obtained, and the local pediatric specialty laboratory 
may be used for serum chemistries and blood counts if needed.  To reduce the potential for 
blood loss from study procedures greater than 1% in any single day, or 3% over a 30-day 
interval, the requirement to obtain recovery samples at Months 3, 4, and 5 (ED 5-15) was 
removed.  Inability to tolerate the blood volumes required for study participation has been 
added as an exclusion criterion.  
Sections affected include:

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
Section 7.1.1, Tabulated overview

Section 7.1.2, Timing of assessments

Section 7.1.2.1, Visit 1 – Screening

Section 7.1.2.2, Visit 2 – Baseline

Section 7.1.2.3, Visit 3 – Month 1

Section 7.1.2.4, Visit 4 – Month 2

Section 7.1.2.5, Visit 5, Part B only; ED ~15 (14 ED +/- 1)

Section 7.1.2.6, Visit – Month 2, only for PUPs

Section 7.1.2.8, Visit – Month 6 or final visit (end of the main study and start of 
the optional extension study)

Section 7.1.2.9, Visit 7 – Month 12 and every 6 months

Section 7.1.2.10, Final visit

Section 7.5.3.3, Standard safety laboratory

Section 7.5.3.4, Inhibitor testing

Section 14.4, Blood draws in subjects weighing less than 10 kg

Section 14.5, Laboratory evaluation for suspected inhibitor
Change 3:  Regulatory agencies requested division of the study procedures required for PTPs 
and PUPs.  The protocol is now revised to more clearly demonstrate that the trial is separated 
in two sections, Part A for PTPs, and Part B for PUPs.  Procedures and timing of visits for 
subjects in Part A is unchanged with the exception of a clarification that the maximum 
interval between the Screening and Baseline visit is 8 weeks and that total study participation 
may be from 6-8 months due to this interval.  A +/- 1 week window has been added to allow 
flexibility with scheduled monthly visits.   
The review of study procedures for Part B highlighted that unifying the schedule of visits for 
PTPs (who are treated 2x/week or more frequently) and PUPs (who may be treated 1x/week) 
was potentially confusing for investigators and could result in unnecessary study visits and 
blood draws.  As the intent of the study is to gather observations of at least 50 ED, it is 
unlikely that PUPs receiving a once-a-week prophylactic regimen could complete the study 
within the 6 month treatment interval specified in the original protocol.  The schedule of visits 
has thus been modified to account for the different dosing frequency, number of study visits, 
scheduled laboratory evaluations, and timeline of the two patient groups.  Required blood 
draws are now correlated to the number of ED and no longer to a strict calendar schedule, and 
have been reduced as discussed above.  It is clarified that the total duration of study 
participation in Part B is the amount of time required to achieve 50 ED.
Sections affected include:

Synopsis – Doses

Synopsis – Duration of treatment

Synopsis – Diagnosis and main criteria for inclusion

Synopsis – Methodology

Section 4, Study design

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
Section 5.1.1, Inclusion criteria

Section 5.1.2, Exclusion criteria

Section 6.1.1, Regular prophylaxis

Section 7.1.1, Tabulated overview

Section 7.1.2, Timing of assessments

Section 7.1.2.1, Visit 1 – Screening

Section 7.1.2.2, Visit 2 – Baseline

Section 7.1.2.3, Visit 3 – Month 1

Section 7.1.2.4, Visit 4 – Month 2

Section 7.1.2.5, Visit 5, Part B only; ED ~15 (14 ED +/- 1)

Section 7.1.2.6, Visit – Month 2, only for PUPs

Section 7.1.2.7, Interim visit – Only for Part B (3-40 ED)

Section 7.1.2.8, Visit – Month 6 or final visit (end of the main study and start of 
the optional extension study)

Section 7.1.2.9, Visit 7 – Month 12 and every 6 months

Section 7.1.2.10, Final visit

Section 8.5, Planned interim analyses

Section 8.6, Determination of sample size
Change 4:  Regulatory agencies requested that the PUP trial be open to all age groups, 
including newborns.  As the original protocol could be interpreted as requiring prophylaxis to 
start immediately or before the first bleeding event, and because prophylaxis is almost never 
started in early infancy, there is concern that the protocol risks those patients who may not be 
able to start prophylaxis for a variety of reasons.  The amendment now allows for a limited 
number of ED prior to start of prophylaxis, an approach more consistent with current pediatric 
practice.  As prophylaxis may begin across a wide range of patient ages, the dose of study 
medication for PUPs has been changed to 15 -50 IU/kg to account for the frequent use of the 
250 IU vial size as a starting dose, irrespective of subject weight.  
Sections affected include:

Synopsis – Doses

Section 6.1.1, Regular prophylaxis

Section 6.4, Dosage and administration

Section 7.1.2.2, Visit 2 – Baseline
Change 5:  The voluntary PK sub-study has been modified to reduce the burden on the
subjects and their families.  The results of the PK assessment in Part A of Study 12954 
demonstrate that BAY 81-8973 behaves similarly to Kogenate® FS/Bayer.  As the PK of the 
currently marketed product is very well characterized in children, this data provide the 
opportunity to reduce the number of blood samples required for the PK sub-study.  The 
48-hour time point is no longer required.  The modified time points are pre-injection, then 

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post-injection at 20-30 minutes, 4 hours, and 24 hours.  This results in 2 additional blood 
draws for subjects in the PK study.  
Feedback from pediatric specialists highlighted that PK measurements may be useful to them 
in making individualized dosing decisions for their patients, and that such evaluations may be 
indicated only after a subject has started a new treatment.  Since PK evaluations may be 
required as part of routine care in subjects of all ages, the amendment opens up voluntary 
participation in the PK sub-study to all age groups in Part A.  It is not added to the PUP study 
due to the need to minimize blood draw volumes.  As increased flexibility of scheduling may 
improve acceptance by families, the protocol is also modified to allow the PK sub-study to be 
performed at any study visit rather than just at the Baseline visit.  
The timing of procedures, wash-out, documentation, and dosage to be used for performance 
of the PK are further defined, as these were not clear in the original protocol.
Sections affected include:

Synopsis – Study objectives

Synopsis – Methodology

Section 2, Study objectives

Section 4, Study design

Section 6.1.2, Breakthrough bleeds and surgeries

Section 6.1.4, Optional pharmacokinetic measurements

Section 6.4, Dosage and administration

Section 7.1.1, Tabulated overview

Section 7.1.2, Timing of assessments

Section 7.1.2.2, Visit 2 – Baseline

Section 7.1.2.3, Visit 3 – Month 1

Section 7.1.2.4, Visit 4 – Month 2

Section 7.1.2.8, Visit – Month 6 or final visit (end of the main study and start of 
the optional extension study)

Section 7.4, Pharmacokinetics

Section 8.3, Variables
Change 6:  Clarification is provided in the protocol regarding the risk of inhibitors, and 
information and instructions added regarding procedures that may reduce the risk, or that need 
to be followed if an inhibitor is detected or clinically suspected.  The definition of an inhibitor 
and how the data will be evaluated is more fully developed in the statistical section.  As 
‘insufficient response’ to treatment could be due to an inhibitor, this has been deleted as a 
criterion for withdrawal from the study.  Supplementary information has been added to clarify 
the laboratory procedures to be followed, and a clause specifying that subjects who develop 
an inhibitor while on study may receive BAY 81-8973 up to 200 IU/kg daily for 18 months 
has been added.  Treatment will be at the direction of the treating physician.  Data on 
treatment, FVIII measurements, and inhibitor levels will continue to be collected.   

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Recent publications suggest the risk of inhibitors may increase when the first factor exposures 
occur during periods of inflammatory risk or are high dose and prolonged.  This data was 
summarized in the original protocol, but is now more developed to provide specific 
recommendations to reduce the risk to the subject.
As ‘insufficient response’ to treatment could be due to an inhibitor, this has been deleted as a 
criterion for withdrawal from the study. 
Sections affected include:

Section 4, Study design

Section 5.2.1, Withdrawal

Section 6.1.1, Regular prophylaxis

Section 6.1.5, Immune tolerance induction (ITI)

Section 7.5.3.4, Inhibitor testing

Section 14.5, Laboratory evaluation for suspected inhibitor
Change 7:  A paragraph providing instructions on handling missed infusions has been added 
in recognition of the difficulties associated with repeated venous access in small children.  
The paragraph clarifies that there are specific situations where missed infusions are 
considered acceptable, and the need for appropriate documentation. 
Sections affected include:

Section 6.1.3, Missed infusions due to difficult venous or family travel
Change 8:  The use and administration of the Healthcare Resources Utilization Questionnaire 
has now been clarified, as specific instructions on its use were missing from the original 
protocol.  It is now clarified that the questionnaire will be administered by the investigator or 
delegate monthly throughout the study period, and that this may occur at any scheduled visit 
or subject contact with the study site.  The questionnaire has received minor modifications to 
simplify administration and to clarify the data to be collected.  
Sections affected include:

Section 7.1.1, Tabulated overview

Section 7.1.2.1, Visit 1 – Screening

Section 7.1.2.2, Visit 2 – Baseline

Section 7.1.2.3, Visit 3 – Month 1

Section 7.1.2.4, Visit 4 – Month 2

Section 7.1.2.5, Visit 5, Part B only; ED ~15 (14 ED +/- 1)

Section 7.1.2.6, Visit – Month 2, only for PUPs

Section 7.1.2.7, Interim visit – Only for Part B (3-40 ED)

Section 7.1.2.8, Visit – Month 6 or final visit (end of the main study and start of 
the optional extension study)

Section 7.1.2.9, Visit 7 – Month 12 and every 6 months

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
Section 7.1.2.10, Final visit

Section 14.3, Healthcare Resources Utilization Questionnaire
Change 9: Clarification of the use of the electronic patient diary (EPD) throughout the study.  
The EPD being used in this study was developed independently from the protocol.  As a 
consequence, the terminology used to collect patient reported outcomes on the device was in 
some cases different from that in the protocol.  Additionally, the instructions for transmitting
data from the EPD to the study site reflected old devices that are no longer in use.  To avoid 
confusion, the terminology in the protocol has been changed to be consistent with that on the 
electronic devices being used in the study and the procedures for transmitting data updated.   
Due to feedback from investigators and subjects that they were unclear on how to report 
response of bleeds to treatment on the scale provided (excellent, good, moderately well, poor), 
suggested definitions are provided.  
Additionally it is clarified that treatments given at the study visits should be documented in 
the CRF and not in the EPD. 
Sections affected include: 

Section 6.7, Treatment compliance

Section 7.3.1, Efficacy variables

Section 7.3.2.1, Incremental recovery

Section 7.3.2.2, Injection logs / bleeding verification
Change 10: Clarification of study objections and outcome variable.  
The secondary objectives of the study have been reworded to provide better understanding of 
the goals of the study, but remain unchanged in content.  Specifically, the objective which 
previously stated, “To assess the tolerability profile of BAY 81-8973 during prophylaxis and 
treatment of breakthrough bleeds and safety and efficacy during surgeries” was redundant 
with the primary objective.  It has been changed to state that the secondary objective is 
specific to the safety and efficacy of the investigational product during surgery.  The objective 
of assessing incremental recovery has been reworded to specify that the recovery of the 
investigational product is measured.  The third objective is unchanged, but now contains 
language to emphasize that participation is voluntary.  
In the text, the primary variable, the annualized number of total bleeds within 48 hours after a 
prophylactic infusion is further defined as being the sum of spontaneous bleeds and trauma 
bleeds combined.
Sections affected include:

Synopsis – Study objectives

Section 2, Study objectives

Section 4, Study design

Section 7.3.1, Efficacy variables

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
Section 8.3, Variables
Change 11: Adaptation/clarification of inclusion criteria.  As minor differences in inclusion 
criteria exist between Parts A and B of the study, the criteria specific to each patient 
population have been separated.  For Part A, it is clarified that enrollment into the study will 
begin with subjects >6 years, before being opened to younger patients, that documented prior 
testing for an inhibitor is required, and that subjects must have received at least 50 ED with 
another FVIII product.  For PUPs, the age group has been expanded in response to regulatory 
agency feedback that documentation of diagnosis is required, but prior testing for an inhibitor 
is not required.  A clause has also been added indicating that the parents of PUPs must agree 
to begin prophylaxis as part of their care.  
Sections affected include:

Section 5.1.1, Inclusion criteria
Change 12: Adaptation/clarification of exclusion criteria.  Exclusion criteria were clarified for 
better understanding.  The exclusion criteria of a serum creatinine value > 2 mg/deciliter (dL) 
was modified to > 2x the upper limit of normal since pediatric normal ranges may vary by age 
group.  Hepatic dysfunction, defined as AST/ALT > 5x upper limit of normal was added as 
such patients may have an acquired bleeding diathesis that may impact the primary study 
variable.  The exclusion criteria were also adapted to better define the medications that should 
not have been taken prior to start of the study.  For Part B, a new exclusion criterion was 
added for inability to tolerate the blood volumes required for study participation.  
Sections affected include:

Section 5.1.2, Exclusion criteria
Change 13:  The exclusion criteria specify that immunosuppressive and immunomodulatory 
medications may not be taken during the study, however many children may use topical or 
inhaled corticosteroids for common pediatric disorders such as eczema or asthma that would 
not be considered contraindications to participation in the study.  Additionally, although the 
recommendation is given that medications that cause a bleeding diathesis, such as aspirin 
should not be used in individuals with hemophilia, other groups of non-steroidal anti-
inflammatory drugs (NSAIDs) are sometimes used for the treatment of joint pain or 
inflammation.  In response to requests for clarification from several ethics committees and 
investigators, a clause has been added to provide further explanation.
Sections affected include:

Section 6.9, Prior and concomitant therapy

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Change 14: Requirements for the physical examination have been modified to be more 
consistent with pediatric practice.  As measurement of length may be more accurate than 
height in infants and small toddlers, this parameter has been added.  Blood pressure 
measurements in children may be inaccurate if appropriate cuff sizes are not used.  As many 
sites may not have the correct pediatric size blood pressure cuffs, this measurement may be 
deferred in preference to documentation of an inaccurate measurement. 
Sections affected include:

Section 7.1.2.1, Visit 1 – Screening

Section 7.1.2.2, Visit 2 – Baseline

Section 7.1.2.3, Visit 3 – Month 1

Section 7.1.2.4, Visit 4 – Month 2

Section 7.1.2.5, Visit 5, Part B only; ED ~15 (14 ED +/- 1)

Section 7.1.2.6, Visit – Month 2, only for PUPs

Section 7.1.2.7, Interim visit – Only for Part B (3-40 ED)

Section 7.1.2.8, Visit – Month 6 or final visit (end of the main study and start of 
the optional extension study)

Section 7.1.2.9, Visit 7 – Month 12 and every 6 months

Section 7.1.2.10, Final visit

Section 7.5.3.1, Vital signs

Section 7.5.3.2, Physical examination
Change 15: Changes in the study administrative structure have been made, specifically, the 
Sponsor’s Study Medical Expert has been replaced.
Sections affected include:

Title page

Signature of the sponsor’s medically responsible person

Section 3, Investigators and other study participants
Change 16:  Updated information was added reflecting current clinical studies using 
BAY 81-8973. The chromogenic assay used to measure the potency of the investigational 
drug is mentioned, since this information may be important to investigators when picking the 
appropriate dosages for subjects. 
Sections affected include:

Introduction
Change 17: Minor editorial clarifications and typographical/grammatical errors were 
corrected throughout the protocol.
Sections affected include:

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
Abbreviations.

Section 5.2.2, Replacement

Section 6.2.1, Manufacture

Section 6.2.2, Supply and packaging

Section 6.2.5, Instructions for administration

Section 6.6, Drug logistics and accountability

Section 6.8, Post-study therapy

Section 7.5.1.1, definitions

Section 8.1, General considerations

Section 8.2, Analysis sets

Section 8.6, Determination of sample size

Section 9.1, Data recording

Section 10, Premature termination of study

Section 11.2, subject information and consent

Section 12, References

Section 14.1, Introduction for use of study medication
13.1.2 Changes to the protocol text:
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol.  In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment.  Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”.  Corrections of typing errors or omissions are not 
highlighted in this amendment.
13.1.2.1
Change 1
Synopsis – Duration of treatment
Original protocol
6 months, >50 exposure days (ED). 
Optional extension study until marketing authorization
Amended to
6 months and/or >50 exposure days (ED). 
Optional extension study until marketing authorization
Synopsis - Methodology
Original protocol
The main study consists of a 6-month treatment period with >50 ED. After Screening and Baseline visits, all 
subjects will be evaluated for inhibitor development at Months 1, 2, and 6. PUPs will be tested every 3-5 ED up 
to ED 20 and will have an additional visit at Month 3. During the optional extension study, 6-monthly clinic 
visits with inhibitor testings are scheduled.

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The study is designed according the requirements defined in the European “Note for Guidance on the clinical 
investigation of recombinant FVIII and FIX products” CPMP/BPWG/1561/99.
Amended to
Part A:
The study consists of 6-months of treatment in PTPs with BAY 81-8973 for prophylaxis and treatment of 
breakthrough bleeding events to achieve at least 50 ED. After Screening and Baseline visits, all subjects will be 
evaluated for inhibitor development and incremental recovery at Months 1, 2, and 6.  Enrollment in the study 
will be staggered, with subjects age >6-12 years entering first, followed by subjects 0-6 years.
Part B:
PUPs will be treated with BAY 81-8973 for all bleeding events and are required to start prophylaxis.  Treatment 
will continue until at least 50 ED.  Screening and baseline visits may be combined for this population.  Subjects 
will be tested for inhibitors every 3-5 ED up to ED 20 and again at ED 50.  Incremental recovery will be 
measured at Baseline, ED 20, and ED 50.
In both Part A and Part B, all infusions and bleeding events will be documented in an electronic patient diary 
(EPD)  throughout the study. 
Optional extension study:
Subjects in both Part A and B will be offered participation in an optional extension study to continue treatment 
with BAY 81-8973 to accumulate at least 100 ED or time of market authorization.  During the extension study, 
visits to the treatment center will take place every 6-months for inhibitor screening.
The study is designed according the requirements defined in the European “Note for Guidance on the clinical 
investigation of recombinant FVIII and FIX products” CPMP/BPWG/1561/99.
Synopsis – Number of Subjects
Original protocol
35-50 plus PUPs
Amended to
Part A:
Total N= 50 PTP; 
age group >6-12 years:  N=25
age group 0-6 years:    N=25
Part B:
N= 25
Total = 75 (includes both Part A and B)
Section 4, Study Design
Original protocol
This is a phase-III multicenter, open-label uncontrolled study to demonstrate safety and 
efficacy of treatment with BAY 81-8973 for prophylaxis, breakthrough bleeds and surgeries 
in children with severe hemophilia A. The study will be conducted worldwide.

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Thirty-five to fifty PTPs (part A) and PUPs  (Part B) (20-25 subjects < 6 years, 15-25 subjects 
6-12 years; minimum of 35 PTPs) will be included and receive prophylaxis administration of 
BAY 81-8973.  
The study (part A) will start after 20 adult/adolescent subjects have received 50 ED with 
BAY 81-8973 without any safety concerns. PUPs (Part B) can be included after 10 children 
have achieved 50 ED. The incremental recovery will be investigated. Participation in 
pharmacokinetic evaluations is optional and may be obtained in a subset of  6 to 13 subjects 
in the age group of 6-12 years,  if parents consent to it.
The total study duration (including screening period) per subject will be approximately 6-
7 months during which the subjects will accumulate at least 50 ED. Thereafter, subjects will 
be offered the participation in an open-label extension study for at least 6-12 months to 
accumulate at least 100 ED or until marketing authorization is obtained.
During the study, all subjects will receive treatment only with BAY 81-8973.  The dosage 
range for prophylaxis treatment will be 25-50 IU/kg administered at least 2 times per week at 
the investigator’s discretion.  Treatment of PUPs may start at a lower dosing frequency with a 
once per week schedule at the investigator’s discretion. 
Amended to
This is a phase-III multicenter, open-label uncontrolled study to demonstrate safety and 
efficacy of treatment with BAY 81-8973 for prophylaxis, breakthrough bleeds, and surgeries 
in children with severe hemophilia A. The study will be conducted worldwide.
The study is divided into two parts:   Part A will investigate a total of 50 PTPs up to 12 years 
of age.  Part B will include 25 PUPs.   All subjects will receive prophylactic administration of 
BAY 81-8973.  Subjects in Part A will be treated with 25-50 IU/kg at least 2x a week, or 
more frequently as needed for prophylaxis.  Treatment in Part B may begin with start of 
prophylaxis with 15-50 IU/kg (minimum dose 250 IU) at least one day a week, or with the 
subject’s first bleeding event.  The study drug will be used both for treatment of bleeding 
events and prevention of bleeds with surgical procedures.   Individual subject dose decisions 
are at the discretion of the investigator.
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in another study.  PTPs ages 7 to 
12 years will begin enrollment first, followed by PTPs 6 years and younger.  Part B, for PUPs, 
will begin enrollment after 20 children in Part A have received 50 ED. 
The total study duration (including screening period) per subject in Part A will be 
approximately 6-8 months during which the subjects will accumulate at least 50 ED.   For 
Part B, subjects will continue in the study until achieving 50 ED.  Consequently the duration 
will vary depending upon the frequency of prophylactic infusion and number of bleeding 
events.   All subjects in both Parts A and B will be offered participation in an open-label 
extension study for an additional 6-12 months to allow observations for at least 100 ED or 
until marketing authorization is obtained.  Enrollment of PUPs in Part B and the extension 
study may continue after Part A and the extension study for PTPs have been completed. 

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During the study, all subjects will receive treatment only with BAY 81-8973 for prophylaxis 
and treatment of bleeds.  In Part A, the dosage range for prophylaxis treatment will be 25-50 
IU/kg administered at least 2 times per week at the investigator’s discretion.  In Part B,  PUPs 
may start at a lower dose at a once per week schedule at the investigator’s discretion. 

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Section 7.1.1, Tabulated overview
Original protocol
Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week)
Visit 4 
Month 2
(+/- 1 
week)
Final visit 
Month 6
)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Interaction between subject/parent and 
investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
    Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 
1
or
ED ~5
Visit 4
Month 
2
or
ED ~10
Visit 5 
Month 
3
or
ED ~15
Visit 6,
Month 4
or
ED ~20
Interim d
Visit
Final 
visit or
ED 50
Extension 
Visit every 
6 months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication 
history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before infusion and inhibitor c
X
X
X
X
X
X
X
Recovery (20-30 min after infusion)
X
X
X
X
Infusion of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Interaction between subject/parent and 
investigator
  weekly                         
  monthly  

Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Amended to
Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week)
Visit 4 
Month 2
(+/- 1 week)
Final visit 
Month 6
(Minimum 50
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
X
    monthly  
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20 -30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
    Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6,
Month 4
or
ED ~20
Interim d
Visit
30-40 ED
Final 
visit or
ED 50
Extension 
Visit every 
6 months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication 
history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before infusion and inhibitor c
X
X
X
X
X
X
X
Recovery (20-30 min after infusion)
X
X
X
X
Infusion of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization 
Questionnaire
X
   monthly 
Interaction between subject/parent and 
investigator
  weekly                                    
  monthly  

Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Section 7.1.2, Timing of assessments
Original protocol
The main study consists of a screening period of up to 8 weeks and a 6-month treatment 
period and a minimum of 50 ED per subject will be accumulated. After the Screening and 
Baseline visits which may be combined to one visit for PUPs, further 3 visits are scheduled at 
Month 1, Month 2 and Month 6. PUPs will have monthly visits for the first 3 months and 
blood sampling every 3-5 ED for inhibitor testing
Thereafter, subjects will be offered to continue treatment in an extension study until a total 
number of at least 100 ED per subject will be accumulated or until marketing authorisation of 
the drug, with additional visits every 6 months. 
Amended to
The main study consists of a Screening period followed by at least 50 ED per subject.  The 
Screening and Baseline visits may be combined to one visit for PUPs.  There is no minimum 
interval between the Screening and Baseline visits for PUPs or PTPs.  For PTPs, no longer 
than 8 weeks should pass between Screening and Baseline visits.
In Part A, PTPs, a minimum of 50 ED will be accumulated during a 6 month treatment period.  
Visits are scheduled at Month 1, Month 2 and Month 6.  
In Part B, the treatment period will be extended until 50 ED have been accumulated.  The 
duration of Part B will vary and is dependent upon the frequency of prophylactic infusion and 
the number of bleeding events.  Blood sampling for inhibitor testing is required every 3-5 
exposure days up to 20 ED, and again at 50 ED.  As most subjects will begin prophylaxis 1x 
week, study visits during the first 20 ED are expected to occur monthly.  However, it is 
understood that bleeding events resulting in added doses, delayed start of prophylaxis after
first bleeds, or missed infusions due to difficult i.v. access may result in some variation in the 
number of ED a patient has obtained at each visit or the exact interval between visits.  
Likewise, those patients who receive more frequent infusions, may require study visits more 
often than once a month.   
After completing Part A or B, all subjects will be offered continued treatment in an extension 
study until a total number of at least 100 ED per subject are accumulated or until marketing 
authorisation of the drug.  Participation will require additional visits every 6 months. 
Section 8.5, Planned interim analyses
Original protocol
The main study has a duration of 6 months and the 6-months data will be analyzed for 
regulatory purposes as an interim analysis. Subjects will continue in the extension trial. The 
overall study will be closed after all subjects have completed the extension trial and an 
additional analysis will include all data from the main trial and the extension part.
Amended to
The main study has a duration of 6 months.  The 6-month data for PTPs will be analyzed for 
regulatory purposes as an interim analysis. When safety has been assessed in 10-20 PTPs who 

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have received at least 50 ED, enrollment will begin in Part B.  All subjects will have the 
option of continuing in the extension trial. The overall study will be closed after all subjects in 
Parts A and B have completed the extension trial and an additional analysis will include all 
data from the main trial and the extension part.
Section 8.6, Determination of sample size
Original protocol
According to the guideline CPMP/BPWG/1561/99 (Note for Guidance on the Clinical 
Investigation of Recombinant Factor VIII and Factor IX Products), at least 20 children under 
the age of 6 years (infants and toddlers) regardless of prior treatment should be included in the 
investigation. The next age group according to the age classification of International 
Conference on Harmonization (ICH)/CPMP guideline E11 (Clinical Investigation of 
Medicinal Products in the Pediatric Population)19 refers to children up to the age of 11 years.
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.
Amended to
Sample size has been determined according to the requirements set forth by guideline 
CPMP/BPWG/1561/99 (Note for Guidance on the Clinical Investigation of Recombinant 
Factor VIII and Factor IX Products), and taking into account the revised draft version, 
CHMP/BPWP/144533/09. Age groups are in accordance with the International Conference on 
Harmonization (ICH)/CPMP guideline E11 (Clinical Investigation of Medicinal Products in 
the Pediatric Population)19 and sample sizes have been confirmed on consultation with the 
EMA/PDCO on submission of the Pediatric Investigation Plan. 

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13.1.2.2Change 2
Section 7.1.1, Tabulated overview
Original protocol
Table 7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
Visit 4 
Month 2
Final visit 
Month 6
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level before injection and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after injection)
X
X
X
Plasma retention sample
Pharmacokinetics in up to 13 children (optional)
    X b  
Injection of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare utilization
monthly
Interaction between subject/parent and 
investigator
  weekly            
Concomitant medication 
X
       continuously     
a. 
Complete Blood Count (CBC), Chemistries
b.
Blood samples at the following time points: before, 20-30 min, 4 h, 24 h post-injection following a washout of 48 h after last dose of FVIII
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
    Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 
1
or
ED ~5
Visit 4
Month 
2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6,
Month 4
or
ED ~20
Interim
Visit
Final 
visit or
ED 50
Extension 
Visit every 
6 months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before injection and inhibitor
X
X
X
X
X
X
X
Recovery (20-30 min after injection)
X
X
X
X
Plasma retention sample
Injection of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Plasma retention sample
Interaction between subject/parent and 
investigator
  weekly                                  monthly  
Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > kg at baseline visit
. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Amended to
Table 7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
Visit 4 
Month 2
Final visit 
Month 6
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level before injection and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after injection)
X
X
X
Pharmacokinetics in up to 13 children (optional)
X b 
Injection of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare utilization
monthly
Interaction between subject/parent and 
investigator
  weekly            
Concomitant medication 
X
       continuously     
a. 
Complete Blood Count (CBC), Chemistries
b.
Blood samples at the following time points: before, 20-30 min, 4 h, 24 h post-injection following a washout of 48 h after last dose of FVIII
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
    Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6 
Month 4
or
ED ~20
Interim
Visit
Final 
visit or
ED 50
Extension 
Visit every 
6 months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication 
history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before injection and inhibitor
X
X
X
X
X
X
X
Recovery (20-30 min after injection)
X
X
X
X
Injection of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Plasma retention sample
Interaction between subject/parent and 
investigator
  weekly                                   monthly  
Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > kg at baseline visit
.   
Interim visit only if less than 40 ED have been achieved by Month 6.

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Section 7.1.2, Timing of assessments
Original protocol
The main study consists of a screening period of up to 8 weeks and a 6-month treatment 
period and a minimum of 50 ED per subject will be accumulated. After the Screening and 
Baseline visits which may be combined to one visit for PUPs, further 3 visits are scheduled at 
Month 1, Month 2 and Month 6. PUPs will have monthly visits for the first 3 months and 
blood sampling every 3-5 ED for inhibitor testing
Thereafter, subjects will be offered to continue treatment in an extension study until a total 
number of at least 100 ED per subject will be accumulated or until marketing authorisation of 
the drug, with additional visits every 6 months. 
Amended to
The main study consists of a Screening period followed by at least 50 ED per subject.  The 
Screening and Baseline visits may be combined to one visit for PUPs.  There is no minimum 
interval between the Screening and Baseline visits for PUPs or PTPs.  For PTPs, no longer 
than 8 weeks should pass between Screening and Baseline visits.
In Part A, PTPs, a minimum of 50 ED will be accumulated during a 6 month treatment period.  
Visits are scheduled at Month 1, Month 2 and Month 6.  
In Part B, the treatment period will be extended until 50 ED have been accumulated.  The 
duration of Part B will vary and is dependent upon the frequency of prophylactic infusion and 
the number of bleeding events.  Blood sampling for inhibitor testing is required every 3-5 
exposure days up to 20 ED, and again at 50 ED.  As most subjects will begin prophylaxis 1x
week, study visits during the first 20 ED are expected to occur monthly.  However, it is 
understood that bleeding events resulting in added doses, delayed start of prophylaxis after 
first bleeds, or missed infusions due to difficult i.v. access may result in some variation in the 
number of ED a patient has obtained at each visit or the exact interval between visits.  
Likewise, those patients who receive more frequent infusions, may require study visits more 
often than once a month.   
After completing Part A or B, all subjects will be offered continued treatment in an extension 
study until a total number of at least 100 ED per subject are accumulated or until marketing 
authorisation of the drug.  Participation will require additional visits every 6 months. 
Section 7.1.2.1, Visit 1 – Screening
Original protocol
At the screening visit, the following procedures and assessments will be performed:
…

Blood samples for laboratory tests complete blood count CBC Chemistry 
(Electrolytes, creatinine, ALT, aspartate aminotransferase [AST], total bilirubin), 
FVIII:C level, frozen serum sample, inhibitor test)

, FVIII:C level, frozen serum sample, inhibitor test

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Amended to
At the screening visit, the following procedures and assessments will be performed:
…

Blood samples for laboratory tests: 
o
Complete blood count [CBC]
o
Serum chemistry (sodium [Na], potassium [K], bicarbonate [CO], chloride 
[Cl], creatinine, alanine and aspartate aminotransferases [ALT, AST], total 
bilirubin.  (See Section 14.4 for children <10 kg) 

FVIII:C level, inhibitor test (not required for PUPs)
Section 7.1.2.2, Visit 2 - Baseline
Original protocol
Blood sample for inhibitor test and determination of FVIII:C trough levels (≥ 48 h after 
last FVIII injection) and HSP-70 antibodies Injection of the first dose of study drug
Note:  
If inhibitor testing is mandatory every 3-5 ED until 20 ED are accumulated
Amended to

HSP-70 antibodies (in children > 7kg)

Blood sample for inhibitor test and determination of FVIII:C trough levels (≥ 48 h 
after last FVIII treatment). 
Section 7.1.2.3, Visit 3 – Month 1 
Original protocol
7.1.2.3  Visit 3 – Month 1

Blood sample for inhibitor test
Note:  If prophylaxis treatment is started in PUPs, inhibitor testing is mandatory every 
3-5 ED until 20 ED are accumulated

Blood sample for the determination of FVIII trough levels (≥ 48 h after last FVIII 
injection)
Amended to
7.1.2.3  Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B

Blood sample for inhibitor test and determination of FVIII:C trough levels (≥ 48 h 
after last FVIII treatment). 

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Section 7.1.2.1, Visit 4 – Month 2 
Original protocol
7.1.2.4  Visit 4 – Month 2

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII injection) and HSP-70 antibodies
Amended to
7.1.2.4  Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment) 
Section 7.1.2.5, Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (added)
7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1)

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment).
Section 7.1.2.6 Visit – Month 3, only for PUPs
Original protocol
7.1.2.6 Visit – Month 3, only for PUPs

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII injection)
Amended to
7.1.2.6 Visit 6 – Part B only; ED 20 (20 ED +/- 1) 

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII infusion).
Section 7.1.2.8 Visit – Month 6 or final visit (end of the main study and start of the 
optional extension study)
Original protocol
7.1.2.8  Visit - Month 6 or final visit (end of the main study and start of the optional 
extension study) 

Blood samples for laboratory tests (CBC, Chemistry (Electrolytes, creatinine, ALT, 
AST, total bilirubin), frozen serum sample)

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII injection) and HSP-70 antibodies Injection of study drug

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Amended to
7.1.2.8  Final Visit - (end of the main study and start of the optional extension study) 

Blood samples for laboratory tests: 
o
Complete blood count [CBC]
o
Serum chemistry (sodium [Na], potassium [K], bicarbonate [CO], chloride 
[Cl], creatinine, alanine and aspartate aminotransferases [ALT, AST], total 
bilirubin.  (See Section 14.4 for children <10 kg) 

Blood sample for inhibitor test and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment).

HSP-70 antibodies (in children > 7 kg).
Section 7.1.2.9 Visit 7 – Month 12 and every 6 months
Original protocol
7.1.2.9  Visit 7 – Month 12 and every 6 months

Blood sample for inhibitor testing
Amended to
7.1.2.9  Extension study visits – 6 months after completion of Part A or B; then every 6 
months)

Blood sample for inhibitor testing and determination of FVIII:C trough level (>48 H 
after last FVIII treatment).
Section 7.1.2.10 Final visit
Original protocol

Blood sample for inhibitor testing
Amended to

Blood sample for inhibitor test and determination of FVIII:C trough level (>48 H after 
last FVIII infusion).
Section 7.5.3.3 Standard safety laboratory
Original protocol
Blood samples will be collected at Screening and Month 6 (or final visit) 
Standard safety laboratory determinations will include the following parameters:

CBC with differential: erythrocytes, hemoglobin, hematocrit, platelets, leukocytes, 
neutrophils, eosinophils, basophils, monocytes, and lymphocytes  

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
Clinical chemistry: electrolytes (sodium [Na], potassium [K], calcium [Ca], chloride
[Cl]), creatinine, alanine and aspartate aminotransferases (ALT, AST), lactate 
dehydrogenase (LDH), total and direct bilirubin, gamma-glutamyl transferase 

HSP-70 antibody
Amended to
The following blood samples will be collected at Screening and Month 6 (or final visit): 

CBC with differential: erythrocytes, hemoglobin, hematocrit, platelets, leukocytes, 
neutrophils, eosinophils, basophils, monocytes, and lymphocytes  

Serum chemistry (electrolytes (sodium [Na], potassium [K], bicarbonate [CO], 
chloride [Cl], creatinine, alanine and aspartate aminotransferases [ALT, AST], total 
bilirubin)
The following blood samples will be collected at Baseline and Month 6 (or final visit): 

HSP-70 antibody (except in subjects <7kg)
Section 7.5.3.4 Inhibitor testing
Original protocol
The FVIII inhibitor testings before study is not applicable for PUPs. However, PUPs must be 
tested for inhibitor development every 3-5 ED until 20 ED are accumulated. The absence of 
inhibitors will be confirmed with the pre-exposure blood sample at baseline.
Subjects participating in the extension study will additionally be tested for inhibitor 
development every 6 months.
The laboratory analyses will be performed at central laboratories. In addition, spare plasma 
sample will be collected and frozen at -70°C. Investigators will be provided with a detailed 
laboratory manual and a copy of the individual results. Inhibitor testing will be done 
according to the Nijmegen modified Bethesda inhibitor assay. A positive inhibitor test is 
defined with a threshold of ≥ 0.6 BU in the central lab. Any positive test must be confirmed 
by a second different sample, for a second titer between 0.3 BU and 0.6 BU, a recovery is 
required for confirmation.
The spare 2 mL plasma samples collected at specified study visits will be for immunology or 
coagulation assays, or for clarification of any clinical or laboratory adverse event and in no 
case for genetic analyses.
Amended to
The requirement for a FVIII inhibitor test before study entry is not applicable for PUPs. The 
absence of inhibitors will be confirmed at the Baseline evaluation. After treatment is started, 
PUPs must be tested for inhibitor development every 3-5 ED until 20 ED are accumulated. 
Subjects participating in the extension study will additionally be tested for inhibitor 
development every 6 months.

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The laboratory analyses will be performed at central laboratories. 
Investigators will be provided with a detailed laboratory manual and a copy of the individual 
results. Inhibitor testing will be done according to the Nijmegen modified Bethesda inhibitor 
assay at the central laboratory. A positive inhibitor test is defined with a threshold of ≥ 0.6 BU 
in the central lab. Any positive test must be confirmed by a second plasma sample.  
Section 14.4 Blood draws in subjects weighing less than 10 kg (added)
14.4  Blood draws in subjects weighing less than 10 kg
Every effort has been made to minimize the volumes of blood required for participation in the 
study.   For the majority of subjects in the study, the volumes drawn at any one visit are not 
expected to exceed more than 1 % of total blood volume, or 3% in any 1 month interval.  
However, in young infants, Part B of the study may require modification to allow 
participation by infants or small toddlers.   
Table 14.4a shows the estimated total blood volume for children 1-10 kg and the 
recommended amount of blood for study purposes.  These volumes should be considered a 
guideline, and may be exceeded if determined to be safe by the investigator.  
Table 14.4a  Recommended Blood Draw Volumes
Body Wt 
(Kg)
Body Wt 
(lbs)
Total blood 
volume (mL)
Allowable volume (mL) 
in one blood draw
( 1% of total blood 
volume)
Total volume (mL) 
drawn in a 30-day 
period (3% of total 
blood volume)
1
2.2
100
1
3
2
4.4
200
2
6
3
6.3
240
2.4
7.2
4
8.8
320
3.2
9.6
5
11
400
4
12
6
13.2
480
4.8
14.4
7
15.4
560
5
16.8
8
17.6
640
6.4
19.2
9
19.8
720
7.2
21.6
10
22
800
8
24
Ernst, D. J. Applied Phlebotomy. Lippincott Williams & Wilkins. 2005
Table 14.4b shows the blood volumes needed for the tubes used for the central laboratory.  
Table 14.4b Volume of blood draws in Part B
Visit 1 
Screening
Visit 2
Baseline
Visit 3 
~5 ED
Visit 4
~10 ED
Visit 5 
~15 ED
Visit 6 
20 ED
Interim 
visit
Final 
visit 
50 ED
Volume of 
blood (ml)
4.2
5.3
2.7
2.7
2.7
4.1
0
7.7
7.7

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For infants at least 7 kg at study enrollment, the volumes listed for each individual visit 
should be well tolerated.  As the Screening and Baseline visits can be combined for PUPs, 
investigators need to be aware that the total volume required could exceed 1% of total blood 
volume in children 9 kg or less.  The total volume at the combined Screening and Baseline 
visit may be reduced if the CBC and chemistries are processed through the local laboratory 
using minimal volumes and the results entered in the CRF.  The decision whether to use the 
local laboratory or to divide the blood sampling over more than one draw is at the 
investigator’s discretion, but the total amount of blood drawn should not exceed 3% of total 
blood volume over a 30 day interval.  
For infants who are 7 kg and smaller at study entry, the sampling schedule will be modified. 
The sample for collection of HSP-70 antibody (1.2 ml) will not be collected.  FVIII trough 
level and inhibitor will be measured using a reduced volume (1.8 ml).  Estimated blood 
volumes based upon these modifications are shown in table 14.4c.   
Table 14.4c   Modified volume of blood in infants less than 7 kg 
Visit 1 
Screening
Visit 2
Baseline
Visit 3 
~5 ED
Visit 4
~10 ED
Visit 5 
~15 ED
Visit 6 
20 ED
Interim 
visit
Final 
visit 
50 ED
Volume of 
blood (ml)
2.4 
4.1
2.7
2.7
2.7
4.1
0
6.5
6.5 (5.2)a
a. (…) Est volume if CBC and chemistries obtained with minimal volumes through local laboratory
For infants less than 7 kg, for whom the Screening and Baseline visits are combined, it is 
recommended that the screening CBC and chemistries be processed through the local 
laboratory using minimal volumes, and the results entered in the CRF.  Capillary samples may 
be used if care is used to minimize the risk of hemolysis.  It is assumed that the minimal 
volume needed for both CBC and chemistries is approximately 1.1 ml.  
Should an investigator wish to enroll a subject who weighs less than 5 kg, discussion with the 
sponsor is required.  
Section 14.5 Laboratory evaluation for suspected inhibitor (added)
14.5  Laboratory evaluation for suspected inhibitor
If an inhibitor is clinically suspected (a bleed that progresses or does not improve following 
appropriate therapy), the subject be managed according to local standard of care.  The 
investigator should immediately notify the sponsor and obtain the following information and 
blood tests:

time and dose of last infusion

infused product (if other than BAY 81-8973) 

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
blood for central laboratory

pre and post FVIII level/ aPTT 

inhibitor to Factor VIII testing by the Nijmegen assay
13.1.2.3
Change 3
Synopsis – Dose(s)
Original protocol
25 -50 IU/kg; prophylaxis with at least 2 injections per week in previously treated patients (PTPs) and at least 1 
injection per week in previously untreated patients (PUPs)
Amended to
Part A:
PTPs: 25 -50 IU/kg (rounded to nearest size vial); prophylaxis with at least 2 infusions per week and treatment 
for breakthrough bleeds
Part B: 
Previously untreated patients (PUPs): 15-50 IU/kg (rounded to nearest size vial); prophylaxis with at least 1 
infusion per week and treatment for bleeds
Synopsis – Duration of treatment
Original protocol
6 months >50 exposure days (ED). 
Optional extension study until marketing authorization
Amended to
6 months and/or >50 exposure days (ED). 
Optional extension study until marketing authorization
Synopsis – Diagnosis and main criteria for inclusion
Original protocol
Severe hemophilia A (< 1% FVIII:C), age 0-12 years, no inhibitor history, no other bleeding disorder
Amended to
Severe hemophilia A (< 1% FVIII:C), 
Part A: male, age 0-12 years, > 50 ED, no inhibitor history, no other bleeding disorder
Part B: male, PUPs, no prior exposure to factor VIII concentrate or plasma
Synopsis - Methodology
Original protocol
The main study consists of a 6-month treatment period with >50 ED. After Screening and Baseline visits, all 
subjects will be evaluated for inhibitor development at Months 1, 2, and 6. PUPs will be tested every 3-5 ED up 

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to ED 20 and will have an additional visit at Month 3. During the optional extension study, 6-monthly clinic 
visits with inhibitor testings are scheduled.
The study is designed according the requirements defined in the European “Note for Guidance on the clinical 
investigation of recombinant FVIII and FIX products” CPMP/BPWG/1561/99.
Amended to
Part A:
The study consists of 6-months of treatment in PTPs with BAY 81-8973 for prophylaxis and treatment of 
breakthrough bleeding events to achieve at least 50 ED. After Screening and Baseline visits, all subjects will be 
evaluated for inhibitor development and incremental recovery at Months 1, 2, and 6.  Enrollment in the study 
will be staggered, with subjects age >6-12 years entering first, followed by subjects 0-6 years.
Part B:
PUPs will be treated with BAY 81-8973 for all bleeding events and are required to start prophylaxis.  Treatment 
will continue until at least 50 ED.  Screening and baseline visits may be combined for this population.  Subjects 
will be tested for inhibitors every 3-5 ED up to ED 20 and again at ED 50.  Incremental recovery will be 
measured at Baseline, ED 20, and ED 50.
In both Part A and Part B, all infusions and bleeding events will be documented in an electronic patient diary 
(EPD)  throughout the study. 
Optional extension study:
Subjects in both Part A and B will be offered participation in an optional extension study to continue treatment 
with BAY 81-8973 to accumulate at least 100 ED or time of market authorization.  During the extension study, 
visits to the treatment center will take place every 6-months for inhibitor screening.
The study is designed according the requirements defined in the European “Note for Guidance on the clinical 
investigation of recombinant FVIII and FIX products” CPMP/BPWG/1561/99.
Original protocol
This is a phase-III multicenter, open-label uncontrolled study to demonstrate safety and 
efficacy of treatment with BAY 81-8973 for prophylaxis, breakthrough bleeds and surgeries 
in children with severe hemophilia A. The study will be conducted worldwide.
Thirty-five to fifty PTPs (part A) and PUPs  (Part B) (20-25 subjects < 6 years, 15-25 subjects 
6-12 years; minimum of 35 PTPs) will be included and receive prophylaxis administration of 
BAY 81-8973.  
The study (part A) will start after 20 adult/adolescent subjects have received 50 ED with 
BAY 81-8973 without any safety concerns. PUPs (Part B) can be included after 10 children 
have achieved 50 ED. The incremental recovery will be investigated. Participation in 
pharmacokinetic evaluations is optional and may be obtained in a subset of  6 to 13 subjects 
in the age group of 6-12 years,  if parents consent to it.
The total study duration (including screening period) per subject will be approximately 6-
7 months during which the subjects will accumulate at least 50 ED. Thereafter, subjects will 
be offered the participation in an open-label extension study for at least 6-12 months to
accumulate at least 100 ED or until marketing authorization is obtained.

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During the study, all subjects will receive treatment only with BAY 81-8973.  The dosage 
range for prophylaxis treatment will be 25-50 IU/kg administered at least 2 times per week at
the investigator’s discretion.  Treatment of PUPs may start at a lower dosing frequency with a 
once per week schedule at the investigator’s discretion. 
Amended to
This is a phase-III multicenter, open-label uncontrolled study to demonstrate safety and 
efficacy of treatment with BAY 81-8973 for prophylaxis, breakthrough bleeds, and surgeries 
in children with severe hemophilia A. The study will be conducted worldwide.
The study is divided into two parts:   Part A will investigate a total of 50 PTPs up to 12 years 
of age.  Part B will include 25 PUPs.   All subjects will receive prophylactic administration of 
BAY 81-8973.  Subjects in Part A will be treated with 25-50 IU/kg at least 2x a week, or 
more frequently as needed for prophylaxis.  Treatment in Part B may begin with start of 
prophylaxis with 15-50 IU/kg (minimum dose 250 IU) at least one day a week, or with the 
subject’s first bleeding event.  The study drug will be used both for treatment of bleeding 
events and prevention of bleeds with surgical procedures.   Individual subject dose decisions 
are at the discretion of the investigator.
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in another study.  PTPs ages 7 to 
12 years will begin enrollment first, followed by PTPs 6 years and younger.  Part B, for PUPs, 
will begin enrollment after 20 children in Part A have received 50 ED. 
The total study duration (including screening period) per subject in Part A will be 
approximately 6-8 months during which the subjects will accumulate at least 50 ED.   For 
Part B, subjects will continue in the study until achieving 50 ED.  Consequently the duration 
will vary depending upon the frequency of prophylactic infusion and number of bleeding 
events.   All subjects in both Parts A and B will be offered participation in an open-label 
extension study for an additional 6-12 months to allow observations for at least 100 ED or 
until marketing authorization is obtained.  Enrollment of PUPs in Part B and the extension 
study may continue after Part A and the extension study for PTPs have been completed. 
During the study, all subjects will receive treatment only with BAY 81-8973 for prophylaxis 
and treatment of bleeds.  In Part A, the dosage range for prophylaxis treatment will be 25-50 
IU/kg administered at least 2 times per week at the investigator’s discretion.  In Part B,  PUPs 
may start at a lower dose at a once per week schedule at the investigator’s discretion. 
Section 5.1.1 Inclusion criteria
Original protocol
In order to be included in the study, subjects must meet all of the following criteria upon 
evaluation at the Screening or Baseline visit:
…
Part B (PUPs) Inclusion of PUPs may start after 10 children  accumulated 50 EDMale, 

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Amended to
In order to be included in the study, subjects must have all of the following criteria upon 
evaluation at the Screening or Baseline visit:
Part A
…

Part B (PUPs) (Enrollment of PUPs may start after safety is evaluated in 20 children 
in Part A with 50 ED)
Section 5.1.2, Exclusion criteria
Original protocol
Subjects who meet any of the following criteria at Screening or Baseline visits will be 
excluded from participating in the study:
Part A and B
…
Part B only
…
Amended to
Subjects who meet any of the following criteria at Screening or Baseline visits will be 
excluded from participating in the study:
Parts A and B
…
Part B only (PUPs):
…
Section 6.1.1 Regular prophylaxis
Original Protocol
Duration:
6 months at least 50 ED at least 100 cumulative ED in subjects 
participating in the optional extension study)
Amended to
Duration:
Part A: 6 months and at least 50 ED 
Part B: 50 ED 
Extension study: at least 100 cumulative ED in subjects 
participating in the optional extension study or until market 
authorization

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(Enrollment of PUPs may continue after PTPs have completed participation in Part A and the 
extension study)

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Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
Visit 4 
Month 2
Final visit 
Month 6
(Minimum 50 
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre injection and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after injection) c
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Injection of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
X
    monthly  
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b.
Blood samples at the following time points: before, 20-30 min, 4 h, 24 h post-following a washout of 48 h after last dose of FVIII
c.
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension

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Table7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and 
procedures 
Main study
Optional extension 
study
    Visit 1 
Screenin
g
Visit 2
Baselin
e
Combined 
Screening 
and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 
2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6 
Month 4
or
ED ~20
Interim d
Visit
30-40 ED
Final visit
or
ED 50
Extension 
Visit every 
6 months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion 
criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical 
history
X
X
Previous medication 
(medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and 
inhibitor
X
X
FVIII level before injection
and inhibitor c
X
X
X
X
X
X
X
Recovery (20-30 min after 
injection)
X
X
X
X
Injection of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) 
documentation
X
      continuously       
Healthcare Resources 
Utilization Questionnaire
X
   monthly 
Interaction between 
  weekly                                     
  monthly  

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subject/parent and 
investigator
Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > kg at baseline visit
c.
Interim visit only if less than 40 ED have been achieved by Month 6.
d. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Amended to
Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week)
Visit 4 
Month 2
(+/- 1 
week)
Final visit 
Month 6
(Minimum 50 
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
X
    monthly  
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and 
procedures 
Main study
Optional extension 
study
    Visit 1 
Screenin
g
Visit 2
Baselin
e
Combined 
Screening 
and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 
2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6,
Month 4
or
ED ~20
Interim d
Visit
30-40 ED
Final visit
or
ED 50
Extension 
Visit every 
6 months
Extensi
on
Final 
visit
Informed consent)
X
X
Inclusion / exclusion 
criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical 
history
X
X
Previous medication 
(medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and 
inhibitor
X
X
FVIII level before infusion
and inhibitor c
X
X
X
X
X
X
X
Recovery (20-30 min after 
infusion)
X
X
X
X
Infusion of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) 
documentation
X
      continuously       
Healthcare Resources 
Utilization Questionnaire
X
   monthly 

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Interaction between 
subject/parent and 
investigator
  weekly                                       monthly  
Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Section 7.1.2, Timing of assessments
Original protocol
The main study consists of a screening period of up to 8 weeks and a 6-month treatment 
period and a minimum of 50 ED per subject will be accumulated. After the Screening and 
Baseline visits which may be combined to one visit for PUPs, further 3 visits are scheduled at 
Month 1, Month 2 and Month 6. PUPs will have monthly visits for the first 3 months and 
blood sampling every 3-5 ED for inhibitor testing
Thereafter, subjects will be offered to continue treatment in an extension study until a total 
number of at least 100 ED per subject will be accumulated or until marketing authorisation of 
the drug, with additional visits every 6 months. 
Amended to
The main study consists of a Screening period followed by at least 50 ED per subject.  The 
Screening and Baseline visits may be combined to one visit for PUPs.  There is no minimum 
interval between the Screening and Baseline visits for PUPs or PTPs.  For PTPs, no longer 
than 8 weeks should pass between Screening and Baseline visits.
In Part A, PTPs, a minimum of 50 ED will be accumulated during a 6 month treatment period.  
Visits are scheduled at Month 1, Month 2 and Month 6.  
In Part B, the treatment period will be extended until 50 ED have been accumulated.  The 
duration of Part B will vary and is dependent upon the frequency of prophylactic infusion and 
the number of bleeding events.  Blood sampling for inhibitor testing is required every 3-5 
exposure days up to 20 ED, and again at 50 ED.  As most subjects will begin prophylaxis 1x 
week, study visits during the first 20 ED are expected to occur monthly.  However, it is 
understood that bleeding events resulting in added doses, delayed start of prophylaxis after
first bleeds, or missed infusions due to difficult i.v. access may result in some variation in the 
number of ED a patient has obtained at each visit or the exact interval between visits.  
Likewise, those patients who receive more frequent infusions, may require study visits more 
often than once a month.   
After completing Part A or B, all subjects will be offered continued treatment in an extension 
study until a total number of at least 100 ED per subject are accumulated or until marketing 
authorisation of the drug.  Participation will require additional visits every 6 months. 
Section 7.1.2.1 Visit 1 – Screening
Original protocol
At the screening visit, the following procedures and assessments will be performed:

Obtainment of written informed consent from the parents/legal representative. Assent 
may be obtained from subjects, depending on their age and intellectual status.
Note: No Screening procedures may be performed unless written informed consent 
(and assent, if applicable) has been obtained (see Section 11.2)

Allocation of a unique PID number (see Section 5.3)

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
Eligibility check
No subject may be allocated to treatment unless adherence to all selection criteria as 
given in Section 5.1 is given. Confirmation of selection criteria may be based on 
medical records for inclusion, but laboratory test results must confirm eligibility 
except the severity of the disease which is based on the FVIII level at diagnosis. 
…

Explanation and dispense of the EPD
Amended to
At the screening visit, the following procedures and assessments will be performed:

Obtain written informed consent from the parents/legal representative. Assent should 
be obtained from subjects, depending on their age and intellectual status or according 
to local practice.
Note: No Screening procedures may be performed unless written informed consent 
(and assent, if applicable) has been obtained. (see Section 11.2)

Assignment of a unique PID number (see Section 5.3)

Eligibility check
No subject may receive treatment with study drug unless all inclusion and exclusion
criteria are met as given in Section 5.1. Confirmation of selection criteria may be 
based on medical records, but laboratory test results must confirm eligibility.  The 
severity of hemophilia may be based on documented FVIII level at diagnosis. 
…

FVIII:C level, inhibitor test (not required for PUPs)

Training on and dispensing of the EPD
Section 7.1.2.2 Visit 2 - Baseline
Original protocol
This visit will serve as the Baseline visit; it will include the first administration of study drug. 
The Baseline visit should take place within 8 weeks after Screening visit and at least 48 h 
after last FVIII administration. Baseline may be combined with the screening visit if all 
selection criteria can be confirmed based on medical records for PUPs without any previous 
FVIII exposure.
This visit should start with the following assessments:

Confirmation of eligibility including check of laboratory test results.
Note: Eligible subjects (except PUPs) must be inhibitor negative at Baseline.
Blood sample for inhibitor test and determination of FVIII:C trough levels (≥ 48 h after 
last FVIII injection) and HSP-70 antibodiesInjection of the first dose of study drug
Note:  
If inhibitor testing is mandatory every 3-5 ED until 20 ED are accumulated.

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
Vital signs (Heart rate, temperature, blood pressure) after injection
…

Documentation of adverse events

Check of EPD documentation and documentation of interval treatment and bleeding 
history.  Repeated training on the device if required.

Instruction on the prophylaxis regimen to be administered to the subject
Regular weekly contacts between parents and the investigator to check the EPD 
documentation until next clinic visit.
Amended to
This visit will serve as the Baseline visit. It will include the first administration of study drug. 
For subjects in Part A (PTPs), the Baseline visit should take place within 8 weeks after 
Screening visit and at least 48 h after last FVIII administration. 
For subjects in Part B (PUPs), the Baseline visit may be combined with the Screening visit if 
all selection criteria can be confirmed based on medical records. The first dose of 
BAY 81-8973 may be for treatment of a bleed.  First treatment should not occur during high 
risk situations, surgery, or bleeds requiring prolonged or intensive treatment.
This visit should start with the following assessments:

Confirmation of eligibility including check of laboratory test results.
Note: Eligible subjects (except PUPs) must be inhibitor negative at Baseline.
Thereafter, the following activities will be performed:
…

Infusion of the first dose of study drug
Note:   For patients in Part B, first exposure to study drug may be either for treatment of 
an uncomplicated bleed or for start of prophylaxis. Inhibitor testing is mandatory every 3-
5 ED until 20 ED are accumulated.  See discussion on treatment of PUPs in Section 6.1.1.

Vital signs (Heart rate, temperature, blood pressure) after infusion.
…

Documentation of adverse events

Check of understanding of EPD use.  Repeat training on the device if required.  

Instruction on the prophylaxis regimen to be administered to the subject
Begin regular weekly contact between parents and the site to check the EPD documentation 
until next clinic visit.  Contacts should be documented in the medical record.
Section 7.1.2.3 Visit 3 – Month 1 

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Original protocol
7.1.2.3  Visit 3 – Month 1
The following procedures and assessments will be performed:

Check of EPD documentation and bleeding history
…

Injection of study drug

Vital signs (Heart rate, temperature, blood pressure) before and after injection
…
Regular weekly contacts between parents and the investigator to check the EPD 
documentation until next clinic visit.
Amended to
7.1.2.3  Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B
The following procedures and assessments will be performed:

Check of EPD entries and bleeding history.  
…

Infusion of study drug (Part A only)

Vital signs after infusion, if given
…
Regular weekly contacts between parents and the site to check the EPD documentation 
until next clinic visit.
Section 7.1.2.1, Visit 4 – Month 2 
Original protocol
7.1.2.4  Visit 4 – Month 2
The following procedures and assessments will be performed:
…

Injection of study drug

Vital signs (Heart rate, temperature, blood pressure) before and after injection
…

Check of EPD documentation and documentation of interval treatment and bleeding 
history.
Regular weekly contacts between parents and the investigator to check the EPD 
documentation until next clinic visit.

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Amended to
7.1.2.4  Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B
The following procedures and assessments will be performed:
…

Infusion of study drug (Part A only)

Vital signs after infusion, if given.  
…

Check of EPD entries of interval treatment and bleeding history.
Regular weekly contacts between parents and the site to check the EPD documentation until 
next clinic visit.
Section 7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (added)
7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1)
The following procedures and assessments will be performed:
…

Check of EPD entries of interval treatment and bleeding history.
Regular weekly contact between parents and the site to check the EPD entries until next clinic 
visit.
Section 7.1.2.6 Visit – Month 3, only for PUPs
Original protocol
7.1.2.6 Visit – Month 3, only for PUPs
The following procedures and assessments will be performed:
…

Injection of study drug

Vital signs (Heart rate, temperature, blood pressure) before and after injection
…

Check of EPD documentation of interval treatment and bleeding history.
Regular weekly contacts between parents and the investigator to check the EPD 
documentation until next clinic visit.
Amended to
Visit 6 – Part B only; ED 20 (20 ED +/- 1) 
The following procedures and assessments will be performed:

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…

Infusion of study drug.

Vital signs after infusion.
…

Check of EPD entries of interval treatment and bleeding history.
Regular weekly contacts between parents and the site to check the EPD documentation until 
next clinic visit.
Section 7.1.2.7 Interim visit – Only for Part B (30-40 ED) (added)
7.1.2.7  Interim visit – Only for Part B (30-40 ED)
Visit only required for PUPs who have less than 40 ED, 6 months after the Baseline visit.  The 
intent is to have at least one scheduled visit between completion of 20 ED and the expected 
date of accumulating 50 ED.   The primary purpose of the visit is to assess the well being of 
the subject, ensure continued compliance with the treatment, and make any needed 
adjustments in dosage or infusion frequency based upon weight or bleeding events.  
The following procedures and assessments will be performed:

Check of EPD entries of interval treatment and bleeding history.
Regular weekly contacts between parents and the site to check the EPD documentation until 
next clinic visit.
Section 7.1.2.8 Visit – Month 6 or final visit (end of the main study and start of the 
optional extension study)
Original protocol
7.1.2.8  Visit - Month 6 or final visit (end of the main study and start of the optional 
extension study) 
This visit will take place 6 months after baseline and at least 50 ED were accumulated or in 
case of early termination.
The following procedures and assessments will be performed:
…

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before and after injection
…

Check of EPD documentation and documentation of interval treatment and bleeding 
history.
For subjects not participating in the optional extension study:

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
Return of EPD  

Return of used and unused study medication for final drug accountability

Follow-up phone call (1-2 weeks after end of treatment)
Call parents/caregiver via telephone and review any new adverse events and 
changes in concomitant medication since the last study visit.
For subjects participating in the optional extension study:

Informed consent signed by parents/legal representative must be available

Continuation of prophylaxis treatment including regular weekly contacts between 
parents and the investigator to check the EPD documentation until next clinic 
visit.
Amended to
7.1.2.8  Final Visit - (end of the main study and start of the optional extension study) 
For subjects in Part A, this visit will take place 6 months after baseline and at least 50 ED
were accumulated, or in case of early termination.
For subjects in Part B, this visit will take place after 50 ED are accumulated, or in the case of 
early termination.  It is expected 50 ED will be achieved for most subjects between 6 and12 
months after start of prophylactic treatment.  
The following procedures and assessments will be performed:
…

Infusion of study drug.

Vital signs after infusion.
…

Check of EPD entries of interval treatment and bleeding history.
For subjects not participating in the optional extension study:

Return of EPD  

Return of used and unused study vials for final drug accountability

Follow-up phone call (1-2 weeks after end of treatment)
Call parents/caregiver via telephone and review any new adverse events and 
changes in concomitant medication since the last study visit.
For subjects participating in the optional extension study:

Informed consent signed by parents/legal representative must be available.

Continuation of prophylaxis treatment 

Begin regular monthly contacts between parents and the site to check the EPD 
documentation until next clinic visit.

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Section 7.1.2.9 Visit 7 – Month 12 and every 6 months
Original protocol
7.1.2.9  Visit 7 – Month 12 and every 6 months
The following procedures and assessments will be performed:
…

Check of EPD documentation and documentation of interval treatment and bleeding 
history
Amended to
7.1.2.9  Extension study visits – 6 months after completion of Part A or B; then every 6 
months)
The following procedures and assessments will be performed:
…

Check of EPD entries of interval treatment and bleeding history
…

Regular monthly contacts between parents and the site to check the EPD 
documentation until next clinic visit.
Section 7.1.2.10 Final visit
Original protocol
This visit will take place at the end of the extension period and at least 100 ED (including 
main study) were accumulated or in case of early termination.
The extension study will be prolonged until marketing authorization.
The final study visit must be performed at the time of switch to commercial drug.
The following procedures and assessments will be performed:
…

Check of EPD documentation and documentation of interval treatment and bleeding 
history

Return of EPD

Return of used and unused study medication for final drug accountability

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Follow-Up Phone Call (1-2 weeks after end of treatment)
Call parents/caregiver via telephone and review any new adverse events since the last study 
visit.
Amended to
This visit will take place at the end of the extension period and at least 100 ED (including 
main study) are accumulated, or in case of early termination.
The extension study will be continued until marketing authorization.
The final study visit must be performed at the time of switch to commercial drug.
The following procedures and assessments will be performed:
…

Check of EPD entries of interval treatment and bleeding history

Return of EPD

Return of used and unused study vials for final drug accountability
Follow-Up Phone Call (1-2 weeks after end of treatment)
Call parents/caregiver via telephone and review any new adverse events since the last study 
visit.
Section 8.5 Planned interim analyses
Original protocol
The main study has a duration of 6 months and the 6-months data will be analyzed for 
regulatory purposes as an interim analysis. Subjects will continue in the extension trial. The 
overall study will be closed after all subjects have completed the extension trial and an 
additional analysis will include all data from the main trial and the extension part.
Amended to
The main study has a duration of 6 months.  The 6-month data for PTPs will be analyzed for 
regulatory purposes as an interim analysis. When safety has been assessed in 10-20 PTPs who 
have received at least 50 ED, enrollment will begin in Part B.  All subjects will have the 
option of continuing in the extension trial. The overall study will be closed after all subjects in 
Parts A and B have completed the extension trial and an additional analysis will include all 
data from the main trial and the extension part.
The trial data will be reviewed periodically by an independent Data Monitoring Committee 
(DMC).  The DMC will review certain safety and efficacy data sets as defined in the charter, 
as well as the planned interim analysis, and provide written reports to the sponsor.  The 
decision to open enrollment to each age group will be made following recommendation of the 
DMC.  

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Section 8.6 Determination of sample size
Original protocol
Therefore, this study will include 20-25 subjects < 6 years (PTPs) and 15-25 subjects aged 
between 6 and 12 years. Thus, the total sample size will be 35-50 subjects, of whom a 
minimum of 35 subjects must be PTPs. The number of PUPs is not specified.
Amended to
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.  This study consists of two parts.  Part A will include 
a total of 50 PTPs; 25 subjects >6 – 12 years and 25 subjects aged 6 years and less. Part B will 
enroll 25 PUPs of all ages.  Total sample size will be 75 subjects.
13.1.2.4
Change 4
Synopsis – Dose(s)
Original protocol
25 -50 IU/kg; prophylaxis with at least 2 injections per week in previously treated patients (PTPs) and at least 1 
injection per week in previously untreated patients (PUPs)
Amended to
Part A:
PTPs: 25 -50 IU/kg (rounded to nearest size vial); prophylaxis with at least 2 infusions per week and treatment 
for breakthrough bleeds
Part B: 
Previously untreated patients (PUPs): 15-50 IU/kg (rounded to nearest size vial); prophylaxis with at least 1 
infusion per week and treatment for bleeds
Section 6.1.1 Regular prophylaxis
Original Protocol
Test drug:
BAY 81-8973 
Dosage:
25-50 International Unit (IU)/kg; ≥ 2 times per week in PTPs, ≥ 
1 injection per week in PUPs. 
Route of administration:
Manual intravenous (IV) injection over 1 – 5 minutes according 
to total volume
Amended to
Test drug:
BAY 81-8973 
Dosage:
25-50 International Unit (IU)/kg; ≥ 2 times per week in PTPs, 
15-50 International Unit (IU)/kg; ≥ 1 time per week in PUPs. 
(Smallest size vial is 250 IU, which may be used for initial treatment of PUPs of any weight)

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Route of administration:
Manual intravenous (IV) infusion over 1 – 5 minutes according 
to total volume
Section 6.4 Dosage and administration
Original Protocol
The dose selections for this study are based on the recommended dosage for Kogenate®
FS/Bayer.6  The study medication, BAY 81-8973, has been shown to have similar biological 
activity to Kogenate® FS/Bayer, which is currently approved in more than 50 countries for the 
treatment of hemophilia A. 
All subjects will receive prophylaxis treatment with BAY 81-8973 injections at least 2 times 
weekly with a dose of 25-50 IU/kg at the choice of the investigator and according to local 
standards and previous treatment.  The dose will always be up-rounded to full vials. If a 
subject begins prophylactic treatment, a low frequency may be selected especially in small 
children. PUPs may start with 1x/week prophylaxis schedule. The frequency as well as the 
dose may be adapted to the individual needs up to daily injections if needed to accommodate 
for the subject’s activities, eg, sports or intensive activities which need a high protection. Any 
instances of breakthrough bleeding occurring in subjects receiving the prophylactic care will 
be treated according to the current standard of care and severity of the bleed. 
Subjects will be injected by parents/caregivers at home or other facility near to subject’s 
home, or by the investigator/delegate during the study visits.  Children may also start with
self-injections after training if they want to do so.
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14.1).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide varying instructions based 
upon the type of surgical procedure to be undertaken.  
Amended to
The dose selections for this study are based on the recommended dosage for Kogenate®
FS/Bayer.6  The study medication, BAY 81-8973, has been shown to have similar biological 
activity to Kogenate® FS/Bayer, which is currently approved in more than 50 countries for the 
treatment of hemophilia A. 
In Part A of this study, subjects will receive prophylaxis treatment with BAY 81-8973 at least 
2 times weekly with a dose of 25-50 IU/kg at the choice of the investigator and according to 
local standards and previous treatment.  The dose should be rounded to the appropriate vial 
size.  In Part B, prophylaxis may be started with a low dose, once a week treatment schedule.  
The recommended dose is 15-50 IU/kg, rounded to the appropriate vial size (minimum 250 
IU).   For all subjects, the frequency as well as the dose may be adapted to the individual 
needs up to daily if needed to accommodate for the subject’s activities or sports participation.
Any bleeding events occurring in subjects receiving prophylactic care will be treated 
according to the local standard of care and severity of the bleed. 
Subjects will be injected by parents/caregivers at home, at a facility near the subject’s home, 
homecare nurse, or by the investigator/delegate during the study visits.  Children may also 

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self-infuse, if under the supervision of a responsible adult to ensure adherence to the 
prescribed treatment regimen.
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14.1).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide instructions based upon 
the type of surgical procedure to be undertaken.  
Section 7.1.2.2 Visit 2 - Baseline
Original protocol
This visit will serve as the Baseline visit; it will include the first administration of study drug. 
The Baseline visit should take place within 8 weeks after Screening visit and at least 48 h 
after last FVIII administration. Baseline may be combined with the screening visit if all 
selection criteria can be confirmed based on medical records for PUPs without any previous 
FVIII exposure.
Blood sample for inhibitor test and determination of FVIII:C trough levels (≥ 48 h after 
last FVIII injection) and HSP-70 antibodiesInjection of the first dose of study drug
Note:  
If inhibitor testing is mandatory every 3-5 ED until 20 ED are accumulated
Amended to
For subjects in Part B (PUPs), the Baseline visit may be combined with the Screening visit if 
all selection criteria can be confirmed based on medical records. The first dose of 
BAY 81-8973 may be for treatment of a bleed.  First treatment should not occur during high 
risk situations, surgery, or bleeds requiring prolonged or intensive treatment.
…
Note:   For patients in Part B, first exposure to study drug may be either for treatment of 
an uncomplicated bleed or for start of prophylaxis. Inhibitor testing is mandatory every 3-
5 ED until 20 ED are accumulated.  See discussion on treatment of PUPs in Section 6.1.1.
13.1.2.5
Change 5
Synopsis – Study objectives
Original protocol
Secondary objectives

To characterize pharmacokinetics in a subset of 6 to 13 the  age group of 6-12 years, if parents consent 
to it (participation for PK sampling is optional).
Amended to
Secondary objectives

To characterize pharmacokinetics in a subset of 6 to 13 previously treated patients ((PTPs) (Part A 
only)), if parents consent to it (participation for PK sampling is optional).
Synopsis – Methodology 

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Original protocol
Safety laboratory tests, human coagulation factor VIII (FVIII) trough level measurements and recovery will be 
performed at the clinic visits during the main study only. 
Amended to:
Pharmacokinetics (PK) samples will be collected in a subset of subjects at pre-infusion and then 20-30 minutes, 
4 h, and 24 h post infusion.   Participation in the PK portion of the study is voluntary and requires specific 
consent.  
Section 2 Study objectives
Original protocol
Primary objective
Secondary objectives

To assess pharmacokinetic parameters in a subset of 6 to 13 children. in the age 
group of 6-12 years (if parents consent to it , participation for pharmacokinetic [PK] 
sampling is optional,).
Amended to
Secondary objectives

To assess pharmacokinetic parameters in a subset of children. (Part A only -
participation in pharmacokinetic [PK] sampling is voluntary and requires consent,).
Section 4 Study Design
Original protocol
Incremental recovery and trough levels will be assessed in all subjects. Other PK parameters 
(maxiumum concentration [Cmax], half life, area under curve [AUC], Mean Residence Time 
[MRT] and clearance) are optional and may be assessed at baseline after the first dose in 6-13 
subjects aged 6-12 years using sparse sampling schedule if parents and children (if 
appropriate) consent to participation. Bleeding and injection information will be collected 
using an electronic subject diary (EPD), which will be provided to the parents/caregivers.
Amended to
Incremental recovery and trough levels of BAY 94-9027 will be assessed in all subjects. 
Subjects enrolled in Part A will be offered participation in the pharmacokinetic (PK) 
evaluation.   Participation is optional, and requires consent.  PK parameters (maximum 
concentration [Cmax], half life, area under curve [AUC], Mean Residence Time [MRT] and 
clearance) may be assessed using a sparse sampling schedule. Bleeding and injection 
information will be collected using an electronic patient diary (EPD), which will be provided 
to the parents/caregivers.
Section 6.1.2 Breakthrough bleeds and surgeries

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Original Protocol
BAY 81-8973 will be used for the treatment of breakthrough bleeds. The dosage will be at the 
discretion of the investigator. 
For any surgery that may occur during the course of the study, BAY 81-8973 should be used. 
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14.2).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide varying instructions based 
upon the type of surgical procedure to be undertaken. Surgery is not allowed as first treatment 
in a PUP.
Amended to
BAY 81-8973 will be used for the treatment of breakthrough bleeds. The dosage will be at the 
discretion of the investigator.  For PUPs in Part B, see Section 6.1.1.
For any surgery that may occur during the course of the study, BAY 81-8973 should be used. 
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14.2).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide varying instructions based 
upon the type of surgical procedure to be undertaken.  For PUPs in Part B, surgery is not 
allowed as first treatment and should be avoided, when possible, during the first 20 ED.
If the study site routinely measures PK prior to surgical procedures, these results may be used 
to fulfill the optional PK in Part A, provided that consent is given in advance, the subject 
undergoes a 48 hour washout, sampling is obtained at the designated time points, and samples 
are sent to the central laboratory for evaluation. 
In case of severe or potentially life threatening bleeding events, or the need for unplanned or 
emergency surgery, the subject should be managed following local standard of care, using 
readily available factor products. 
Section 6.1.4 Optional pharmacokinetic measurements
Original Protocol
6.1.4  Optional pharmacokinetic measurements
Test drug:
BAY 81-8973 
Dosage:
50 IU/kg as a single IV injection, at least 48 h after any previous 
FVIII injection.
Amended to
6.1.4  Optional pharmacokinetic measurements (Part A only)
Test drug:
BAY 81-8973 
Dosage:
50 IU/kg as a single IV infusion, at least 48 h after any previous 
treatment with FVIII.

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Section 6.1.5 Immune tolerance induction (ITI)
Original Protocol
If a subject develops an inhibitor, an ITI treatment should be considered. 
Test drug:
BAY 81-8973 
Dosage:
200 IU/kg per day as initial dose, either once a day one injection of 
200 IU/kg or twice a day 100 IU/kg at the investigator’s discretion 
until the inhibitor is eradicated successfully or until failure or for a 
maximum of 18 months. The regimen of 2x100 IU/kg per day is 
recommended.
The following criteria are applied for success:
1. no detectable inhibitor based on Nijmegen assay (< 0.6 BU)
2. normal recovery (> 66% of predicted)
3. normal half life (≥ 6 h, absence of anamnestic response)
Failure is defined as no response (< 20% decrease in the inhibitor level) within a 6 months 
period after the first 3 months in the absence of any infection. The detailed treatment plan 
should be agreed with the Coordinating Investigator.
Amended to
If a subject develops an inhibitor, ITI should be considered.  All treatments, FVIII 
measurements, and inhibitor levels will be documented.  
Test drug:
BAY 81-8973 
Dosage:
200 IU/kg per day as initial dose, either once a day or 100 IU/kg
twice a day at the investigator’s discretion until the inhibitor is 
eradicated successfully, or until failure, for a maximum of 18 
months. The detailed treatment plan should be agreed with the 
Coordinating Investigator.
The following criteria are applied for success:
1. no detectable inhibitor based on Nijmegen assay (< 0.6 BU)
2. normal recovery (> 66% of predicted)
3. normal half life (≥ 6 h)
Failure is defined as no response (< 20% decrease in the inhibitor level) within a 6 months 
period in the absence of any infection. 

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Section 6.4 Dosage and administration
Original Protocol
For the optional PK study, each subject will receive a dose of approximately 50 IU/kg of 
BAY 81-8973.  The dose will be prepared by a pharmacist or nurse at the study center.  This 
dose would be expected to increase the plasma level of FVIII to approximately 80-100% 
FVIII activity in the severe hemophilia subjects.
Amended to
For the optional PK study (Part A only), each subject will receive an exact dose of 50 IU/kg 
of BAY 81-8973.  The dose will be prepared by a pharmacist or nurse at the study site.  This 
dose is expected to increase the plasma level of FVIII to approximately 80-100% FVIII 
activity.

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Section 7.1.1 Tabulated overview
Original protocol
Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 week)
Visit 4 
Month 2
(+/- 1 week)
Final visit 
Month 6
(Minimum 50 
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
X
    monthly  
Interaction between subject/parent and investigatord
  weekly             
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. 
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Amended to
Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week)
Visit 4 
Month 2
(+/- 1 
week)
Final visit 
Month 6
(Minimum 50 
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
X
    monthly  
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Section 7.1.2 Timing of assessments
Original protocol
The main study consists of a screening period of up to 8 weeks and a 6-month treatment 
period and a minimum of 50 ED per subject will be accumulated. After the Screening and 
Baseline visits which may be combined to one visit for PUPs, further 3 visits are scheduled at 
Month 1, Month 2 and Month 6. PUPs will have monthly visits for the first 3 months and 
blood sampling every 3-5 ED for inhibitor testing
Thereafter, subjects will be offered to continue treatment in an extension study until a total 
number of at least 100 ED per subject will be accumulated or until marketing authorisation of 
the drug, with additional visits every 6 months. 
Amended to
The main study consists of a Screening period followed by at least 50 ED per subject.  The 
Screening and Baseline visits may be combined to one visit for PUPs.  There is no minimum 
interval between the Screening and Baseline visits for PUPs or PTPs.  For PTPs, no longer 
than 8 weeks should pass between Screening and Baseline visits.
In Part A, PTPs, a minimum of 50 ED will be accumulated during a 6 month treatment period.  
Visits are scheduled at Month 1, Month 2 and Month 6.  
In Part B, the treatment period will be extended until 50 ED have been accumulated.  The 
duration of Part B will vary and is dependent upon the frequency of prophylactic infusion and 
the number of bleeding events.  Blood sampling for inhibitor testing is required every 3-5 
exposure days up to 20 ED, and again at 50 ED.  As most subjects will begin prophylaxis 1x 
week, study visits during the first 20 ED are expected to occur monthly.  However, it is 
understood that bleeding events resulting in added doses, delayed start of prophylaxis after 
first bleeds, or missed infusions due to difficult i.v. access may result in some variation in the 
number of ED a patient has obtained at each visit or the exact interval between visits.  
Likewise, those patients who receive more frequent infusions, may require study visits more 
often than once a month.   
After completing Part A or B, all subjects will be offered continued treatment in an extension 
study until a total number of at least 100 ED per subject are accumulated or until marketing 
authorisation of the drug.  Participation will require additional visits every 6 months. 
Section 7.1.2.2 Visit 2 - Baseline
Original protocol

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
injection.

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Amended to

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion.

Optional PK (only for subjects participating in Part A): Additional blood samples at 4 
h and 24 h post infusion (obtained only once during study). 
Section 7.1.2.3 Visit 3 – Month 1 
Original protocol
7.1.2.3  Visit 3 – Month 1
The following procedures and assessments will be performed:

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
injection.
Amended to
7.1.2.3  Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B
The following procedures and assessments will be performed:

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion.
Section 7.1.2.1 Visit 4 – Month 2 
Original protocol
7.1.2.4  Visit 4 – Month 2

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
injection.
Amended to
7.1.2.4  Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion. (Part A only)

Optional PK (only for subjects participating in Part A): Additional blood samples at 4 
h and 24 h post infusion (obtained only once during study). 
Section 7.1.2.8 Visit – Month 6 or final visit (end of the main study and start of the 
optional extension study)
Original protocol

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
Blood sample for the determination of recovery to be taken at 20-30 min after end of 
injection.
Amended to
7.1.2.8  Final Visit - (end of the main study and start of the optional extension study) 

Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion.

Optional (only for subjects participating in Part A): Additional blood samples at 4 h 
and 24 h post infusion obtained only once during study
Section 7.4 Pharmacokinetics (optional)
Original protocol
7.4  Pharmacokinetics (optional)
Participation in the PK evaluations is optional.  The minimal number of subjects in the 
optional PK is 6. Up to 13 subjects of the age group 6-12 years may participate if parents 
consent to the PK. If parents are consenting to participate in the PK, a sparse sampling 
approach will be followed with reduced number of sampling time points. The 
pharmacokinetics of the study drug in plasma will be determined after the 1st administration at 
Baseline visit. There must be a washout of previous FVIII of at least 48 h before the first 
injection of study drug and the subject must have no signs or symptoms of an acute bleeding 
episode. 
Subjects will be administered a dose of 50 IU/kg. Blood samples will be obtained pre-
injection and at 20-30 min, 3-5 h, 22-26 h and 46-50 h after the end of injection of study 
medication. Approximately 5 mL blood will be drawn at each time point. FVIII levels will be 
determined by the one-stage assay and chromogenic assay. Details of the blood sampling and 
processing procedures for all laboratory measurements will be provided in the Study 
Procedure Manual (SPM) that accompanies this protocol.
Based on the plasma concentration time data the following pharmacokinetic parameters will 
be calculated:  Cmax, recovery, AUC, half-life (t1/2), MRT and clearance (CL). 
Amended to
7.4  Pharmacokinetics – Part A only (optional – consent required)
Participation in the PK evaluations is optional.  The minimal number of subjects in the 
optional PK is 6.  If consent/assent is obtained, PK will be assessed using the sampling time 
points specified in this protocol. The pharmacokinetics of the study drug in plasma can be 
determined at any time during the main study, and should be scheduled to coincide with a 
scheduled visit to measure incremental recovery, if possible.  There must be a washout of 
previous FVIII of at least 48 h before the first infusion of study drug and the subject must 
have no signs or symptoms of an acute bleeding episode.  All samples will be processed in the 
central laboratory.

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Subjects will be administered a dose of 50 IU/kg. Blood samples will be obtained pre-infusion 
and at 20-30 min, 4 h, and 24 h after the end of infusion of study medication.. FVIII levels 
will be determined by the chromogenic assay. Details of the blood sampling and processing 
procedures for all laboratory measurements will be provided in the Study Procedure Manual 
(SPM) that accompanies this protocol.  A dose preparation worksheet will be provided in the 
Pharmacy manual.
Based on the plasma concentration time data the following pharmacokinetic parameters will 
be calculated:  Cmax, recovery, AUC, half-life (t1/2), MRT and clearance (CL). 
Section 8.3 Variables 
Original protocol
Pharmacokinetics / pharmacodynamics (Optional)
For investigation of drug exposure and potential relationships to drug effects, selected 
subjects from selected centers only will participate in pharmacokinetic (PK) sampling. 
Subject’s participation in PK sampling is voluntary and parents have to consent to it. PK 
sampling will be performed in centers which have experience in PK studies and volunteer to 
participate. For further details of PK sampling, please refer to Section 7.1.1.  
Based on the known PK variability of FVIII in hemophilia subjects it is expected that a sparse
sampling strategy will be sufficient to calculate relevant pharmacokinetic parameters. 
Blood samples for population PK analyses will be collected according to a sampling schedule 
in predefined windows. Blood sampling for the determination of FVIII concentration in 
plasma will be taken at baseline after the first injection at 20-30 minutes, 3-5 h, 22-26 h and 
46-50 h after end of injection (or at pre dose,  the dosing time of the preceding dose will be 
documented).  Samples which are collected outside of the predefined windows will 
nevertheless be valid for PK analysis. Start and end time of dose and exact sampling times 
should be documented. 
A minimal number of 6 subjects is required. The following parameters will be calculated: 
Cmax, AUC, recovery, clearance, MRT and t ½ using non-compartmental methods.
Amended to
Pharmacokinetics / pharmacodynamics (Optional)
For investigation of drug exposure and potential relationships to drug effects, selected 
subjects from selected centers only will participate in pharmacokinetic (PK) sampling. 
Subject’s participation in PK sampling is voluntary and consent/assent is required. PK 
sampling will be performed in centers which have experience in PK studies and volunteer to 
participate. 
Based on the known PK of FVIII in hemophilia subjects it is expected that a reduced
sampling strategy will be sufficient to calculate relevant pharmacokinetic parameters. 
Blood samples for population PK analyses will be collected according to a sampling schedule. 
Blood sampling for the determination of FVIII concentration in plasma will be taken at 

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baseline before the infusion (pre-infusion) at 20-30 minutes, 4 h, and 24 h after end of 
infusion. Attempt should be made to collect the sample as close as possible to the times 
indicated above.  If there is a delay in collecting a sample, the sample should still be collected 
so that there are at least 3 samples post infusion.  In all cases the exact time of start and end of 
infusion and the time of actual sample collection should be noted in the CRF.   
A minimal number of 6 subjects is required. The following parameters will be calculated: 
Cmax, AUC, recovery, clearance, MRT and t ½ using non-compartmental methods.
13.1.2.6
Change 6
Section 4 Study Design (added)
In the event that any subject acquires an inhibitor to FVIII, Immune Tolerance Induction (ITI) 
will be offered. The subject may receive BAY 81-8973 up to 200 IU/kg daily for 18 months.  
Treatment will be at the direction of the treating physician.  Data on treatment, FVIII 
measurements, and inhibitor levels will be collected. 
Section 6.1.1 Regular prophylaxis
Original Protocol
Effective prophylaxis requires replacement therapy in order to maintain a FVIII in above 1%. 
Based on the kinetics 3 week application schedule. It is well known that the FVIII clearance is 
higher in children than in adults. In order to maintain a FVIII trough level above 1%, the 
application schedule for children is every other day.
Nevertheless, the frequent injections may be difficult for small children and their parents. The 
benefit must be evaluated against the high burden mainly in the first 6 months of treatment. In 
addition, it has been shown, that the first exposures may be critical for the tolerance of the 
drug. The CANAL study showed that high dosages for surgeries and severe bleeds increased 
the risk for inhibitor development whereas the prophylaxis decreased this risk 17. This 
observation was also confirmed by treatment centers in Germany 18.
Taking into account these observations, the following prophylaxis schedule is recommended:

with a once-a-week schedule and a low dose of 250 IU (15-25 IU/kg)

, increase frequency if required clinically because of bleeds or increased physical activity
If first treatment is required for a surgery, the subject cannot be included (see Section 5.1)
If first treatment is required for a bleed, treat the bleed with moderate dosages and continue 
with prophylaxis once a week, increase frequency if required
Perform inhibitor testing every 3-5 ED until 20 ED are accumulated or in case of non-
response to treatment. 
Amended to

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Effective prophylaxis requires replacement therapy in order to maintain FVIII activity in the 
blood above 1%. Based on the kinetics, optimal prophylactic treatment requires infusion at 
least 3 times a week. As FVIII clearance is higher in children than in adults, the optimal 
infusion schedule for children may require treatment as frequently as every other day.  
Frequent injections may be difficult for small children and their caretakers.  Consequently, the 
benefit for each individual child must be evaluated against this burden, particularly in very 
young children for whom venous access may be difficult.
Recent studies have demonstrated that the timing of the first exposures to FVIII may be 
critical for the tolerance of the drug. The CANAL study showed that early intensive treatment 
such as that required for surgery or severe bleeds increased the risk for inhibitor development,
whereas regular prophylaxis was associated with a lower risk 17. This observation was 
subsequently supported by studies demonstrating lower inhibitor rates in boys treated with 
low dose early prophylaxis in treatment centers in Germany 18.
Taking into account these observations, the following is recommended for PUPs participating 
in Part B:

Prophylaxis should begin after a minimal number of on-demand FVIII exposures with 
BAY 81-8973 (no more than 2-3 bleeding events) or when the child is large enough to 
tolerate weekly infusion.  

Begin prophylaxis with a once-a-week schedule low dose of 250 IU (15-25 IU/kg); the 
starting dose may be tailored to the patient’s weight or demonstrated bleeding tendency.

Avoid starting prophylaxis during febrile illness or other identified inflammatory events.

Increase frequency of infusion or dose as needed for breakthrough bleeding, increased 
physical activity, or weight gain.

Avoid surgery or need for high dose intensive treatment lasting more than 4 days during 
the first 20 exposure days.

Do not give FVIII as prophylaxis for vaccinations.
After treatment with BAY 81-8973 begins, inhibitor testing every 3-5 ED is required until 20 
ED are accumulated or in case of non-response to treatment (Section 14.5).
Section 5.2.1 Withdrawal
Original protocol

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Subjects must be withdrawn from the study for the following reasons:

At their own request or at the request of their legally acceptable representative

At any time during the study and without giving reasons, a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being

At the specific request of the sponsor

A positive inhibitor result at screening or baseline before first injection
Subjects may be withdrawn from the study for the following reasons:

At the specific request of the sponsor

Insufficient response to FVIII treatment

If, in the judgment of the investigator or the sponsor, the subject is not compliant with 
the protocol.
Amended to
Subjects must be withdrawn from the study for the any of the following reasons:

At their own request or at the request of their parent/legal representative

At any time during the study and without giving reasons, a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being

A positive inhibitor result at Screening or Baseline visits

At the request of the sponsor

If, in the judgment of the investigator or the sponsor, the subject is not compliant with 
the protocol.
Section 7.5.3.4 Inhibitor testing
Original protocol
Premise for inclusion in this study is the availability of a negative test result of inhibitor at 
Baseline. 
Blood samples for FVIII inhibitor testing will be taken at Screening, Baseline, Month 1, 
month 2, 3 and Month 6 (or final visit). Premise for inclusion of PTPs in this study is the 
availability of a negative test result of inhibitor as measured in the blood sample at Screening. 
A further sample will be taken at baseline before the first injection. If the inhibitor test result 

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changed from negative at screening to positive at baseline before the first injection of study 
medication, the subject must be withdrawn from the trial.
Amended to
Premise for inclusion requires confirmed diagnosis of severe hemophilia A (<1% FVIII) and 
documentation of a negative test result of inhibitor at Baseline. 
Blood samples for FVIII inhibitor testing will be taken at Screening (PTPs only), Baseline, at 
regularly scheduled intervals throughout the study, and at the final visit. Premise for inclusion 
of PTPs in this study is the availability of a negative inhibitor result as measured in the blood 
sample at Screening. A further sample will be taken at baseline before the first infusion. If the 
inhibitor test result changes from negative at screening to positive at baseline, before the first 
infusion of study medication, the subject must be withdrawn from the trial.
Section 14.5 Laboratory evaluation for suspected inhibitor (added)
14.5  Laboratory evaluation for suspected inhibitor
If inhibitor is confirmed, the subject may receive immune tolerance therapy using 
BAY 81-8973.  (See section 6.1.4)
If an inhibitor is detected as part of scheduled testing, the investigator will be notified.  A 
positive inhibitor test is defined with a threshold of ≥ 0.6 BU in the central lab. Any positive 
test must be confirmed by a second plasma sample.  Pre and post infusion samples will be 
required for confirmation.
13.1.2.7
Change 7
Section 6.1.3 Missed infusions due to difficult venous access or family travel (added)
6.1.3  Missed infusions due to difficult venous access or family travel
During the trial, it is expected that all reasonable attempts will be made to ensure that subjects 
will comply with and adhere to their designated prophylaxis infusion schedule with few 
interruptions.  However, there may be situations when problems related to difficult venous 
access, or travel to locations where appropriate support for infusions is not available, may 
necessitate a brief hiatus in the treatment schedule.  Parents should inform the investigator of 
all such situations, and the reason documented in the medical record.   Prolonged or repeated 
breaks in the prophylaxis schedule should be avoided, and could result in the subject being 
removed from the study.
13.1.2.8
Change 8
Section 7.1.1 Tabulated overview
Original protocol

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Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week)
Visit 4 
Month 2
(+/- 1 
week)
Final visit 
Month 6
(Minimum 50 
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. 
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension

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Table7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
    Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6,
Month 4
or
ED ~20
Interim d
Visit
30-40 ED
Final visit
or
ED 50
Extension 
Visit 
every 6 
months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before infusion and inhibitor c
X
X
X
X
X
X
X
Recovery (20-30 min after infusion)
X
X
X
X
Infusion of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Interaction between subject/parent and 
investigator
  weekly                                   
  monthly  

Concomitant medication
X
       continuously     
a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Table7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week)
Visit 4 
Month 2
(+/- 1 week)
Final visit 
Month 6
(Minimum 50
ED)
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor
X
X
X
X
X
X
Recovery (20-30 min after infusion) c
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire
X
    monthly  
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
CBC, Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
c.
Measured at least 48 h after last dose of FVIII
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension study
    Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6,
Month 4
or
ED ~20
Interim d
Visit
30-40 
ED
Final 
visit
or
ED 50
Extension 
Visit every 
6 months
Extension
Final visit
Informed consent)
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before infusion and inhibitor c
X
X
X
X
X
X
X
Recovery (20-30 min after infusion)
X
X
X
X
Infusion of study drug
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization 
Questionnaire
X
   monthly 
Interaction between subject/parent and 
investigator
  weekly                                        monthly  
Concomitant medication
X
       continuously     
a.
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d. 
Interim visit only if less than 40 ED have been achieved by Month 6.

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Section 7.1.2.1 Visit 1 – Screening
Original protocol

Recording of prior and concomitant medication
Amended to

Recording of prior and concomitant medication and Healthcare Resources Utilization 
Questionnaire. (Appendix 14.3).  Measurement of vital signs: Systolic and diastolic 
blood pressure, heart rate, and body temperature.  
Section 7.1.2.2 Visit 2 - Baseline
Original protocol

Update of concomitant medication and questionnaire on healthcare utilisation
(Appendix 14.3) 
Amended to

Update of concomitant medication and Healthcare Resources Utilization 
Questionnaire. (Appendix 14.3) 
Section 7.1.2.3 Visit 3 – Month 1 
Original protocol
7.1.2.3  Visit 3 – Month 1
The following procedures and assessments will be performed:

Check of EPD documentation and bleeding history including adverse events and 
questionnaire on healthcare utilisation (Appendix 14.3)
Amended to
7.1.2.3  Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B
The following procedures and assessments will be performed:

Check of EPD entries and bleeding history.  Collect information on, adverse events 
and Healthcare Resources Utilization Questionnaire. (Appendix 14.3).

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Section 7.1.2.1 Visit 4 – Month 2 
Original protocol
7.1.2.4  Visit 4 – Month 2

Documentation of interval history including adverse events and concomitant 
medication and questionnaire on healthcare utilisation (Appendix 14.3)
Amended to
7.1.2.4  Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (added)
7.1.2.5, Visit 5 – Part B only; ED ~15 (14 ED +/- 1)

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 7.1.2.6 Visit – Month 3, only for PUPs
Original protocol
7.1.2.6 Visit – Month 3, only for PUPs

Documentation of interval history including adverse events and concomitant 
medication and healthcare utilisation (Appendix 14.3)
Amended to
7.1.2.6 Visit 6 – Part B only; ED 20 (20 ED +/- 1) 

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 7.1.2.7 Interim visit – Only for Part B (30-40 ED) (added)
7.1.2.7  Interim visit – Only for Part B (30-40 ED)

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 7.1.2.8 Visit – Month 6 or final visit (end of the main study and start of the 
optional extension study)
Original protocol

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7.1.2.8  Visit - Month 6 or final visit (end of the main study and start of the optional 
extension study) 

Documentation of interval history including adverse events and concomitant 
medication 
Amended to
7.1.2.8  Final Visit - (end of the main study and start of the optional extension study) 

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 7.1.2.9 Visit 7 – Month 12 and every 6 months
Original protocol
7.1.2.9  Visit 7 – Month 12 and every 6 months

Documentation of interval history including adverse events and concomitant 
medication
Amended to
7.1.2.9  Extension study visits – 6 months after completion of Part A or B; then every 6 
months)

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 7.1.2.10 Final visit
Original protocol

Documentation of interval history including adverse events and concomitant 
medication
Amended to

Documentation of interval history including adverse events and concomitant 
medication and Healthcare Resources Utilization Questionnaire (Appendix 14.3).  
Section 14.3 Healthcare Resources Utilization Questionnaire
Original protocol 
Dear Parent/Caregiver, 
We appreciate you taking time to complete this questionnaire about your son’s health 
care resource utilization. All your answers are confidential. For the following questions, 
we would like to ask you to follow the instructions below. 

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
Only one parent or caregiver, the person with whom the child relates most closely, 
should answer the questions. 

Are you   the Mother?  the Father? Other: _________________________

Please read each question carefully.
Study Center: _____________Subject  number:__________
1. Did your child have any contact with health professionals this week? 
_____NO     ____YES    (If no, then go to question 2.)
If yes, then
Date(s) of contact______________________ 
Type of contact (Office visit_______ Phone call________)
Reason for contact______________________________________
Whom did your child see? 
Hematologist_______________________
Family physician__________________
Nurse___________________________
Pharmacist_______________________
Other (specify)____________________________
2. Did your child have any procedures performed this week?
________NO   ________YES
(If no, then go to question 3.)
If yes, please check below: 
Blood test________
Date:______________ Number of times:_________
Biopsy___________ 
Date: _____________ 
Number of times:_________
X-ray____________ 
Date: _____________ 
Number of times:_________
MRI_____________
Date: _____________ 
Number of times:_________
CT scan__________ 
Date:______________ Number of times:_________
Other____________ 
Date:______________ Number of times:_________
3. Did your child have any lab tests performed this week?  ____NO   _____YES
(If no, then go to question 4.)
If yes, please list: ___________________________________________
4. Did your child have any joint-related surgery this week?  ____NO  ______YES
5. Was your child prescribed any medications this week? ____NO   ______YES
(If no, then go to question 6.)
If yes, please list:

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Name of medication_____________ To take for how many days?______
Reason for taking medication____________________________________
6. Was your child hospitalized this week? ______NO   _____YES
(If no, then go to question 7.)
If yes, Date of hospitalization______ Date of discharge___________
Reason for hospitalization?__________________________________
7. Did your child have an emergency room (ER) visit this week? _____NO   _____YES
(If no, then go to question 8.)
If yes, Date of ER visit__________________ 
Reason for ER visit?________________________________________
8. Was your child in the intensive care unit (ICU) this week? ___NO   _____YES
(If no, then skip to 9)
If yes, Date of admission to ICU________________________
Date of discharge____________________________________
Reason for ICU?_____________________________________
9. Work/productivity loss:
In the past week, how many days of school has your child missed due to Hemophilia?  
_____________
Amended to 
The Healthcare Resources Utilization Questionnaire will be used to collect data on the subject.  
This will include number of days lost from school, medical procedures or laboratory tests, 
complications, and hospitalizations due to hemophilia or other medical needs.  The 
questionnaire should be administered by the investigator or delegate monthly throughout the 
study period by interviewing a parent/caregiver. This can be performed either at scheduled 
study visits, or during regularly scheduled contact between the study site and the 
parent/caregiver. The answers will be entered on the paper questionnaire by the study site.  
The completed questionnaire is a source document subject to review by the monitor.  
Healthcare Resources Utilization Questionnaire in LEO Kids (13400)
Instructions for the interviewer:
1.
Only one parent or caregiver, the person with whom the child relates most closely, should answer 
the questions consistently 
2.
Please record the answers in English.  
3.
Please do not write any other information on the form.
Study Center: _________________ Subject number: __________   

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Date of interview: ___________________ (MM/DD/YYYY) 
This form is being completed for the month of  _________________________ and year  __________.
For example:   Month of  June and year 2011  (answers include contacts from June 1 to June 30, 2011).
1. Did your son have any contact with health professionals this past month that were not required as part of the 
LEO Kids study? 
_____NO    ____YES
                        If yes, then complete:
Type of contact:  _______Office visit    ______ Phone call   (Check or enter how many if  
more than one.)
Reason for contact:  _________________________________________________________
Whom did your child see? Please check all that apply:
___Hematologist
___Family physician
___Pediatrician
___Nurse
___Pharmacist
___Other, specify:  ___________________________________________________    
2. Did your son have any procedures or tests performed in the past month that were not required as part of the 
LEO Kids study?
______NO   _____YES
If yes, please check all that apply: 
___ Blood test
  Number of times blood was drawn:  ______ (even if multiple tubes were 
collected)
                             ___ Urine test         Number of times specimen collected:  _______
___ Biopsy
  Number of times:  _________
___ X-ray
  Number of times:  _________   (can include multiple views)
___ MRI 
  Number of times:  _________
___ CT scan
  Number of times: _________
___ Joint surgery   Number of times: _________
3.  Did your son have any hospital visits in the past month? 
      ______NO   _____YES
            If yes, check the kind of visit:
            ___Hospital admission.  For how many nights? _____   (Include nights in ICU/PICU)
                          ___Emergency Department visit.  For how many nights? _____
                          ___Intensive Care Unit or Pediatric Intensive Care Unit (ICU or PICU).
                                  For how many nights? ___________
           Reason: ____________________________________________________
4.   Did your son miss any days of school due to hemophilia in the past month?
       ______NO    _____YES   If yes, number of days missed? ________

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13.1.2.9
Change 9
Section 6.7 Treatment of compliance
Original Protocol
Parents/caregivers will be provided with an electronic patient diary (EPD) for the whole study 
(for details see Section 7.3.2.2). These logs will be used to collecting the injection data and 
bleeding episodes by the parents/caregivers and interact on a weekly basis with the 
Investigator or delegate to verify and complete the weekly injection and bleeds on the EPD.
Parents/caregivers must transmit the treatment records electronically using the EPDdevice at 
least once every week. EPD will be utilized to assess the compliance with the prophylaxis 
treatment schedule and with the recording of injection information for bleeding events and 
medication inventory.  
Participation in the study may be terminated at the sponsor's discretion if a subject fails to 
comply with critical protocol requirements. 
Empty vials of study medication must be returned to the study center for drug accountability
at each visit during the study.  At the end of the study, all used and unused study medication
must be collected for final drug accountability.
Amended to
Parents/caregivers will be provided with an electronic patient diary (EPD) for the whole study 
(for details see Section 7.3.2.2). These logs will be used to collecting the treatment data and 
bleeding episodes.  The subject/parent/caregiver will interact with the Investigator or delegate 
weekly to verify and complete the EPD entries, and monthly during the extension study.
Data on the EPD will be transmitted after each treatment is entered.  The EPD will be used to 
assess the subject’s compliance with the prophylaxis treatment schedule and with the 
recording of treatments and bleeding events, and assist in study medication inventory.  See 
Section 6.1.3 for discussion of missed treatments.
Participation in the study may be terminated at the sponsor's discretion if a subject fails to 
comply with the above protocol requirements. 
Empty vials of study medication must be returned to the study center at each study visit.  At 
the end of the study, all used and unused study drug vials will be counted and collected by the 
sponsor’s representative for final drug accountability.
Section 7.3.1 Efficacy variables
Original protocol

Physician’s / subject’s/parents’ assessment of the response in treatment of mayor
bleeding events which is assessed as excellent, good, moderate or none.
Amended to

Subject/parents’ assessment of response to treatment of bleeding events, which is 
assessed as excellent, good, moderate or poor.

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Section 7.3.2.1 Incremental recovery
Original protocol
7.3.2.1  Incremental recovery 
Samples for FVIII trough levels will be collected in the hospital setting before the next 
planned injection as scheduled. Recoveries should be performed in conjunction with planned 
prophylaxis injection. 
FVIII levels will be determined in a central laboratory with both the one-stage and the 
chromogenic assays. The same type of assay should be used throughout the study.
FVIII trough levels will be determined in the blood samples collected before the 
BAY 81-8973 injections at Baseline, Month 1, Month 2, and Month 6 (or final visit). The 
measurement should be performed after an at least 48-h treatment-free interval.
Incremental recovery at 20-30 min after end of injection will be determined at Baseline, 
Month 1, 2 and Month 6 (or final visit). Incremental recovery should only be measured when 
the subject is not actively bleeding. The exact sampling times before and after injection have 
to be documented in the CRF.
Amended to
7.3.2.1  Incremental recovery of Factor VIII
Samples for FVIII trough levels will be collected in the clinic before the next planned 
prophylactic infusion as scheduled. Recoveries should be performed in conjunction with 
planned prophylaxis infusions, using the subjects usual dose (exception, during optional PK in 
Part A). Infusions given at study visits will not be recorded in the EPD, but in the site patient 
records, which will be the source document and will be used to enter this information in the 
CRF.
Levels of BAY 81-8973 will be determined in a central laboratory with the chromogenic 
method. 
FVIII trough levels will be determined in the blood samples collected before the scheduled
BAY 81-8973 infusions at Baseline, Month 1, Month 2, and Month 6 (or final visit) in Part A; 
or at Baseline, ED 20, and final visit (ED 50) in Part B. The measurement should be 
performed at least 48-h after last infusion of BAY 81-8973.
Incremental recovery at 20-30 min after end of infusions will be determined at Baseline, 
Month 1, 2 and Month 6 (or final visit). Incremental recovery should only be measured when 
the subject is not actively bleeding. The exact sampling times before and after infusion have 
to be documented in the CRF.
Section 7.3.2.2 Injection logs / bleeding verification
Original protocol

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7.3.2.2 Injections logs / bleeding verification
Injection logs are commonly used for hemophilia subjects for documentation of their home 
treatment. Home treatment and bleeding frequency are key variables evaluated in this study.  
Study specific injection logs will be provided in national language. The preferred system for 
this study will be electronic patient diary (EPD) devices since they are interactive, allow for 
real time data transmission to the sites, record-stamp date and time of fulfillment and facilitate 
the clarification of data with the site and also the data cleaning process.
Subjects/parents/caregivers will be provided with electronic patient diaries (EPDs) for the 
whole study. At Screening and Baseline visits, subjects and parents/caregivers will be trained 
in the use of the device. These logs will be used to collecting the injection data and bleeding 
episodes by the parents/caregivers or subjects, and interact on a basis with the investigator or 
delegate to verify and complete the weekly injections and bleeds on the EPD. Thus, the EPD 
will be considered the source for these data.
For each injection of study medication including the injections administered during a planned 
visit for evaluation of recovery, information must be recorded on the Injection Logs as 
follows:
1. Date and time
2. Lot numbers / number of vials administered
3. Reason for injection (regular prophylaxis, preventative prophylaxis, spontaneous bleed 
first treatment, trauma bleed first treatment, follow-up treatment, recovery, surgery, 
other)
If treatment is for a bleeding episode: site of bleeding, severity (severe, moderate, mild), and 
response to treatment (excellent, good, moderate, none).  
In case of major bleeds or surgery, also the investigator will assess the response to treatment 
(excellent, good, moderate, none).
Injections administered in the hospital must be planned in connection with the scheduled 
prophylactic injection of the study drug.
Amended to
7.3.2.2  Treatment logs / bleeding verification
Treatment logs are commonly used for hemophilia subjects for documentation of their home 
treatment. Home treatment and bleeding frequency are key variables evaluated in this study.  
Study specific logs will be provided in national language. The preferred system for this study 
will be electronic patient diary (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 also the data cleaning process.
Subjects/parents/caregivers will be provided with electronic patient diaries (EPDs) for the 
whole study. At Screening and Baseline visits, subjects and parents/caregivers will be trained 

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in the use of the device. These logs will be used to collect the treatment data and bleeding 
episodes by the parents/caregivers or subjects, and interact on a regularly scheduled basis with 
the investigator or delegate to verify and complete the data on the EPD. Thus, the EPD will be 
considered the source for these data.
For each use of study medication including the infusions administered during a planned visit 
for evaluation of recovery, information must be recorded on the Treatment Logs as follows:
1. Date and time
2. Lot numbers / number of vials administered
3. Reason for treatment (prophylaxis, spontaneous bleed first treatment, trauma bleed first 
treatment, follow-up treatment, surgery, other). (If an infusion is given in response to a 
fall or identified trauma, such as may occur when a child has an uncomplicated blow to 
the head and there is no clinical sign or evidence of bleeding, the event should be 
recorded as prophylaxis.)
If treatment is for a bleeding episode: site of bleeding, severity (severe, moderate, mild), and 
response to treatment (excellent, good, moderate, poor, too early to tell) are to be recorded.  If 
‘too early to tell’ is entered, the subject will be queried for a response the next time they use 
the device.   For guidance to the subject or their caregivers, the following definitions for 
response to treatment are suggested.  Individual subject responses may vary:

Excellent: Abrupt pain relief and /or improvement in signs of bleeding with no 
additional infusion administered

Good:  Definite pain relief and/or improvement in signs of bleeding, but possibly 
requiring more than one infusion for complete resolution

Moderate:  Probable or slight improvement in signs of bleeding, with at least one 
additional infusion for complete resolution 

Poor:  No improvement at all between infusions or condition worsens.
13.1.2.10 Change 10
Synopsis – Study objectives
Original protocol
Primary objective  

to demonstrate the safety and efficacy of  treatment with BAY 81-8973 for prophylaxis and 
breakthrough bleeds in children with severe hemophilia A 
Secondary objectives

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
To assess the tolerability profile of BAY 81-8973 during prophylaxis and treatment of breakthrough 
bleeds and safety and efficacy during surgeries, 

To assess incremental recovery 

To characterize pharmacokinetics in a subset of 6 to 13 the  age group of 6-12 years, if parents consent 
to it (participation for PK sampling is optional).
Amended to
Primary objective  

To demonstrate the safety and efficacy of treatment with BAY 81-8973 for prophylaxis and 
breakthrough bleeds in children with severe hemophilia A 
Secondary objectives

To assess the safety and efficacy of BAY 81-8973 during surgeries, 

To assess incremental recovery of BAY 81-8973.

To characterize pharmacokinetics in a subset of 6 to 13 previously treated patients ([PTPs) (Part A 
only]), if parents consent (participation for PK sampling is optional).
Section 2 Study objectives
Original protocol
Primary objective
The primary objective is to evaluate the safety and efficacy of the treatment with 
BAY 81-8973 for prophylaxis and treatment of breakthrough bleeds in children with 
hemophilia A
Secondary objectives
The secondary objectives are

To assess the tolerability profile of BAY 81-8973 during prophylaxis and 

treatment of breakthrough bleeds and safety and efficacy during surgeries, 

To assess incremental recovery 

To assess pharmacokinetic parameters in a subset of 6 to 13 children. in the age group 
of 6-12 years (if parents consent to it , participation for pharmacokinetic [PK] 
sampling is optional,).
Amended to
The primary objective is to evaluate the safety and efficacy of the treatment with 
BAY 81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe
hemophilia A
Secondary objectives
The secondary objectives are

To assess the safety and efficacy of BAY 81-8973 during surgeries.

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
To assess incremental recovery of BAY 81-8973.

To assess pharmacokinetic parameters in a subset of children. (Part A only -
participation in pharmacokinetic [PK] sampling is voluntary and requires consent,).
Section 4 Study Design
Original protocol
Primary variable
The primary variable is the response to treatment in relation to
1. number of bleeds within 48 hour (h) after a prophylaxis injection
2. assessment of response in treatment of bleeds
Amended to
Primary variable
Annualized number of total bleeds (sum of spontaneous bleeds and trauma bleeds) within 48 
hours (h) after a prophylactic infusion.
Section 7.3.1 Efficacy variables
Original protocol
The primary variable is the annualized number of all bleeds within 48 hours after a 
prophylaxis injection.
The clinical important variable is the number of breakthrough bleeds during prophylaxis,  
occurring during 48 h after the prophylaxis injection. The bleeding pattern in small children is 
expected to be different from adults. Joint bleeds are not the primary bleeding site in small 
children.  Additional efficacy parameters include:

Annualized number of bleeds during prophylaxis treatment

Physician’s / subject’s/parents’ assessment of response in treatment of bleeds during 
surgical interventions

Number of injections infusions for the treatment of a bleed

Consumption of FVIII
The main surrogate efficacy parameter is the recovery. The complete list of variables to be 
analyzed for this study will be provided in the statistical analysis plan.
Amended to
The primary variable is the annualized number of total bleeds (sum of spontaneous bleeds and 
traumatic bleeds) during prophylaxis that occur within 48 h of the last prophylaxis infusion. 
Both joint and non-joint bleeding will be assessed.  Additional efficacy parameters include:

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
Annualized number of total bleeds (sum of spontaneous and trauma bleeds) during 
prophylaxis treatment

Assessment of adequacy of hemostasis during surgical interventions

Number of infusions for the treatment of a bleed

Consumption of FVIII
The main surrogate efficacy parameter is the recovery of FVIII after infusion.
If an infusion is given to control a bleed at the same location within 48 hours of the previous 
dose for a bleed at that site, it is to be considered a follow-up infusion and not treatment of a 
new bleed. 
Section 8.3 Variables 
Original protocol
Extent of Exposure
Extent of exposure to the study drug, including injection characteristics, will be documented 
in subject diaries and summarized for each subject receiving any amount of drug.
Safety
Safety data will be summarized for all subjects in the safety population.  Laboratory findings, 
adverse events, concomitant medications, and medical history data will be provided in subject 
listings.
Laboratory values and vital signs will be summarized.  Individual listings of AEs [including 
age, weight, height, body mass index (BMI), gender, AEs as reported, start, duration, severity, 
relation to study drug] will be provided.  The incidence of treatment-emergent AEs will be 
summarized using the Medical Dictionary for Regulatory Affairs (MedDRA).
Inhibitor development, as measured by Nijmegen assay, will be summarized by time point 
and presented in subject listings.  The frequency of subjects who develop positive inhibitor 
titers (Bethesda > 0.6 BU) will be presented by time point.
The rate of inhibitor development associated with BAY 81-8973 will be determined.  Subjects 
with no inhibitors are required to have at least 50 ED to be counted in the denominator.  
Efficacy
Efficacy data will be summarized for all subjects in the ITT population.  The primary efficacy 
variable will be the annualized number of all bleeds within 48 hours after a prophylaxis 
injection.  Other variables summarized will be the physician’s/parents’ assessment of the 
response to treatment of bleeds (none, moderate, good, or excellent) and during surgeries.  
The number of treatments required to control bleeds, the number of prophylaxis injections
with less than expected therapeutic effect (LETE) (defined as a prophylaxis injection followed 

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by a bleed within 48 hours), annualized number of all bleeds during prophylaxis,  factor VIII 
usage and recovery will be summarized.
Amended to
Extent of Exposure
Extent of exposure to the study drug, including treatment characteristics, will be documented 
in subject diaries and summarized for each subject receiving any amount of drug.
Safety
Safety data will be summarized for all subjects in the safety population.  Laboratory findings, 
adverse events, concomitant medications, and medical history data will be provided in subject 
listings.
Laboratory values and vital signs will be summarized.  Individual listings of AEs [including 
AEs as reported, start, duration, severity, relation to study drug] will be provided.  The 
incidence of treatment-emergent AEs will be summarized using the Medical Dictionary for 
Regulatory Affairs (MedDRA).
Inhibitor development, as measured by Nijmegen assay, will be summarized by time point 
and presented in subject listings. The purpose of the listing is to delineate the clinical factors 
which may be positively associated with development of the inhibitor. The frequency of 
subjects who develop positive inhibitor titers (Bethesda > 0.6 BU) and confirmed by repeat 
measurement will be presented by time point.  If the inhibitor value drops below 0.6 BU on 
repeat measure without intervention, the inhibitor will be determined as being transient.   We 
will classify inhibitor patients as being either low titer or high titer based upon persistence of 
an inhibitor >5 BU.
The rate of inhibitor development associated with BAY 81-8973 will be determined.  Subjects 
with no inhibitors are required to have at least 50 ED to be counted in the denominator.  
Efficacy
Efficacy data will be summarized for all subjects in the intent-to-treat (ITT) population.  The 
primary efficacy variable will be the annualized number of total bleeds (sum of spontaneous 
bleeds and traumatic bleeds) within 48 hours after a prophylaxis infusion.  Other variables 
summarized will be the physician’s/subject’s/parents’ assessment of the response to treatment 
of bleeds (excellent, good, moderate, poor) and during surgeries.  The number of treatments 
required to control bleeds, the proportion of prophylaxis infusions with less than expected 
therapeutic effect (LETE) (defined as a prophylaxis infusion followed by a bleed within 48 
hours), annualized number of total bleeds (sum of spontaneous bleeds and trauma bleeds) 
during prophylaxis, factor VIII usage and recovery will be summarized. A detailed Statistical 
Analysis Plan with be provided.

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13.1.2.11 Change 11
Section 5.1.1 Inclusion criteria
Original protocol
In order to be included in the study, subjects must meet all of the following criteria upon 
evaluation at the Screening or Baseline visit:
1. Male, aged ≤ 12 years
2. Severe hemophilia A defined as < 1% factor VIII concentration (FVIII:C) based on 
medical records and/or screening laboratory
3.
> 50 ED with any high purity FVIII; 
4. No current evidence of inhibitor antibody measured using the Nijmegen-modified 
Bethesda assay [<0.6 Bethesda units (BU)/mL] within 2-3 week after of last 
administration.  Subjects may not receive FVIII within 48 h prior to the collection of 
samples for inhibitor testing.
5. No history of FVIII inhibitor formation. Documentation of negative result in medical 
records required, except for PUPs. [Subjects with a maximum historical titer of 1.0 BU on 
no more than 1 occasion with the classical Bethesda assay but at least 3 successive 
negative (<0.6 BU) results thereafter are eligible.] 
6. Willingness and ability of subjects and/or parents to complete training in the use of the 
study electronic patient diary (EPD) and to document injection information during the 
study.
7. Written informed consent by parent/legal representative. Assent should be sought from 
subjects if appropriate
Part B (PUPs) Inclusion of PUPs may start after 10 children  accumulated 50 ED Male, 
Severe hemophilia A defined as < 1% FVIII:C based on medical records and/or screening 
laboratory
no previous exposure to any FVIII  PUPs may be included if they will receive their first 
FVIII dose as regular prophylaxis or on-demand treatment for bleedings,  and are willing to 
continue with  prophylaxis. 
Amended to
In order to be included in the study, subjects must have all of the following criteria upon 
evaluation at the Screening or Baseline visit:
Part A
1. Male, age ≤ 12 years.  Enrollment will begin with subjects >6-12 years before it is opened 
to all age groups.
2. Severe hemophilia A defined as < 1% factor VIII concentration (FVIII:C) based on 
documented prior testing and/or screening laboratory
3.
> 50 ED with any FVIII concentrate; 

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4. No current evidence of inhibitor antibody measured using the Nijmegen-modified 
Bethesda assay [<0.6 Bethesda units (BU)/mL] within 2-3 weeks of last FVIII
administration.  PTPs may not receive FVIII within 48 h prior to the collection of samples 
for inhibitor testing at the Screening visit.  
5. No history of FVIII inhibitor formation. Documentation of negative result in medical 
records required. [Subjects with a maximum historical titer of 1.0 BU on no more than 1 
occasion with the classical Bethesda assay but at least 3 successive negative (<0.6 BU) 
results thereafter are eligible.] 
6. Willingness and ability of subjects and/or parents to complete training in the use of the 
electronic patient diary (EPD) and to document infusions during the study.
7. Written informed consent by parent/legal representative. Assent should be sought from 
subjects if appropriate
Part B (PUPs) (Enrollment of PUPs may start after safety is evaluated in 20 children in Part A 
with 50 ED)
1.  Male, 6 years and under
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing and
confirmed on screening laboratory
3.  No previous exposure to any FVIII product
4.  PUPs may be included if they will receive their first FVIII dose with BAY 81-8973 for
treatment of first bleeds and agree to start prophylaxis as part of their care. 
5.  Willingness and ability of parents to complete training in the use of the electronic patient 
diary (EPD) and to document all treatment during the study.
6.  Written informed consent by parent/legal representative.
13.1.2.12 Change 12
Section 5.1.2 Exclusion criteria
Original protocol
Subjects who meet any of the following criteria at Screening or Baseline visits will be 
excluded from participating in the study:
Part A and B
1. Any individuals with another bleeding disease that is different from Hemophilia A (eg, 
von Willebrand disease, Hemophilia B)
2. Any individual with thrombocytopenia (platelet count < 100 000/mm3) based on medical 
records or screening laboratory

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3. Any individual with abnormal renal function (serum creatinine > 2.0 mg/dL) based on 
medical records or screening laboratory
4. Any individual without any documented negative inhibitor test (except for PUPs)
5. Any individual who is receiving or has received other experimental drugs within 3 months 
prior to study entry or has participated in a FVIII study within the last month
6. Any individual who requires any pre-medication to tolerate FVIII injections
(eg, antihistamines)
7. Any individual who is unwilling to comply with study visits or other protocol 
requirements, for example (eg) prophylaxis treatment or is not suitable for participation in 
this study for any reason, according to the Investigator
8. Known hypersensitivity to active substance, mouse or hamster protein.
9. Previous participation in  this study
Part B only
10. For PUPs: first treatment with BAY 81-8973 
Amended to
Subjects who meet any of the following criteria at Screening or Baseline visits will be 
excluded from participating in the study:
Parts A and B
1. Any individual with another bleeding disorder that is different from Hemophilia A (eg, 
von Willebrand disease, Hemophilia B)
2. Any individual with thrombocytopenia (platelet count < 100 000/mm3) 
3. Creatinine > 2x upper limit of normal or AST/ALT > 5x upper limit of normal 
4. Any individual without a documented negative inhibitor test based on medical records or 
screening laboratory test (except for PUPs)
5. Any individual who is receiving chemotherapy, immune modulatory drugs (IVIG, 
cyclosporine, chronic use of oral or i.v. corticosteroids), has participated in another FVIII 
study within the last month, or received another experimental drug within the last
3 months.
6. Any individual who requires any pre-medication to tolerate FVIII treatment 
(eg, antihistamines).
7. Any individual who is unwilling to comply with study visits or other protocol 
requirements, for example (eg. prophylaxis treatment) or is not suitable for participation in 
this study for any reason, according to the Investigator’s judgement.
8. Known hypersensitivity to active substance, mouse or hamster protein.
9. Previous participation in  this study

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Part B only (PUPs):
10. First treatment with BAY 81-8973 for high risk bleeding situations (eg, surgery, 
intracranial bleed), or requiring intensive or prolonged treatment.
11. Unable to tolerate volume of blood draws required for study participation (See Section 
14.4).
13.1.2.13 Change 13
Section 6.9 Prior and concomitant therapy
Original Protocol
BAY 81-8973 will be used as the sole FVIII source. Pre-medications are not to be 
administered for injections of BAY 81-8973. 
All medications and blood products required by the subject during the study will be listed in 
the appropriate CRF.  No other experimental drugs may be taken during the subject's 
participation in this study. 
Medications which cause a bleeding diathesis (for example, Aspirin® or any acetylsalicylic 
acid) are contraindicated in any individual with hemophilia and must not be taken by study 
subjects. However, non-steroidal anti-inflammatory drugs to treat pain or acute synovitis are 
allowed.
No immunosuppressive/immunomodulatory drugs may be taken during the subject’s 
participation in the study.  If such therapy will be deemed necessary for the subject’s welfare 
due to pre-existing illness, the situation should be discussed with the Sponsor before 
enrollment.
All concurrent prescription and non-prescription medications including over-the-counter and 
alternative preparations (including herbal remedies, vitamins, and health food supplements) 
should be recorded at screening and throughout the treatment and follow-up periods.
Amended to
BAY 81-8973 will be used as the sole FVIII source.  Pre-medications to tolerate treatment 
with BAY 81-8973 are not allowed.  Use of topical anesthetics prior to venipuncture is 
permitted.  
All medications and blood products required by the subject during the study will be listed in 
the CRF.  No other experimental drugs may be taken during the subject's participation in this 
study. 
No immunosuppressive/immunomodulatory drugs may be taken during the subject’s 
participation in the study.  If such therapy is deemed necessary for the subject’s welfare, or 
due to pre-existing illness, the situation should be discussed with the Sponsor before 
enrollment.  Medications which cause a bleeding diathesis (for example, Aspirin® or 
acetylsalicylic acid) are contraindicated in any individual with hemophilia and should be 

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avoided, except as specifically prescribed by a treating physician. Use of non-steroidal anti-
inflammatory drugs, COX-2 inhibitors, or brief courses of corticosteroids to treat pain or 
acute synovitis, or inhaled or topical steroid medications (as for the treatment of asthma or 
eczema) are allowed.
All concurrent prescription and non-prescription medications including over-the-counter and 
alternative preparations (including herbal remedies, vitamins, and health food supplements) 
will be recorded in the CRF at screening and throughout the treatment and follow-up periods.
13.1.2.14 Change 14
Section 7.1.2.1 Visit 1 – Screening
Original protocol
At the screening visit, the following procedures and assessments will be performed:
…

Recording of prior and concomitant medication

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature

Physical examination including measurement of body height and weight
Amended to
At the screening visit, the following procedures and assessments will be performed:
…

Recording of prior and concomitant medication and Healthcare Resources Utilization 
Questionnaire. (Appendix 14.3).  Measurement of vital signs: Systolic and diastolic 
blood pressure, heart rate, and body temperature.  Blood pressure may be deferred if 
appropriate cuff size or equipment is not available.  

Physical examination including measurement of body height/length and weight
Section 7.1.2.2 Visit 2 - Baseline
Original protocol
Thereafter, the following activities will be performed:

Measurement of body height and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before injection
Amended to
Thereafter, the following activities will be performed:

Measurement of body height/length and weight

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
Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before infusion.  (Blood pressure may be deferred if appropriate cuff size 
or equipment is not available).  
Section 7.1.2.3 Visit 3 – Month 1 
Original protocol
7.1.2.3  Visit 3 – Month 1
The following procedures and assessments will be performed:

Measurement of body height and weight
Amended to
7.1.2.3  Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B
The following procedures and assessments will be performed:

  Measurement of body height/length and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.   (Blood pressure may be deferred if appropriate cuff size or equipment is 
not available).  
Section 7.1.2.1 Visit 4 – Month 2 
Original protocol
7.1.2.4  Visit 4 – Month 2
The following procedures and assessments will be performed:

Measurement of body height and weight
Amended to
7.1.2.4  Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B
The following procedures and assessments will be performed:

Measurement of body height/length and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.   (Blood pressure may be deferred if appropriate cuff size or equipment is 
not available).  
Section 7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (added)
7.1.2.5, Visit 5 – Part B only; ED ~15 (14 ED +/- 1)
The following procedures and assessments will be performed:

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
Measurement of body height/length and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.   (Blood pressure may be deferred if appropriate cuff size or equipment is 
not available).  
Section 7.1.2.6 Visit – Month 3, only for PUPs
Original protocol
7.1.2.6, Visit – Month 3, only for PUPs
The following procedures and assessments will be performed:

Measurement of body height and weight
Amended to
Visit 6 – Part B only; ED 20 (20 ED +/- 1) 
The following procedures and assessments will be performed:

Measurement of body height/length and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.   (Blood pressure may be deferred if appropriate cuff size or equipment is 
not available).  
Section 7.1.2.7 Interim visit – Only for Part B (30-40 ED) (added)
7.1.2.7  Interim visit – Only for Part B (30-40 ED)
The following procedures and assessments will be performed:

Measurement of body height/length and weight
…

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.   (Blood pressure may be deferred if appropriate cuff size or equipment is 
not available).  
Section 7.1.2.8 Visit – Month 6 or final visit (end of the main study and start of the 
optional extension study)
Original protocol
7.1.2.8  Visit - Month 6 or final visit (end of the main study and start of the optional 
extension study) 
The following procedures and assessments will be performed:

Physical examination including measurement of body height and weight

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
Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before and after injection
Amended to
7.1.2.8  Final Visit - (end of the main study and start of the optional extension study) 
The following procedures and assessments will be performed:

Physical examination including measurement of body height/length and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature.   (Blood pressure may be deferred if appropriate cuff size or equipment is 
not available).  
Section 7.1.2.9 Visit 7 – Month 12 and every 6 months
Original protocol
7.1.2.9  Visit 7 – Month 12 and every 6 months
The following procedures and assessments will be performed:

Measurement of body height and weight
Amended to
7.1.2.9  Extension study visits – 6 months after completion of Part A or B; then every 6 
months)
The following procedures and assessments will be performed:

Measurement of body height/length and weight
Section 7.1.2.10 Final visit
Original protocol
The following procedures and assessments will be performed:

easurement of body height and weight
Amended to
The following procedures and assessments will be performed:

Measurement of body height and weight
Section 7.5.3.1 Vital signs
Original protocol
Systolic and diastolic blood pressure, heart rate, and body temperature will be measured at 
Screening, Baseline, Month 1, 2, 3 (PUPs) and Month 6 (or at the final visit).
Amended to

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Systolic and diastolic blood pressure, heart rate, and body temperature will be measured at all 
visits.  Blood pressure may be deferred in infants if appropriate size cuff or equipment is not 
available.
Section 7.5.3.2 Physical examination
Original protocol
A complete physical examination including the measurement of body height, weight and 
temperature will be performed at Screening visit and at Month 6 (or final visit). 
At the visits at Months 2 and the additional visits of the optional extension study (Months 12 
and 18, every 6 months until switch to commercial drug), only the subject’s body height, 
temperature and weight will be measured.
Amended to
A complete physical examination including the measurement of body height, weight and 
temperature will be performed at Screening visit and at Month 6 (or final visit). Body length 
will be measured instead of height, as age appropriate.
At the other visits, and during the optional extension study (every 6 months until switch to 
commercial drug), only the subject’s body height, temperature and weight will be measured.
13.1.2.15 Change 15
Title page
Original protocol
Bayer Schering Pharma
Aprather Weg 18 a
42096 Wuppertal, Germany 
Amended to
Bayer HealthCare Pharmaceuticals, Inc.
P.O. Box 1000
Montville, New Jersey USA
Tel. 
PPD
PPD
PPD
PPD

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Signature of the sponsor’s medically responsible person
Original protocol
Name:
Role:  
Global Clinical Leader 
(GCL)/Medical Expert
Amended to
Name:
Role:  
Global Clinical Leader 
(GCL)/Medical Expert
Section 3 Investigators and other study participants
Original protocol
Sponsor’s Medical Expert
Name: 
Title:
Address:
Bayer Schering Pharma AG
Aprather Weg 18 a
42096 Wuppertal, Germany 
Amended to
Sponsor’s Medical Expert
Name: 
Title:    
Address:    
Bayer HealthCare Pharmaceuticals, Inc.
P.O. Box 1000
Montville, New Jersey USA
13.1.2.16 Change 16
Introduction
Original protocol
Background
…
Other significant changes to rFVIII manufacturing have been introduced.  Compared to its 
predecessors, BAY 81-8973 has more complete sialic acid capping of N-terminal glycan 
groups on the molecular surface, a post-translational modification step that is critical to the 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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activity and stability of some mammalian proteins.  Although pathogen contamination of a 
recombinant protein product is a theoretical possibility, the BAY 81-8973 purification process 
achieves a greater level of viral clearance than the current process through the addition of a 
new viral filtration step.  Overall, the complexity of the rFVIII manufacturing process has 
been substantially simplified for BAY 81-8973 compared to its predecessor products.  This 
allows for a faster production time that may also reduce the buildup of aggregation and 
breakdown products, which may be linked to suboptimal yields of rFVIII products.  In 
addition, any human or animal additives have been eliminated from the fermentation process. 
The result of the technological innovations implemented for BAY 81-8973 is the production 
of a full-length unmodified rFVIII product that more consistently reflects the conformation 
and glycan structure of the native human FVIII protein
Rationale of the study
The study is planned to demonstrate safety and efficacy of BAY 81-8973 for prophylaxis 
therapy and treatment of breakthrough bleeds in children with severe hemophilia A. 
The overall clinical program will consist of 3 safety and efficacy studies, one study  in 
subjects ≥ 12 years of age (adults and adolescents)  including two pharmacokinetic 
evaluations (baseline and month 6), one study in adults and adolescents ≥ 12 years of age 
comparing on-demand and prophylaxis treatment and the present study in children from 0-12 
years. The first study in adults and adolescents is ongoing. The comparative pharmacokinetic 
of BAY 81-8973 and Kogenate FS/Bayer has been completed and non-inferiority to the 
licensed product Kogenate FS/Bayer was demonstrated.
Benefit-risk assessment
…
Further details can be found in the investigator's brochure, which contains comprehensive 
information on the study drug.
Amended to
Background
…
Other significant changes to rFVIII manufacturing have been introduced.  BAY 81-8973 has 
the same amino acid composition as Kogenate® FS/Bayer. Compared to its predecessors, 
BAY 81-8973 has more complete sialic acid capping of N-terminal glycan groups on the 
molecular surface, a post-translational modification step that is critical to the activity and 
stability of some mammalian proteins.  Although pathogen contamination of a recombinant 
protein product is a theoretical possibility, the BAY 81-8973 purification process achieves a 
greater level of viral clearance than the current process through the addition of a new viral 
filtration step.  Overall, the complexity of the rFVIII manufacturing process has been 
substantially simplified for BAY 81-8973 compared to its predecessor products.  This allows 
for a faster production time that may also reduce the buildup of aggregation and breakdown 
products, which may be linked to suboptimal yields of rFVIII products.  In addition, any 
human or animal additives have been eliminated from the fermentation process. The result of 

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the technological innovations implemented for BAY 81-8973 is the production of a full-
length unmodified rFVIII product that more consistently reflects the conformation and glycan 
structure of the native human FVIII protein
Based on PK data from 26 subjects who received a single 50 IU/Kg dose of BAY 81-8973 
and Kogenate FS in a cross over fashion, it has been demonstrated that BAY 81-8973 is non-
inferior to Kogenate® FS/Bayer
Rationale of the study
The study is planned to demonstrate safety and efficacy of BAY 81-8973 for prophylaxis 
therapy and treatment of breakthrough bleeds in children with severe hemophilia A. 
The overall clinical program consists of 3 safety and efficacy studies, one study  in subjects ≥ 
12 years of age (adults and adolescents)  including two pharmacokinetic evaluations (baseline 
and month 6), one study in adults and adolescents ≥ 12 years of age comparing on-demand 
and prophylaxis treatment, and the present study in children from 0-12 years.  The first study 
in adults and adolescents is ongoing and has completed enrollment. The comparative 
pharmacokinetic of BAY 81-8973 and Kogenate FS/Bayer has been completed and non-
inferiority to the licensed product Kogenate FS/Bayer was demonstrated.  The demonstration 
of safety in at least 20 adolescents and adults who received a minimum of 50 ED was a 
necessary requirement to open this study to enrollment of children 12 years of age and 
younger.
13.1.2.17 Change 17
Abbreviations
Original Protocol
EPD
Electronic Subject Diary
X-linked
A gene on the X chromosome that expresses itself only when there is no 
different gene present at that locus (spot on the chromosome). 
IVRS
Interactive voice randomization system
SAS
Statistical Analysis System
SUSAR
Suspected unexpected adverse reaction
Amended to
Amd 1
Amendment 1
DMC
Data Monitoring Committee
EPD
Electronic Patient Diary
X-linked
A gene on the X chromosome 
RAVE
Data base for electronic case report form
SUSAR
Serious unexpected suspected adverse reaction
Section 5.2.2 Replacement
Original protocol

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Subjects who are withdrawn after start of treatment will not be replaced. Subjects who are 
withdrawn due to a positive inhibitor result at screening/baseline will be replaced.
Amended to
Subjects who are withdrawn after start of treatment will not be replaced. Subjects who are 
withdrawn due to failure to met screening criteria, or who have a positive inhibitor result at 
screening/baseline will be replaced.
Section 6.2.1 Manufacture
Original Protocol
The rFVIII molecule itself is comparable to the current Kogenate® FS/Bayer molecule, with 
some overall differences, such as reduced high molecular weight proteins.  The molecule is 
highly glycosylated, with increased levels of highly branched glycans and more consistently 
high sialylation of terminal galactose residues. For further details see Section 1 and
Investigator Brochure.
Amended to
The rFVIII molecule itself is comparable to the current Kogenate® FS/Bayer molecule, with 
some overall differences, such as reduced high molecular weight proteins.  The molecule is 
highly glycosylated, with increased levels of highly branched glycans and more consistently 
high sialylation of terminal galactose residues. For further details see Investigator Brochure.
Section 6.2.2 Supply and Packaging
Original Protocol
BAY 81-8973 will be supplied lyophilized in BIO-SET® glass vials.  Study vials may contain 
250 IU, 500 IU or 1000 IU of FVIII activity.  The nominal potency of the drug, as determined 
by chromogenic assay will be indicated on the labels of each vial unit pack.  The medication 
is manufactured at Bayer HealthCare in Berkeley, California, United States. The vials of 
BAY 81-8973 will be packaged together with a pre-filled syringe of the appropriate amount 
of sterile water for injection, European and US Pharmacopeia (EP) (USP), for reconstitution.  
For BAY 81-8973, the volume of the solvent is 2.5 mL for all vial sizes. The BAY 81-8973 
vials will also be supplied with the following medical devices to facilitate the injection: 
TERUMO Europe NV, SV-S25FL35 infusion set with filter and needle protection, plunger 
rod, and 10 mL sterile syringe.  
Amended to
BAY 81-8973 will be supplied lyophilized in BIO-SET® glass vials.  Study vials may contain 
250 IU, 500 IU or 1000 IU of FVIII activity.  The nominal potency of the drug, as determined 
by chromogenic assay, will be indicated on the labels of each vial unit pack.  The medication 
is manufactured at Bayer HealthCare in Berkeley, California, United States. The vials of 
BAY 81-8973 will be packaged together with a pre-filled syringe of the appropriate amount 
of sterile water for injection, European and US Pharmacopeia (EP) (USP), for reconstitution.  

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For BAY 81-8973, the volume of the solvent is 2.5 mL for all vial sizes. The BAY 81-8973 
vials will also be supplied with the following medical devices to facilitate the treatment: 
TERUMO Europe NV, SV-S25FL35 infusion set with filter and needle protection, plunger 
rod, and 10 mL sterile syringe.  
Section 6.2.5 Instructions for Administration
Original Protocol
The rate of administration can be adapted to the response of the individual subject.  
Experience with Kogenate® FS/Bayer indicates that a dose may be administered over a period 
of 1 to 15 minutes. For PK and recovery studies, the entire dose should be administered over a 
2-5-minute period depending on the total volume.  
Parents/caregivers will receive training and detailed information regarding the administration 
of their study medication. 
Amended to
The rate of administration can be adapted to the response of the individual subject.  
Experience with Kogenate® FS/Bayer indicates that a dose may be administered over a period 
of 1 to 15 minutes. For PK and recovery studies, the entire dose should be administered over a 
5-minute period depending on the total volume.  
Parents/caregivers will receive training and detailed information regarding the administration 
of the study medication. 
Section 6.6 Drug logistics and accountability
Original Protocol
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 study file; the site-relevant 
elements of this information will be available in the investigator site file.  The responsible site 
personnel will confirm receipt of study drug in writing or via interactive voice randomization 
system (IVRS) and 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.
Amended to
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 study file; the site-relevant 

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elements of this information will be available in the investigator site file.  The responsible site 
personnel will confirm receipt of study drug in writing and 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.
Section 6.8, Post-study therapy
Original Protocol
At the end of the study, all study participants who completed the study will be offered the
participation in an extension study with continuation of treatment for at least further 50 ED or 
until marketing authorization. Documentation of injections is mandatory during the extension 
study.
After completion of the extension study, or if the subjects or their parents/caregivers are not 
willing to participate in the extension study, the further treatment will be mutually agreed 
upon by the parents/caregivers and the investigator.
Amended to
At the end of the study, all participants who have completed Part A or B will be offered 
participation in an extension study.   Participation in the extension study will allow
continuation of treatment for at least 50 ED or until marketing authorization.  The extension 
study requires continued documentation of infusions, bleeding events, monthly interaction 
with the treatment center, and visits every 6 months for inhibitor screening.
After completion of the extension study, or if the subjects or their parents/caregivers are not 
willing to participate in the extension study, treatment with study drug will end.  Subsequent
treatment will be mutually agreed upon by the parents/caregivers and the investigator.
Section 7.5.1.1 Definitions
Original protocol
Note:  Any bleeding event occurring during the study will not be documented as AE, because 
this is captured in the assessment of efficacy. However, if the bleed requires hospitalization, it 
must be reported as a Serious Adverse Event (SAE) (see Section 7.5.1.4).
Amended to
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, it must be reported as a Serious Adverse Event (SAE) (see Section 7.5.1.4).

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Section 8.1 General considerations
Original protocol
Statistical analyses will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the statistical analysis plan.
Amended to
Statistical analyses will be performed using SAS release 9.1 or higher (SAS Institute Inc., 
Cary, North Carolina [NC], United States of America [USA]).  The version used will be 
specified in the Statistical Analysis Plan.
Section 8.2 Analysis sets
Original protocol
Efficacy and safety data will be collected from all subjects who received study medication.  
All subjects given any study drug will be included in the safety and intent-to-treat (ITT) 
populations.
Amended to
Efficacy and safety data will be collected from all subjects who received study medication.  
The intent-to-treat (ITT) population will include all subjects randomized into the study who 
received study drug.  The per-protocol population will exclude subjects who are deemed 
invalid in the Validity Review Report.  Subjects from Part A and Part B will be summarized 
separately.
Section 8.6 Determination of sample size
Original protocol
According to the guideline CPMP/BPWG/1561/99 (Note for Guidance on the Clinical 
Investigation of Recombinant Factor VIII and Factor IX Products), at least 20 children under 
the age of 6 years (infants and toddlers) regardless of prior treatment should be included in the 
investigation. The next age group according to the age classification of International 
Conference on Harmonization (ICH)/CPMP guideline E11 (Clinical Investigation of 
Medicinal Products in the Pediatric Population)19 refers to children up to the age of 11 years.
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.
Therefore, this study will include 20-25 subjects < 6 years (PTPs) and 15-25 subjects aged 
between 6 and 12 years. Thus, the total sample size will be 35-50 subjects, of whom a 
minimum of 35 subjects must be PTPs. The number of PUPs is not specified.
Amended to
Sample size has been determined according to the requirements set forth by guideline 
CPMP/BPWG/1561/99 (Note for Guidance on the Clinical Investigation of Recombinant 
Factor VIII and Factor IX Products), and taking into account the revised draft version, 

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CHMP/BPWP/144533/09. Age groups are in accordance with the International Conference on 
Harmonization (ICH)/CPMP guideline E11 (Clinical Investigation of Medicinal Products in 
the Pediatric Population)19 and sample sizes have been confirmed on consultation with the 
EMA/PDCO on submission of the Pediatric Investigation Plan. 
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.  This study consists of two parts.  Part A will include 
a total of 50 PTPs; 25 subjects >6 – 12 years and 25 subjects aged 6 years and less. Part B will 
enroll 25 PUPs of all ages.  Total sample size will be 75 subjects.
Section 9.1 Data recording
Original protocol
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site. The site must implement processes to ensure this 
happens.  A source document checklist will be used at the site to identify the source data for 
all data points collected and the monitor will work with the site to complete this.
The patient reported data may be entered directly into the EPD, for all other data source 
documentation must be available.  
Monitoring
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.
Amended to
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.  A source document is defined as the first place data are 
recorded; the CRF is not a source document. The site must ensure the existence of source 
documents A source document checklist will be used at the site to identify the source data for 
all data points collected and the monitor will work with the site to complete this.
The patient reported data may be entered directly into the EPD, for all other data source 
documentation must be available.  
Monitoring
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.

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Section 10 Premature termination of study
Original protocol
For any of the above closures, the following applies:
Closures should occur only after consultation between involved parties.
All affected institutions (eg, 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 given by the sponsor for destruction.
In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Amended to
For any of the above closures, the following applies:
Closure should occur only after consultation between involved parties.
All affected institutions (eg, 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 given by the sponsor for destruction.
In case of a partial study closure, ongoing subjects, including those in post-study 
follow-up, must be treated of in an ethical manner.
Section 11.2 Subject information and consent
Original protocol
For minors or adults under legal protection, consent shall be given by the legal guardian(s).  
The consent of a minor or adult under legal protection shall also be requested where such a 
person is able to express his/her own will.  His/her refusal or the withdrawal of his/her 
consent may not be disregarded.
Amended to
For minors or adults under legal protection, consent shall be given by the parents/legal 
representative.  The assent of a minor or adult under legal protection shall also be requested 
where such a person is able to express his/her own will.  His/her refusal or the withdrawal of 
his/her consent may not be disregarded.

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Section 12 References
Original protocol 
18.
Kurnik K (Munich, Germany), Bidlingmaier C, Engl W, Chehadeh H, Reipert B, 
Auerswald G. New early prophylaxis regimen that avoids immunological danger 
signals can reduce FVIII inhibitor development. Haemophilia. 2009:[Epub ahead of 
print].
Amended to 
18.
Kurnik K (Munich, Germany), Bidlingmaier C, Engl W, Chehadeh H, Reipert B, 
Auerswald G. New early prophylaxis regimen that avoids immunological danger 
signals can reduce FVIII inhibitor development. Haemophilia. 2010 Mar;16(2):256-
62.
Section 14.1 Instruction for use of Study medication
Original protocol 
14. Inject the solution intravenously over several minutes, keeping an eye on the position 
of the needle. The speed of administration should be based on the subject’s comfort, 
but should not be faster than 2ml\min (maximum rate of injection).
Amended to 
14. Inject the solution intravenously over several minutes, keeping an eye on the position 
of the needle. The speed of administration should be based on the subject’s comfort, 
but should not be faster than 2ml\min (maximum rate of infusion).

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13.2
Amendment 3
Description of Amendment
The PK sampling is no longer limited to patients in Part A and the limitation to 13 
participants has been deleted.  All sites and all patients may now participate in the PK sub-
study, and PK sampling, if not done earlier, may be done at any visit during the extension 
phase.
The number of subjects that may be enrolled in Part B (PUPs) has been increased to at least 
25, up to a maximum of approximately 50, making the total sample size at least 75, up to a 
maximum of approximately 100, to allow more subjects to participate in the study.
Clinically relevant inhibitor development is defined as the occurrence of at least 2 positive 
inhibitor titers combined with a decreased recovery.
Amendment 3 also implements revisions and clarifications in response to specific questions 
and comments received from pediatric specialists and investigators.  These include an 
improved explanation of the staggered enrollment by subject age, and clarification of which 
evaluations are required at which visit.  The schedule of evaluations has been revised to 
reflect changes already made to some text sections in Amendment 1, and the changes in 
Amendment 3.  Inclusion and exclusion criteria were clarified to be more consistent (with 
pediatric practice).  Any gene mutation (if known) has been added to the demographic 
characteristics to be recorded at Screening.
The possibility of an interim analysis of Part B data has been included, if this should be 
required for regulatory purposes. 
Finally, changes in the study administrative structure, editorial changes, correction of 
typographical errors, and minor revisions of language were made to ensure clarity and 
consistency throughout the document.
13.2.1
Overview of changes
Change 1: In order to allow more patients to participate in the optional PK study, it has been 
opened to patients in Part B as well as those in Part A.  The scheduled blood sampling may be 
done not only at any study visit, but also at any visit during the extension phase. In addition, 
patients at all centers may now participate in the PK analysis, and there is no restriction on the 
number of patients who participate in the PK study.
Sections affected include:

Synopsis, Study objectives

Section 2, Study objectives

Section 4, Study design

Section 6.1.2, Breakthrough bleeds and surgeries

Section 6.1.4, Optional pharmacokinetic measurements

Section 6.4, Dosage and administration

Section 7.1.1, Tabulated overview

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
Section 7.1.2.2 – Section 7.1.2.6, Visits

Section 7.1.2.8, Visit

Section 7.1.2.9, Visit

Section 7.4, Pharmacokinetics

Section 8.3, Variables
Change 2: Adaption/clarification of inclusion criteria concerning age of the subjects in Part A 
(<6 years and 6-12 years) and Part B (<6 years), number of exposure days with any FVIII 
concentrate (≥50), definition of severe hemophilia (based on prior documented testing or
confirmed on screening laboratory), and the availability of a negative inhibitor result at 
screening.
Sections affected include:

Synopsis

Section 4, Study design

Section 5.1.1, Inclusion criteria

Section 5.1.2, Exclusion criteria

Section 8.6, Determination of sample size
Change 3: Adaptation/clarification of exclusion criterion 5 concerning prior therapy. An 
exception is made for patients who received Kogenate FS/Bayer (Bayer factor VIII study 
drugs) in clinical studies within 1 month prior to study entry.
Sections affected include:

Section 5.1.2, Exclusion criteria

Section 6.1.1, Regular prophylaxis

Section 6.9, Prior and concomitant therapy
Change 4: Any gene mutation (if known) has been added to the demographic characteristics 
to be recorded at Screening.
Sections affected include:

Section 7.2.1, Demographics
Change 5: Clinically relevant inhibitor development is defined as the occurrence of at least 2 
positive inhibitor titers combined with a decreased recovery. 
Sections affected include:

Section 6.1.5, Immune tolerance induction
Change 6: If an infusion is given to control a bleed at the same location within 72 hours of the 
previous infusion for a bleed at that site, it is to be considered a follow-up infusion and not 
treatment of a new bleed, unless both bleeds are skin/mucosa bleeds.
Sections affected include:

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
Section 7.3.1, Efficacy variables
Change 7: The option of recruiting more than 25 PUPs has been included.
Sections affected include:

Synopsis, Number of subjects

Section 4, Study design

Section 8.6, Determination of sample size
Change 8: If required for regulatory purposes, Part B data will be described in an interim 
analysis if at least 5 PUPs have been recruited.
Sections affected include:

Section 8.5, Planned interim analyses
Change 9: Changes in the study administrative structure have been made, specifically, the 
Sponsor’s Study Medical Expert has been replaced.
Sections affected include:

Title page

Signature of the sponsor’s medically responsible person

Section 3, Investigators and other study participants
Change 10: Minor editorial clarifications to ensure consistency, add clarity, and to reflect 
current practice (highlighted) and the correction of typographical/grammatical errors 
throughout the protocol (not highlighted).
Sections affected include:

Section 4, Study design

Section 6.2.2, Supply and packaging

Section 7.1.2.1, Visit 1

Section 7.1.2.3, Visit 3

Section 7.1.2.9, Extension study visits

Section 7.1.2.10, Final visit
13.2.2
Changes to the protocol text:
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol.  In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment.  Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”.  Corrections of typing errors or omissions are not 
highlighted in this amendment.

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13.2.2.1
Change 1
Synopsis, Study objectives
Old text:
To characterize pharmacokinetics in a subset of 6 to 13 previously treated patients (PTPs) 
(Part A only), if parents consent (participation for PK sampling is optional).
New text:
To characterize pharmacokinetics (PK) in a subset of a minimum of 6 previously treated 
patients (PTPs) or previously untreated patients (PUPs) if parents consent (participation for 
PK sampling is optional). 
Section 2, Study objectives
Old text

To assess pharmacokinetic parameters in a subset of children. (Part A only -
participation in pharmacokinetic [PK] sampling is voluntary and requires 
consent). (as of Amd 1)
New text

To assess pharmacokinetic parameters in a subset of children. (PTPs and PUPs -
participation in pharmacokinetic [PK] sampling is voluntary and requires 
consent). (as of Amd 1, Amd 3)
Section 4, Study design
Old text
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in another study.  PTPs ages 7 to 
12 years will begin enrollment first, followed by PTPs 6 years and younger.  Part B, for 
PUPs, will begin enrollment after 20 children in Part A have had 50 ED. 
…
Incremental recovery and trough levels of BAY 94-9027 will be assessed in all subjects. 
Subjects enrolled in Part A will be offered participation in the pharmacokinetic (PK) 
evaluation.  Participation is optional, and requires consent.  PK parameters (maximum 
concentration [Cmax], half-life, area under curve [AUC], Mean Residence Time [MRT] and 
clearance) may be assessed using a sparse sampling schedule.
New text
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in previous studies with BAY 81-
8973.  PTPs age 6 to 12 years will begin enrollment first, followed by PTPs <6 years.  Part B, 
for PUPs, will begin enrollment after 20 children in Part A have had 50 ED. 
…

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Incremental recovery and trough levels of BAY 81-8973 will be assessed in all subjects. 
Suitable subjects will be given the opportunity to participate in the pharmacokinetic (PK) 
evaluation.  Participation is optional, and requires consent.  PK parameters (maximum 
concentration [Cmax], half-life, area under curve [AUC], Mean Residence Time [MRT] and 
clearance) may be assessed using a sparse sampling schedule.
Section 6.1.2, Breakthrough bleeds and surgeries
Old text:
If the study site routinely measures pharmacokinetic (PK) prior to surgical procedures, these 
results may be used to fulfill the optional PK in Part A, provided that consent is given in 
advance, the subject undergoes a 48 hour washout, sampling is obtained at the designated 
time points, and samples are sent to the central laboratory for evaluation.
New text:
If the study site routinely takes pharmacokinetic (PK) measurements prior to surgical 
procedures, these results may be used to fulfill the optional PK, provided that consent is given 
in advance, the subject undergoes a 48 hour washout, sampling is obtained at the designated 
time points, and samples are sent to the central laboratory for evaluation.
Section 6.1.4, Optional pharmacokinetic measurements (Part A only)
Additional text:
Suitable subjects will be given the opportunity to participate in the PK sub-study, either 
during the main study, or during the extension period.
Section 6.4, Dosage and administration
Old text:
For the optional PK study (Part A only), each subject will receive an exact dose of 50 IU/kg 
of BAY 81-8973.
New text:
For the optional PK study, each subject will receive an exact dose of 50 IU/kg of 
BAY 81-8973.
Section 7.1.1, Tabulated overview

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Old text:
Table 7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week) (as 
of Amd 1)
Visit 4 
Month 2
(+/- 1 week) 
(as of 
Amd 1)
Final visit 
Month 6
(Minimum 50 
ED (as of 
Amd 1))
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
X
X
FVIII baseline level and inhibitor 
X
FVIII level pre infusion and inhibitor (as of Amd 1)
X
X
X
X
X
X
Recovery (20-30 min after infusion) c (as of Amd 1)
X
X
X
X
Pharmacokinetics in up to 13 children (optional)
    X b  
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire 
(as of Amd 1)
X (as of 
Amd 1)
    monthly  
Interaction between subject/parent and 
investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.CBC, Chemistries
b Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to be entered 
into CRF
c Measured at least 48 h after last dose of FVIII (as of Amd 1)
d Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension 

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional 
extension study
Visit 1 
Screening
Visit 2
Baselin
e
Combine
d 
Screenin
g and 
Baseline
Visit 3 
Month 
1
or
ED ~5
Visit 4
Month 
2
or
ED ~10
Visit 5 
Month 
3
or
ED ~15
Visit 6,
Month 
4
or
ED ~20
Interim d
Visit
30-40 ED 
(as of 
Amd 1)
Final 
visit
or
ED 50
Extension 
Visit every 
6 months
Exten
sion
Final 
visit
Informed consent
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
X b
X b
FVIII baseline level and inhibitor
X
X
FVIII level before infusion and inhibitor c(as of Amd 1)
X
X
X
X
X
X
X
Recovery (20-30 min after infusion) (as of Amd 1)
X
X
X
X
Infusion of study drug (as of Amd 1)
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
X
      continuously       
Healthcare Resources Utilization Questionnaire (as 
of Amd 1)
X (as of 
Amd 1)
   monthly 
Interaction between subject/parent and investigator
  weekly                             
  monthly  

Concomitant medication
X
       continuously     
a. CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b.  In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c.  Measured at least 48 h after last dose of FVIII
d. Interim visit only if less than 40 ED have been achieved by Month 6.

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New text:
Table 7-1a: Schedule of evaluations (Part A – PTPs; >50 ED) 
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week) (as 
of Amd 1)
Visit 4 
Month 2
(+/- 1 week) 
(as of 
Amd 1)
Final visit 
Month 6
(Minimum 50 
ED [as of 
Amd 1])
Extension 
Visit every 6 
months
Extension
Final visit
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events (as of Amd 3)
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies (as of Amd 3)
X
X
FVIII baseline level and inhibitor(one stage) (Amd 3) 
X
FVIII level pre infusion and inhibitor (as of Amd 1)
X
X
X
X
X
X
Recovery (20-30 min after infusion) c (as of Amd 1)
X
X
X
X
Pharmacokinetics (optional) (as of Amd 3)
-----------------------    X b ---------------------------------------------
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
      continuously       
Healthcare Resources Utilization Questionnaire (as 
of Amd 1)
X (as of 
Amd 1)
    monthly  
Interaction between subject/parent and investigatord
  weekly             
  monthly 
Concomitant medication 
X
       continuously     
a.
Complete Blood Count (CBC), Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to be entered into CRF
c. 
Measured at least 48 h after last dose of FVIII (as of Amd 1)
d
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension;   min: minute

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 
1
or
ED ~5
Visit 4
Month 
2
or
ED ~10
Visit 5 
Month 
3
or
ED ~15
Visit 6,
Month 
4
or
ED ~20
Interim d
Visit
30-40 ED 
(as of 
Amd 1)
Final 
visit
or
ED 
50
Extension 
Visit 
every 6 
months
Extension
Final visit
Informed consent)
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies (as of Amd 3)
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) (as of 
Amd 3)
X
X
FVIII level before infusion and inhibitor c(as of Amd 1)
X
X
X
X
X
X
X
Recovery (20-30 min after infusion) (as of Amd 1)
X
X
X
X
Pharmacokinetics (optional)
-----------------------    X e ------------------------------------------------
Infusion of study drug (as of Amd 1)
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
          continuously         
Healthcare Resources Utilization Questionnaire(as of 
Amd 1)
X (as of 
Amd 1)
         monthly        
Interaction between subject/parent and investigator
          weekly                                     monthly    
Concomitant medication
X
          continuously          
a.
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b.
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c.
Measured at least 48 h after last dose of FVIII
d.
Interim visit only if less than 40 ED have been achieved by Month 6.
e.
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF

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Section 7.1.2.2 – Section 7.1.2.6, Visits, and Section 7.1.2.8, Visits
Additional text:
Optional PK: Additional blood samples at 4 h and 24 h post infusion, for Part B patients also 
at 20-30 min after end of infusion (can also be performed at a later visit; to be obtained only 
once during study).
Note to investigators: In compliance with EMA guidance and for patient safety, no more than 
1% blood volume may be obtained at any one visit, and no more than 3% may be taken in one 
month (see Section 14.4).  If additional PK samples are taken, the total volume of blood 
drawn in 24 h will be too high for infants weighing less than 9 kg who must therefore be 
excluded from the PK sub-study. 
Section 7.1.2.9, Visits
Additional text:
Optional PK: Additional blood samples at 20-30 min, 4 h and 24 h post infusion (can also be 
performed at a later visit; to be obtained only once during study).
Note to investigators: In compliance with EMA guidance and for patient safety, no more than 
1% blood volume may be obtained at any one visit, and no more than 3% may be taken in one 
month (see Section 14.4).  If additional PK samples are taken, the total volume of blood 
drawn in 24 h will be too high for infants weighing less than 9 kg, who must therefore be 
excluded from the PK sub-study.
Section 7.4, Pharmacokinetics
Old text
Details of the blood sampling and processing procedures for all laboratory measurements will 
be provided in the Study Procedure Manual (SPM) that accompanies this protocol.  
New text
Details of the blood sampling and processing procedures for all laboratory measurements will 
be provided in the Laboratory Manual, developed by the central laboratory, which 
accompanies this protocol.
…
Note to investigators: In compliance with EMA guidance and for patient safety, no more than 
1% blood volume may be obtained at any one visit, and no more than 3% may be taken in one 
month (see Section 14.4).  If additional PK samples are taken, the total volume of blood 
drawn in 24 h will be too high for infants weighing less than 9 kg, who must therefore be 
excluded from the PK sub-study.
Section 8.3, Variables
The following text is deleted:

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PK sampling will be performed in centers which have experience in PK studies and volunteer 
to participate.
13.2.2.2
Change 2
Synopsis, Methodology, Number of subjects
Old text:
Enrollment in the study will be staggered, with subjects age >6-12 years entering first, 
followed by subjects 0-6 years.
New text:
Enrollment in the study will be staggered, with subjects age 6-12 years entering first, followed 
by subjects <6 years.
Synopsis, Number of subjects
Old text:
age group >6-12 years: N=25
age group 0-6 years: N=25
Part B: N=25
Total = 75 (includes both Part A and B)
New text:
age group 6-12 years: N=25
age group <6 years: N=25
Part B: N= at least 25, up to a maximum of approximately 50 PUPs
Age group <6 years
Total = at least 75, up to a maximum of approximately 100 (includes both Part A and B) 
Section 4, Study design
Old text:
Part A will start after 20 adult/adolescent subjects have received 50 ED with BAY 81-8973 
without safety concerns in another study.  PTPs ages 7 to 12 years will begin enrollment first, 
followed by PTPs 6 years and younger.
New text:
Part A will start after 20 adult/adolescent subjects have received 50 ED with BAY 81-8973 
without safety concerns in previous studies with BAY 81-8973.  PTPs age 6 to 12 years will 
begin enrollment first, followed by PTPs <6 years.
Section 5.1.1, Inclusion criteria
Old text:

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Part A
1.
Male, age ≤ 12 years.  Enrollment will begin with subjects >6-12 years before it is 
opened to all age groups.
2.
Severe hemophilia A defined as < 1% factor VIII concentration (FVIII:C) based on 
documented prior testing and/or screening laboratory
3.
> 50 ED with any FVIII concentrate;
New text:
Part A
1.
Male, age ≤ 12 years.  Enrollment will begin with subjects 6-12 years before it is 
opened to all age groups.
2.
Severe hemophilia A defined as < 1% factor VIII concentration (FVIII:C) based on
documented prior testing or screening laboratory
3.
≥ 50 ED with any FVIII concentrate;
Old text:
Part B
Part B (PUPs) (Enrollment of PUPs may start after safety is evaluated in 20 children in Part A 
with 50 ED)
1.  Male, 6 years and under
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing and
confirmed on screening laboratory.
New text:
Part B (PUPs) (Enrollment of PUPs may start after safety is evaluated in 20 children in Part A 
with 50 ED)
1.  Male, <6 years
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or
confirmed on screening laboratory.
Section 5.1.2, Exclusion criteria
Old text:
4. Any individual without a documented negative inhibitor test based on medical records
or screening laboratory test (except for PUPs)
New text:
4. Any individual without a negative inhibitor test at screening (except for PUPs)

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Section 8.6, Determination of sample size
Old text:
This study consists of two parts.  Part A will include a total of 50 PTPs; 25 subjects > 6 – 12 
years and 25 subjects aged 6 years and less. Part B will enroll 25 PUPs of all ages. The total 
sample size will be 75 subjects.
New text:
This study consists of two parts.  Part A will include a total of 50 PTPs; 25 subjects age 6 – 12 
years and 25 subjects age <6 years. Part B will enroll at least 25, up to a maximum of 
approximately 50 PUPs age <6 years. The total sample size will be at least 75, up to a 
maximum of approximately 100 subjects.
13.2.2.3
Change 3
Section 5.1.2
Old text:
5.
Any individual who is receiving chemotherapy, immune modulatory drugs (IVIG, 
cyclosporine, chronic use of oral or i.v. corticosteroids), has participated in another FVIII 
study within the last month, or received another experimental drug within the last 3 months.
New text:
5.
Any individual who is receiving chemotherapy, immune modulatory drugs (IVIG, 
cyclosporine, chronic use of oral or i.v. corticosteroids), has received another investigational 
FVIII product within the last month, or received another experimental drug within the last 
3 months.
Section 6.1.1
Additional text:
Note: PTPs will continue their previous treatment up to 48 h before the first dose of BAY 81-
8973.
Section 6.9
Old text:
BAY 81 8973 will be used as the sole FVIII source.  Pre-medications to tolerate treatment 
with BAY 81 8973 are not allowed.  Use of topical anesthetics prior to venipuncture is 
permitted.  
New text:
BAY 81 8973 will be used as the sole FVIII source.  Pre-medications to tolerate treatment 
with BAY 81 8973 are not allowed.  Use of topical anesthetics prior to venipuncture is 

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permitted.  Note: PTPs will continue their previous treatment up to 48 hours before the first 
dose of BAY 81-8973.
13.2.2.4
Change 4
Section 7.2.1, Demographics
Old text:
Demographic characteristics to be recorded at Screening will include age and race. In 
addition, a complete physical examination including pulse, blood pressure, body temperature, 
height, weight, and a review of body systems will be performed and the results documented.
New text:
Demographic characteristics to be recorded at Screening will include age and race. In 
addition, a complete physical examination including pulse, blood pressure, body temperature, 
height, weight, and a review of body systems will be performed and the results documented. 
If known, any gene mutation should be noted.
13.2.2.5
Change 5
Section 6.1.5, Immune tolerance induction
Old text:
If a subject develops an inhibitor, ITI should be considered.  All treatments, FVIII 
measurements, and inhibitor levels will be documented.
New text:
If a subject develops an inhibitor, ITI should be considered.  Clinically relevant inhibitor 
development is defined as the occurrence of at least 2 positive inhibitor titers combined with a
decreased recovery.  All treatments, FVIII measurements, and inhibitor levels will be 
documented.
13.2.2.6
Change 6
Section 7.3.1, Efficacy variables
Old text:
If an infusion is given to control a bleed at the same location within 48 hours of the previous 
dose for a bleed at that site, it is to be considered a follow-up infusion and not treatment of a 
new bleed.
New text:
If an infusion is given to control a bleed at the same location within 72 hours of the previous 
dose for a bleed at that site, it is to be considered a follow-up infusion and not treatment of a 
new bleed, unless both bleeds are skin/mucosa bleeds.

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13.2.2.7
Change 7
Synopsis, Number of subjects
Old text
Part B
N= 25 PUPs
age group <6 years
Total = 75 (includes both Part A and B)
New text
Part B
N= at least 25, up to a maximum of approximately 50 PUPs
age group <6 years
Total = at least 75, up to a maximum of approximately 100 (includes both Part A and B)
Section 4, Study design
Old text
Part B will include 25 PUPs.
New text
Part B will include at least 25, up to a maximum of approximately 50 PUPs.
Section 8.6, Determination of sample size
Old text
Part B will enroll 25 PUPs age <6 years.  The total sample size will be 75 subjects.
New text
Part B will enroll at least 25, up to a maximum of approximately 50 PUPs age <6 years.  The 
total sample size will be at least 75, up to a maximum of approximately 100 subjects.
13.2.2.8
Change 8
Section 8.5, Planned interim analyses
Old text
The main study has a duration of 6 months.  The 6-month data for PTPs will be analyzed for 
regulatory purposes as an interim analysis.  The overall study will be closed after all subjects 
in Parts A and B have completed the extension trial and an additional analysis will include all 
data from the main trial and the extension part.
New text

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The main study has a duration of 6 months.  The 6-month data for PTPs will be analyzed for 
regulatory purposes as an interim analysis.  If required for regulatory purposes, Part B data 
will be described in an interim analysis if at least 5 PUPs have been recruited.  The overall 
study will be closed after all subjects in Parts A and B have completed the extension trial and 
an additional analysis will include all data from the main trial and the extension part.
13.2.2.9
Change 9
Title page
Old text:
Sponsor’s medical expert: 
Bayer Healthcare Pharmaceuticals Inc.
P.O. Box 1000
Montville, New Jersey, USA
Tel.
New text:
Sponsor’s medical expert: 
Bayer Healthcare Pharmaceuticals Inc.
P.O. Box 1000
Montville, New Jersey, USA
Tel. 
Signature of the sponsor’s medically responsible person
Old text:
Name:
 Role:
Global Clinical Leader (GCL)/Medical Expert
New text:
Name:
 Role:
Global Clinical Leader (GCL)/Medical Expert
Section 3, Investigators and other study participants
Old text:
Name: 
Title:    
Address:    
Bayer HealthCare Pharmaceuticals, Inc.
P.O. Box 1000
Montville, New Jersey USA
New text:
Sponsor’s Medical Expert
Name: 
Title:    
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Address:    
Bayer HealthCare Pharmaceuticals, Inc.
P.O. Box 1000
Montville, New Jersey USA
13.2.2.10 Change 10
Section 4, Study design
Old text:
Incremental recovery and trough levels of BAY 94-9027 will be assessed in all subjects.
New text:
Incremental recovery and trough levels of BAY 81-8973 will be assessed in all subjects.
Section 6.2.2, Supply and packaging
Old text:
BAY 81-8973 will be supplied lyophilized in BIO-SET® glass vials.  Study vials may contain 
250 IU, 500 IU or 1000 IU of FVIII activity.  The nominal potency of the drug, as determined 
by chromogenic assay, will be indicated on the labels of each vial unit pack.  The medication 
is manufactured at Bayer HealthCare in Berkeley, California, United States. The vials of 
BAY 81-8973 will be packaged together with a pre-filled syringe of the appropriate amount 
of sterile water for injection, European and US Pharmacopeia (EP) (USP), for reconstitution.  
For BAY 81-8973, the volume of the solvent is 2.5 mL for all vial sizes. The BAY 81-8973 
vials will also be supplied with the following medical devices to facilitate the treatment: 
TERUMO Europe NV, SV-S25FL35 infusion set with filter and needle protection, plunger 
rod, and 10 mL sterile syringe.
New text:
BAY 81-8973 will be supplied lyophilized in glass vials.  Study vials may contain 250 IU, 
500 IU or 1000 IU of FVIII activity.  The nominal potency of the drug, as determined by 
chromogenic assay, will be indicated on the labels of each vial unit pack.  The medication is 
manufactured at Bayer HealthCare in Berkeley, California, United States. The vials of 
BAY 81-8973 will be packaged together with a pre-filled syringe of the appropriate amount 
of sterile water for injection, European and US Pharmacopeia (EP) (USP), for reconstitution.  
For BAY 81-8973, the volume of the solvent is 2.5 mL for all vial sizes. The BAY 81-8973 
vials will also be supplied with the following medical devices to facilitate the treatment: an 
infusion set with filter and needle protection, plunger rod, and 10 mL sterile syringe.  Before 
infusion, the product should be filtered using the infusion set provided or another approved 
filtration device.
PPD

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Section 7.1.2.1, Visit 1
Old text:

Training on and dispensing of the EPD
New text:

Training on and dispensing of the EPD.  Note: the EPD may be given to the 
patients to take home at any time between Screening and Baseline, but no entries 
are to be made before the first injection at Baseline.
Section 7.1.2.3, Visit 3
Old text:

Check of EPD entries and bleeding history.  Collect information on adverse events and 
Healthcare Resources Utilization Questionnaire. (Appendix 14.3).
New text:

Check of EPD entries and bleeding history.  Collect information on adverse events, 
update of concomitant medication and completion of Healthcare Resources Utilization 
Questionnaire. (Appendix 14.3).
Section 7.1.2.9, Extension study visits
Old text:
Regular monthly contacts between parents and the site to check the EPD 
documentation until next clinic visit.
New text:
Regular monthly contacts between parents and the site to check the EPD 
documentation, update information on adverse events and concomitant medication, 
completion of Healthcare Resources Utilization Questionnaire before next clinic visit.
Section 7.1.2.10, Final visit
Old text:
This visit will take place at the end of the extension period and at least 100 ED (including 
main study) are accumulated, or in case of early termination.
New text:
This visit will take place at the end of the extension period, or in the event of early 
termination.

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13.3
Amendment 4
Description of Amendment
Amendment 4 involved the following changes:

Optional biomarker (pharmacogenetic) analysis was added to collect data to 
evaluate genetic differences, to better understand the causes and risk factors for 
potential development of inhibitors in haemophilia A patients on recombinant 
FVIII.  This information will be collected only in PUPs.

Epitope mapping of samples from subjects confirmed positive for inhibitor 
antibodies was added to identify the binding sites of the FVIII inhibitor.

Specification of the need to document ITI therapy was added.

Text describing the duration of treatment in the extension study was added to 
ensure consistency throughout the document.

Typographic error on time for infusion was corrected.

The time-window for final and extension visits was specified to provide guidance.
13.3.1
Overview of changes
Change 1: To collect data to evaluate genetic information in subjects (pharmacogenetics). 
Sections affected:
Section 7.1.1
Tabulated overview
Section 7.1.2
Timing of assessments
Section 7.6
Other procedures and variables – subsection added
Change 2: To collect data to perform epitope mapping in subjects who develop inhibitors.
Sections affected:
Section 7.1.1
Tabulated overview
Section 7.5.3.4
Inhibitor testing
Section 7.6
Other procedures and variables – subsection added
Change 3: To specify the need to document ITI therapy in subjects who develop inhibitors.
Sections affected:

Section 6.1.5
Immune tolerance induction (ITI)

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Change 4: To describe the duration of treatment in the extension study consistently.
Sections affected:

Synopsis

Section 7.1.2.10
Final visit
Change 5: To correct a typographic error on the time for infusion.
Sections affected:

Section 6.1.1
Change 6: To specify the time-window for the final and extension visits.
Sections affected:

Section 7.1.1
13.3.2
Changes to the protocol text:
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol.  In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment.  Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”.
13.3.2.1
Change 1
Additional text:
Section 7.1.1
Tabulated overview

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Table 7-2b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional 
extension study
Visit 1 
Screenin
g
Visit 2
Baselin
e
Combine
d 
Screenin
g and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 2
or
ED ~10
Visit 5 
Month 
3
or
ED ~15
Visit 6 
Month 4
or
ED ~20
Interim d
Visit
30-40 ED 
(as of 
Amd 1)
Final 
Visit
or
50 ED 
g
Extensio
n 
Visit
every 
6 months 
g
Extens
ion
Final 
Visit g
Informed consent)
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) 
(Amd 3)
X
X
FVIII level before infusion and inhibitor c 
(Amd 1)
X
X
X
X
X
X
X
Epitope mapping (inhibitor positive patients) 
(Amd 4)
   X f 
Recovery (20-30 min after infusion) (Amd 1)
X
X
X
X
Pharmacokinetics (optional) (Amd 3)
    X e 
Biomarker investigation (optional) (Amd 4)
    X h 
Infusion of study drug (Amd 1)
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
            continuously             
Healthcare Resources Utilization 
Questionnaire(Amd 1)
X (Amd 1)
       monthly      
Interaction between subject/parent and 
investigator
        weekly                                   
  monthly  
Concomitant medication
X
          continuously        
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
Measured at least 48 h after last dose of FVIII

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Interim visit only if less than 40 ED have been achieved by Month 6.
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to 
be entered into CRF
Epitope mapping to be performed in combination with confirmatory retest for inhibitory antibodies (as of Amd 4)
The Final Visit can be performed as soon as a minimum of 50 ED is achieved, but no later than 2 weeks after achieving 50 ED.  For the regular Extension Visit 
(performed every 6 months), a window of ±2 weeks is allowed.  The Extension Final Visit should take place no later than 2 weeks after 100 ED is achieved or until 
market authorization is obtained (as of Amd 4)
The optional biomarker investigation (pharmacogenetics) requires a separate signed informed consent.  The single blood sample for this analysis can be taken at 
any visit except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional blood draw.  (as of Amd 4)

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Additional text for the-below visits:
Section 7.1.2
Timing of assessments
Section 7.1.2.2  Visit 2 – Baseline

Optional pharmacogenetics in PUPs (Part B and extension):
collect blood sample for biomarker investigation – requires signed informed consent.  
This blood draw will be done once only, and can be performed at any visit except 
Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is 
suitable for an additional blood draw (as of Amd 4)
Section 7.1.2.3  Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B (as of Amd 1),
Section 7.1.2.4  Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B (as of Amd 1),
Section 7.1.2.5  Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (as of Amd 1),
Section 7.1.2.6  Visit 6 – Part B only; ED 20 (20 ED +/- 1) (as of Amd 1),
Section 7.1.2.8  Final Visit (end of the main study and start of the optional extension study, 
Section 7.1.2.9  Extension study visits – 6 months after completion of Part A or B; then
   every 6 months) (as of Amd 1)
Section 7.1.2.10  Final visit

Optional pharmacogenetics in PUPs (Part B and extension):
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amd 4)
Additional text:
Section 7.6.2
Biomarker investigation (pharmacogenetics) (optional – consent required) 
(as of Amd 4)
The purpose of this genetic analysis is to identify markers for risk of inhibitor development in 
subjects treated with BAY 81-8973.  The markers to be analyzed are type of FVIII gene 
mutation if not available, single nucleotide polymorphisms (SNPs) in immunoregulators (eg, 
IL-10), HLA genotype, and FVIII polymorphisms. This biomarker analysis is exploratory and 
will be analyzed for previously untreated patients (PUPs) only. (as of Amd 4)
A separate informed consent for pharmacogenetic sampling is required and participation is 
optional.  (as of Amd 4)
If a subject elects to participate, a blood sample can be collected at any visit except Screening, 
ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional 
blood draw.  Samples will be prepared and labeled according to laboratory specifications.  
Details of the sample collection and shipment procedures will be provided in the Laboratory 
Manual. (as of Amd 4)
A subject does not need to agree to participate in the pharmacogenetic sub-study to be
enrolled in the main study. (as of Amd 4)

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13.3.2.2
Change 2
Additional text
Section 7.1.1
Tabulated overview
Additional text is shown in the tabulated overview together with Change 1 (see 
Section 13.3.2.1).
Section 7.5.3.4
Inhibitor testing
For any subject confirmed positive for inhibitors, epitope mapping will be performed (see 
Section 7.6.1 for details).  (as of Amd 4)
Section 7.6
Other procedures and variables (as of Amd 4)
Not applicable. 
Section 7.6.1
Epitope mapping (as of Amd 4)
In the event a subject tested positive for inhibitor, additional blood, up to a maximum 
allowable as described in Table 14-4a, should be taken to confirm the result (retesting).  
If the result upon retesting is also positive, epitope mapping will be performed with the 
additional blood sample that was taken.  Details of sample collection and shipment procedures 
will be provided in the Laboratory Manual. (as of Amd 4)
13.3.2.3
Change 3
Section 6.1.5
Immune tolerance induction (ITI)
Additional text
Dosage:
Details on ITI therapy should be documented.  Technical guidance on how 
to document this information will be provided in the study manual. (as of 
Amd 4)
13.3.2.4
Change 4
Synopsis
Old text:
Duration of treatment
6 months and/or >50 exposure days (ED). (as of Amd 1)
Optional extension study until marketing authorization 
New text:
Duration of treatment
6 months and/or >50 exposure days (ED). (as of Amd 1)
Optional extension study for at least 100 cumulative ED or (as of Amd 4)
until marketing authorization 

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Section 7.1.2.10
Final visit
Old text:
The extension study will be continued (as of Amd 1) until marketing authorization.
New text:
The extension study will be continued (as of Amd 1) for at least 100 cumulative ED or (as of 
Amd 4) until marketing authorization.
13.3.2.5
Change 5
Section 6.1.1
Regular prophylaxis
Old text:
Route of administration:
Manual intravenous (IV) infusion over 1 – 5 minutes according 
to total volume (as of Amd 1)
New text:
Route of administration:
Manual intravenous (IV) infusion over 1 – 15 minutes (as of 
Amd 4) according to total volume (as of Amd 1)
13.3.2.6
Change 6
Additional text
Section 7.1.1
Tabulated overview
Additional text affecting Part A is shown below.
Additional text affecting Part B is shown together with Change 1 (see Section 13.3.2.1).

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Table 7-1a: Schedule of evaluations (Part A – PTPs; >50 ED)
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 week)
(as of 
Amd 1)
Visit 4 Month
2
(+/- 1 week) 
(as of 
Amd 1)
Final visit 
Month 6
(Minimum 50 ED
[as of Amd 1])
Extension 
Visit every 
6 months e
Extension
Final Visit  e
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
FVIII baseline level and inhibitor(one stage) (Amd 3) 
X
FVIII level pre infusion and inhibitor (as of Amd 1)
X
X
X
X
X
X
Recovery (20-30 min after infusion) c (as of Amd 1)
X
X
X
X
Pharmacokinetics (optional)
-----------------------    X b ------------------------------------------------
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
      continuously       
Healthcare Resources Utilization Questionnaire (as of Amd 1)
X (as of 
Amd 1)
       monthly     
Interaction between subject/parent and investigatord
     weekly                
  monthly 
Concomitant medication 
X
         continuously       
Complete Blood Count (CBC), Chemistries
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to be entered into CRF
Measured at least 48 h after last dose of FVIII (as of Amd 1)
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension min: minute
For the regular Extension Visit every 6 months, a window of ±2 weeks is allowed.  The Extension Final Visit should take place no later than 2 weeks after 100 ED is achieved or until 
market authorization is obtained (as of Amd 4)

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13.4
Amendment 6
Description of Amendment
Amendment 6 involved the following changes:

Requirements for inhibitor testing during the extension phase clarified.

FVIII:C determination at screening.

Transfer device (Vial adapter) to be used for reconstitution.

Clarification of Part B visit schedule.

Update synopsis to reflect that plasma exposure is not exclusion criteria.

Addition of recovery measurement is required at the first extension visit at
6 months and at final visit.

Inclusion of minimally treated patients (MTPs) now possible in Part B.

Addition of inhibitor evaluation at screening in MTPs only (ie, unnecessary to 
evaluate in PUPs) (include retention sample for inhibitor assessment by ELISA for 
MTPs) in Part B.

Use of remaining rest of plasma samples.

Interim analysis in Part B when 25 PUPs have reached 50 ED clarified.

Addition of further details on choice of on-demand vs prophylaxis for initiation of 
treatment in PUPs.

Addition of further information on monitoring of subjects commenced on ITI 
therapy in extension study.

Changes in the study administrative structure.

Minor editorial changes made (not listed in detail).
13.4.1
Overview of changes
Change 1: Requirements for inhibitor testing during the extension phase are clarified. 
Inhibitor testing is required every 6 months after start of the extension, until finalization of the 
study.
Rationale: Clarification. 
Sections affected include:
Section 7.1.1
Tabulated overview
Section 7.5.3.4
Inhibitor testing

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Change 2: FVIII:C is to be determined at screening to confirm the diagnosis if necessary.
Rationale: FVIII:C determination at screening should confirm the diagnosis if the local result 
does not clearly confirm the required inclusion criterion. 
Sections affected include:
Section 7.1.1
Tabulated overview
Section 7.1.2.1
Visit 1 – Screening
Change 3: Vial adapter to be used for reconstitution.
Rationale: To allow reconstitution of the medication if necessary, this vial adapter is provided 
as an option.
Sections affected include:
Section 6.2.2
Supply and packaging
Section 14.1.2
Presentation of vial and the vial adapter – new section
Change 4: Clarification of visit scheduling in Part B
Rationale: Since visits in Part B are scheduled according to ED, giving 
informative approximate time frames for visits in months has led to confusion. In order to 
improve clarity, those visits are now listed by their ED threshold only.
Section affected includes:
Section 7.1.1
Tabulated overview
Change 5: Update synopsis to reflect exposure to plasma is not exclusion criteria
Rationale: Exclusion limited to exposure to FVIII concentrate to keep it consistent to section 
5.1.1 Inclusion criteria.
Section affected includes:
Synopsis

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Change 6: Addition of recovery measurement is required at the first extension visit at 6 
months and at final visit. 
Rationale: As per Guideline, addition of recovery measurements following a positive inhibitor 
test, as well as at the first extension visit at 6 months and at final visit.
Sections affected include:

Section 6.8
Post-study therapy

Section 7.1.1
Tabulated overview

Section 7.1.2.2
Visit 2 – Baseline

Section 7.1.2.9
Extension study visits – 6 months after completion of Part A or 
B; then every 6 months)

Section 7.1.2.10
Extension final visit

Section 7.3.2.1
Incremental recovery of Factor VIII (as of Amd 1)

Section 7.5.3.4
Inhibitor testing
Change 7: Addition of MTPs into the protocol now possible in Part B. In addition to PUPs, 
MTPs are now eligible to participate in Part B. MTPs are defined as patients who have not 
previously received more than 3 injections with any FVIII product and who have no current 
evidence of inhibitor antibody measured using the Nijmegen-modified Bethesda assay 
assessed by central laboratory prior to first exposure in this study. In case of MTPs, the 
screening visit should only take place after a washout period of at least 48 h following any 
previous treatment with any FVIII replacement product.
Rationale: Emergency treatment of a bleed or trauma as first treatment is frequent in this very 
rare population and results in non-eligibility of subjects for the study according to the current 
protocol. Treatment with up to 3 injections does not affect the objective of the study and may 
support recruitment. 
Sections affected include:
Synopsis
Section 1
Introduction
Section 2
Study objectives
Section 4
Study design
Section 5.1.1
Inclusion criteria
Section 5.1.2
Exclusion criteria
Section 6.1.1
Regular prophylaxis
Section 6.1.2
Breakthrough bleeds and surgeries
Section 7.1.1
Tabulated overview
Section 7.1.2
Timing of assessments
Section 7.1.2.1
Visit 1 – Screening
Section 7.1.2.2
Visit 2 – Baseline
Section 7.1.2.3
Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B
Section 7.1.2.4
Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B

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Section 7.1.2.5
Visit 5 – Part B only; ED ~15 (14 ED +/- 1)
Section 7.1.2.6
Visit 6 – Part B only; ED 20 (20 ED +/- 1)
Section 7.1.2.7
Interim visit - Only for Part B (30-40 ED) (as of Amd 1)
Section 7.1.2.8
Final Visit (end of the main study and start of the optional 
extension study) 
Section 7.1.2.9
Extension study visits – 6 months after completion of Part A or 
B; then every 6 months)
Section 7.1.2.10
Final visit
Section 7.5.3.4
Inhibitor testing
Section 7.6.2
Biomarker investigation (pharmacogenetics) (optional – consent 
required)
Section 8.6
Determination of sample size
Change 8: Addition of inhibitor evaluation at screening in MTPs only (ie, unnecessary to 
evaluate in PUPs) (include retention sample for inhibitor assessment by ELISA for MTPs) in 
Part B.
Rationale: Inhibitor testing only needed for MTPs as they have had prior exposure to FVIII.
Sections affected include:
Section 7.1.1
Tabulated overview
Section 7.1.2.1
Visit 1 – Screening
Section 7.1.2.2
Visit 2 – Baseline
Change 9: Use of remaining rest of plasma samples collected. 
Rationale: Usage for immunology or additional coagulation analysis, or for clarification of 
any clinical or laboratory adverse event.
Sections affected include:

Section 7.5.3.4
Inhibitor testing
Change 10: Clarification of the interim analysis for 25 PUPs after they have completed Part 
B.
Rationale: Further detail added to the protocol to clarify that interim analysis will be 
undertaken in 25 PUPs after they will have completed Part B for regulatory purposes.
Sections affected include:
Section 8.5
Planned interim analyses

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Change 11: Additional information added to clarify that on-demand treatment is an option, as 
well as initiating prophylaxis directly.
Rationale: Either on-demand treatment or prophylaxis are options for PUPs starting in the 
study, and further emphasis has been added to the protocol.
Section affected includes:
Section 6.1.1
Regular prophylaxis
Section 7.1.2.2
Visit 2 – Baseline
Change 12: Subjects who commence ITI therapy in Part B will be followed up within the 
extension study.
Rationale: Further clarification on how to monitor subjects who have inhibitors and plan to 
start ITI therapy, as subjects will leave the main study but require documented visits within 
the extension study.
Sections affected include:
Section 4
Study design
Section 6.1.5
Immune tolerance induction
Change 13: Changes in the study administrative structure have been made, specifically, the 
Sponsor’s Medical Expert has been replaced.
Sections affected include:
Title Page
Signature of the sponsor’s medically responsible person
Section 3
Investigators and other study participants
13.4.2
Changes to the protocol text:
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol.  In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment.  Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”.
13.4.2.1
Change 1
Section 7.1.1 Tabulated overview

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Old text:
Table 7-1a: Schedule of evaluations (Part A – PTPs; >50 ED)
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3 
Month 1
(+/- 1 
week) (as 
of Amd 1)
Visit 4 
Month 2
(+/- 1 week) 
(as of 
Amd 1)
Final visit 
Month 6
(Minimum 50 
ED [as of 
Amd 1])
Extension 
Visit every 
6 months e
Extension
Final Visit  e
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
FVIII baseline level and inhibitor(one stage) (Amd 3) 
X
FVIII level pre infusion and inhibitor (as of Amd 1)
X
X
X
X
X
X
Recovery (20-30 min after infusion) c (as of Amd 1)
X
X
X
X
Pharmacokinetics (optional)
-----------------------    X b ------------------------------------------------
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Patient diary (EPD) documentation
      continuously       
Healthcare Resources Utilization Questionnaire (as of 
Amd 1)
X (as of 
Amd 1)
       monthly     
Interaction between subject/parent and investigatord
     weekly                
  monthly 
Concomitant medication 
X
         continuously       
Complete Blood Count (CBC), Chemistries
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to 
be entered into CRF
Measured at least 48 h after last dose of FVIII (as of Amd 1)
Weekly contact during Part A,  monthly during extension and 1-2 weeks after last study visit extension min: minute
For the regular Extension Visit every 6 months, a window of ±2 weeks is allowed.  The Extension Final Visit should take place no later than 2 weeks after 100 EDs 
is achieved or until market authorization is obtained.  (as of Amd 4)

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Table 7-2 b: Schedule of evaluations (Part B – PUPs; no prior FVIII exposure)
Assessments and procedures 
Main study
Optional extension 
study
Visit 1 
Screening
Visit 2
Baseline
Combined 
Screening 
and 
Baseline
Visit 3 
Month 1
or
ED ~5
Visit 4
Month 2
or
ED ~10
Visit 5 
Month 3
or
ED ~15
Visit 6 
Month 4
or
ED ~20
Interim d
Visit
30-40 ED 
(as of 
Amd 1)
Final 
Visit or
50 ED g
Extension 
Visit
every 
6 months g
Extensi
on
Final 
Visit g
Informed consent)
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) 
(Amd 3)
X
X
FVIII level before infusion and inhibitor c (Amd 1)
X
X
X
X
X
X
X
Epitope mapping (inhibitor positive patients)
(Amd 4)
   X f 
Recovery (20-30 min after infusion) (Amd 1)
X
X
X
X
Pharmacokinetics (optional) (Amd 3)
    X e 
Biomarker investigation (optional) (Amd 4)
    X h 
Infusion of study drug (Amd 1)
   continuously in accordance with the prophylaxis regimen  
Patient diary (EPD) documentation
            continuously             
Healthcare Resources Utilization 
Questionnaire(Amd 1)
X (Amd 1)
       monthly      
Interaction between subject/parent and 
investigator
        weekly                                   
  monthly  
Concomitant medication
X
          continuously        
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
Measured at least 48 h after last dose of FVIII
Interim visit only if less than 40 ED have been achieved by Month 6.

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Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times need to 
be entered into CRF
Epitope mapping to be performed in combination with confirmatory retest for inhibitory antibodies (as of Amd 4)
The Final Visit can be performed as soon as a minimum of 50 EDs is achieved, but no later than 2 weeks after achieving 50 EDs.  For the regular Extension Visit 
(performed every 6 months), a window of ±2 weeks is allowed. The Extension Final Visit should take place no later than 2 weeks after 100 EDs is achieved or until 
market authorization is obtained  (as of Amd 4)
The optional biomarker investigation (pharmacogenetics) requires a separate signed informed consent.  The single blood sample for this analysis can be taken at 
any visit except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional blood draw  (as of Amd 4)

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New text:
Table 7–1a: Schedule of evaluations (Part A – PTPs; >50 ED)
Assessments and procedures
Main study
Optional extension study
    Visit 1 
Screening
Visit 2 
Baseline
Visit 3
Month 1
(+/- 1 
week) (as 
of Amd 1)
Visit 4 
Month 2
(+/- 1 week) 
(as of 
Amd 1)
Final visit 
Month 6
(Minimum 50 
ED [as of 
Amd 1])
Extension 
Visit every 
6 months e
Extension
Final Visit  e
Inclusion (date of written informed consent)
X
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Height, weight
X
X
X
X
X
X
X
Medical and surgical history
X
Previous medication (medication history)
X
Physical examination
X
X
Adverse events 
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
Laboratory examination a
X
X
HSP-70 antibodies
X
X
FVIII baseline level and inhibitor (one stage) (Amd 3) 
X
FVIII level pre infusion and inhibitor (as of Amd 1)
X
X
X
X
X
X
Recovery (20-30 min after infusion) c (as of Amd 1)
X
X
X
X
X f(Amd 6)
X (Amd 6)
Pharmacokinetics (optional)
-----------------------    X b ------------------------------------------------
Infusion of study drug
   continuously in accordance with the prophylaxis regimen 
Electronic patient diary (EPD) documentation
      continuously       
Healthcare Resources Utilization Questionnaire (as of 
Amd 1)
X (as of 
Amd 1)
       monthly     
Interaction between subject/parent and investigatord
     weekly                
  monthly 
Concomitant medication 
X
         continuously       
a.
Complete Blood Count (CBC), Chemistries
b
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact 
times need to be entered into CRF
c. 
Measured at least 48 h after last dose of FVIII (as of Amd 1)
d
Weekly contact during Part A, monthly during extension and 1-2 weeks after last study visit extension min: minute
e.
For the regular Extension Visit every 6 months, a window of ±2 weeks is allowed.  The Extension Final Visit should take place no later than 2 weeks 
after 100 ED is achieved or until market authorization is obtained. (as of Amd 4)
f.
At the first extension visit 6 months after the start of the extension and at any time in case of  inhibitor development (as of Amd 6)

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Table 7–2b: Schedule of evaluations (Part B – PUPs/MTPs)
Assessments and procedures 
Main study
Optional extension 
study
Visit 1 
Screening 
k
Visit 2
Baselin
e
Combine
d 
Screenin
g and 
Baseline
(PUPs only)
(as of Amd 6)
Visit 
3 
ED 
~5
(as of 
Amd 6)
Visit 4
ED 
~10
(as of 
Amd 6)
Visit 
5 
ED 
~15
(as of 
Amd 6)
Visit 6 
ED 
~20
(as of 
Amd 6)
Interimd
Visit
30-40 
ED (as 
of Amd 1)
Final 
Visit
or
50 ED f
Extensio
n 
Visit
every 
6 month
s f
Extensio
n
Final 
Visit f
Informed consent
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) (Amd 3)
X h (Amd 6)
X 
X
FVIII level before infusion and inhibitor c (Amd 1)
X
X
X
X
X
X j
X
Epitope mapping (inhibitor positive patients) (Amd 4)
   X e 
Recovery (20-30 min after infusion) (Amd 1)
X
X
X
X
X j
(Amd 6)
X
(Amd 6)
Pharmacokinetics (optional) (Amd 3)
    X d 
Biomarker investigation (optional) (Amd 4)
    X g 
Infusion of study drug (Amd 1)
   continuously in accordance with the prophylaxis regimen  
Electronic patient diary (EPD) documentation
            continuously             
Healthcare Resources Utilization Questionnaire(Amd 1)
X (Amd 1)
       monthly      
Interaction between subject/parent and investigator
        weekly                       
  monthly  
Concomitant medication
X
          continuously        
For footnotes please see next page

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a. 
CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
e
Epitope mapping to be performed in combination with confirmatory retest for inhibitory antibodies (as of Amd 4)
f
The Final Visit can be performed as soon as a minimum of 50 ED is achieved, but no later than 2 weeks after achieving 50 ED. For the regular Extension 
Visit (performed every 6 months), a window of ±2 weeks is allowed. The Extension Final Visit should take place no later than 2 weeks after 100 ED is 
achieved or until market authorization is obtained  (as of Amd 4)
g
The optional biomarker investigation (pharmacogenetics) requires a separate signed informed consent.  The single blood sample for this analysis can be 
taken at any visit except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional blood draw  (as of Amd 4)
h
Inhibitor to be evaluated at screening in MTPs only (ie, unnecessary to evaluate in PUPs) (as of Amd 6, include retention sample for inhibitor assessment by 
ELISA for MTPs)
j
At the first extension visit 6 months after the start of the extension, and at any time in case of inhibitor development (as of Amd 6)
k
In case of MTPs, the screening visit should only take place after a washout period of at least 48 hours following any previous treatment with any FVIII 
replacement product (as of Amd 6).  

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Section 7.5.3.4  Inhibitor testing
Old text:
[…]
The requirement for a (as of Amd 1) FVIII inhibitor test before study entry (as of Amd 1) is 
not applicable for PUPs. The absence of inhibitors will be confirmed at the Baseline 
evaluation. After treatment is started (as of Amd 1), PUPs must be tested for inhibitor 
development every 3-5 EDs until 20 EDs are accumulated. 
Subjects participating in the extension study will additionally be tested for inhibitor 
development every 6 months.
[…]
New text:
[…]
In Part B, the requirement for a (as of Amd 1) FVIII inhibitor testing before study entry (as 
of Amd 1) is not applicable for PUPs but is applicable for MTPs (as of Amd 6).The absence 
of inhibitors will be confirmed at the Baseline evaluation. After treatment is started (as of 
Amd 1), PUPs/MTPs must be tested for inhibitor development every 3-5 ED until 20 ED are 
accumulated (as of Amd 6). Afterwards, blood samples for inhibitor testing and 
determination of FVIII:C trough level (>48 h after last FVIII treatment) are to be taken:

every 6 months in the extension study until finalization of the study, and at the 
final visit (as of Amds 1 and 6).
[…]
13.4.2.2
Change 2
Section 7.1.1 Tabulated overview
Additional text in this section is detailed in the respective section in Change 1.
Section 7.1.2.1 Visit 1 – Screening
Old text:

FVIII:C level, inhibitor test (not required for PUPs) (as of Amd 1)
New text:

FVIII:C level for PUPs and MTPs, inhibitor testing (not required for PUPs but 
required for MTPs incl. a retention sample for ELISA) (as of Amds 1 and 6)

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13.4.2.3
Change 3
Section 6.2.2 Supply and packaging
Additional text:
For preparing reconstitution, BAY 81-8973 will be provided in either of two presentations:
1) Vial with BIO-SET reconstitution cap:  See Section 14.1.1 for Instructions for Use.
Before infusion, the product should be filtered using the infusion set provided or 
another approved filtration device (as of Amds 3 and 6). 
2) Vial and vial adapter: (see section 14.1.2 for Instructions for Use). (as of Amd 6).
Section 14 Appendices
Additional text:
14 Appendices
14.1 Instruction for use of study medication
14.1.1 Presentation of vials with Bio-SET reconstruction cap
[…]
14.1.2 Presentation of vial and vial adapter (as of Amd 6)
Note: This section was introduced by amendment 6.
How to use BAY 81-818973

This medicine is intended for injection into a vein only and should be used within 
3 hours after reconstitution. 

Use only the items (vial adapter, pre-filled syringe containing solvent and 
venipuncture set) that are provided with each package of this medicine.  If these 
components cannot be used, please contact your doctor. If any component of the 
package is opened or damaged, do not use it.

You must filter the reconstituted product before administration to remove potential 
particulate matter in the solution. You are filtering by using the vial adapter.

This medicine must not be mixed with other infusion solutions. Follow the directions 
given by your doctor closely and use the detailed instructions for reconstitution and 
administration provided in the Annex of this leaflet below.

You will need alcohol swabs, gauze pads and plasters.

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ANNEX: Detailed instructions for reconstitution and administration for presentation 
with vial adapter:
1.
Wash your hands thoroughly using soap and warm water.
2.
Warm both an unopened vial and a syringe in your hands to a comfortable temperature 
(do not exceed 37°C).
3.
Remove the protective cap from the vial (A) and wipe the rubber 
stopper on the vial with an alcohol swab and allow it to air dry before 
use.  
4.
Place product vial on a firm, non-skid surface. Peel off the paper 
cover on the vial adapter plastic housing. Do not remove the adapter 
from the plastic housing. Holding the adapter housing, place over the 
product vial and firmly press down (B). The adapter will snap over the 
vial cap. Do not remove the adapter housing at this point.
5.
Hold the pre-filled water for injections syringe upright, grasp the 
plunger rod as per the diagram and attach the rod by turning it firmly 
clockwise into the threaded stopper (C).
6.
Holding the syringe by the barrel, snap the syringe cap off the tip (D). 
Do not touch the syringe tip with your hand or any surface. Set the 
syringe aside for further use.
7.
Now remove and discard the adapter housing (E).
8.
Attach the pre-filled syringe to the threaded vial adapter by turning 
clockwise (F).

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9.
Inject the diluent by slowly pushing down on the plunger rod (G).
10.
Swirl vial gently until all material is dissolved (H). Do not shake vial. 
Be sure that the powder is completely dissolved. Inspect visually for 
particulate matter and discoloration prior to administration. Do not use 
solutions containing visible particles or that are cloudy.
11.
Hold the vial on end above the vial adapter and syringe (I). Fill the 
syringe by drawing the plunger out slowly and smoothly. Ensure that 
the entire content of the vial is drawn into the syringe. Hold the syringe 
upright and push the plunger until no air is left in the syringe.
12.
Apply a tourniquet.
13.
Determine the point of injection and clean the skin with an alcohol swab.
14.
Puncture the vein and secure the venipuncture set with a plaster.
15.
Holding the vial adapter in place, remove the syringe from the vial 
adapter (the latter should remain attached to the vial). Attach the 
syringe to the venipuncture set and ensure that no blood enters the 
syringe (J).
16.
Remove tourniquet.
17.
Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of the 
needle. The speed of administration should be based on your comfort, but should not be 
faster than 2 mL per minute.
18.
If a further dose needs to be administered, use a new syringe with product reconstituted 
as described above.
19.
If no further dose is required, remove the venipuncture set and syringe. Hold a pad 
firmly over the injection site on your outstretched arm for approximately 2 minutes. 
Finally, apply a small pressure dressing to the injection site and consider if a plaster is 
necessary.

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13.4.2.4
Change 4
Section 7.1.1 Tabulated overview
Additional text in this section is detailed in the respective section in Change 1.
13.4.2.5
Change 5
Synopsis
Old text:
Diagnosis and main criteria for
inclusion
Severe hemophilia A (< 1% Factor VIII concentration [FVIII:C]), 
Part A: male, age 0-12 years, > 50 Exposure days (ED) (as of Amd 1), no 
inhibitor history, no other bleeding disorder
Part B: male, PUPs, no prior exposure to factor VIII concentrate or
plasma (as of Amd 1)
New text:
Diagnosis and main criteria for
inclusion
Severe hemophilia A (< 1% Factor VIII concentration [FVIII:C]), 
Part A: male, age 0-12 years, > 50 ED (as of Amd 1), no inhibitor history, 
no other bleeding disorder
Part B: male, PUPs, no prior exposure to factor VIII (FVIII) concentrate 
(as of Amds 1 and 6) [...]
13.4.2.6
Change 6
Section 6.8 Post-study therapy
Additional text:
At the end of the study, all participants who have completed Part A or B (as of Amd 1) will 
be offered participation in an extension study.  Participation in the extension study will allow 
(as of Amd 1) continuation of treatment for at least 100 ED or until marketing authorization.  
The extension (as of Amd 1) study requires continued documentation of infusions, bleeding 
events, monthly interaction with the treatment center, and visits every 6 months for 
inhibitor testing and recovery measurements. (as of Amds 1 and 6)
Section 7.1.1 Tabulated overview
Additional text in this section is detailed in the respective section in Change 1.
Section 7.1.2.2 Visit 2 – Baseline

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Additional text:
Blood sample for the determination of recovery to be taken at 20-30 min after end of 
infusion. (as of Amd 1) (Only for subjects who start prophylaxis at Baseline, for others, 
recovery should be done when prophylaxis is started [as of Amd 6].)
Section 7.1.2.9 Extension study visits – 6 months after completion of Part A or B; then 
every 6 months) (as of Amd 1)
Additional text:

Blood sample for recovery measurement to be collected only at the first extension
visit at 6 months. Blood sample to be taken at 20-30 min after end of infusion (as of 
Amd 6).
Section 7.1.2.10 Extension final visit
Additional text:

Recovery measurement, blood sample to be taken at 20-30 min after end of infusion.
(as of Amd 6)
Section 7.3.2.1 Incremental recovery of Factor VIII (as of Amd 1)
Old text:
[…]
Incremental recovery at 20-30 min after end of infusions (as of Amd 1) will be determined 
at Baseline, Month 1, 2 and Month 6 (or final visit). Incremental recovery should only be 
measured when the subject is not actively bleeding. The exact sampling times before and after 
infusion (as of Amd 1) have to be documented in the CRF.
New text:
[…]
Incremental recovery at 20-30 min after end of infusions (as of Amd 1) will be determined 
at Baseline, Month 1, 2, Month 6 (or final visit), 1st extension visit and final extension visit
(as of Amd 6). Incremental recovery should only be measured when the subject is not actively 
bleeding. The exact sampling times before and after infusion (as of Amd 1) have to be 
documented in the CRF.

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Section 7.5.3.4 Inhibitor testing
Old text.
[…]
Investigators will be provided with a detailed laboratory manual and a copy of the individual 
results. Inhibitor testing will be done according to the Nijmegen modified Bethesda inhibitor 
assay at the central laboratory (as of Amd 1). A positive inhibitor test is defined with a 
threshold of ≥ 0.6 BU in the central lab. Any positive test must be confirmed by a second 
plasma (as of Amd 1) sample. 
[…]
New text:
[…]
Investigators will be provided with a detailed laboratory manual and a copy of the individual 
results. Inhibitor testing will be done according to the Nijmegen modified Bethesda inhibitor 
assay at the central laboratory (as of Amd 1). A positive inhibitor testing is defined with a 
threshold of ≥ 0.6 BU in the central laboratory. Any positive test must be confirmed by a 
second plasma (as of Amd 1) sample and a determination of recovery should be performed. 
(as of Amd 6)
[…]
13.4.2.7
Change 7
Synopsis
Old text:
[…]
Study objective(s)
Primary objective  

To demonstrate the safety and efficacy of  treatment with 
BAY 81-8973 for prophylaxis and breakthrough bleeds in 
children with severe hemophilia A 
Secondary objectives

To assess the safety and efficacy (as of Amendment 1 [Amd 1])
of BAY 81-8973 during surgeries, 

To assess incremental recovery of BAY 81-8973. (as of Amd 1)

To characterize pharmacokinetics in a subset of a minimum of 6
previously treated patients (PTPs) or previously untreated 
patients (PUPs) if parents’ consent (participation for 
pharmacokinetic (PK) sampling is optional). (as of Amd 3)
[…]

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Dose(s)
Part A:
PTPs: 25 -50 International Units (IU)/kilogram (kg) (rounded to nearest 
size vial); prophylaxis with at least 2 infusions per week and treatment for 
breakthrough bleeds (as of Amd 1)
Part B: 
PUPs: 15-50 IU/kg (rounded to nearest size vial); prophylaxis with at 
least 1 infusion per week and treatment for bleeds (as of Amd 1)
[…]
Diagnosis and main criteria for
inclusion
Severe hemophilia A (< 1% Factor VIII concentration [FVIII:C]), 
Part A: male, age 0-12 years, > 50 Exposure days (ED) (as of Amd 1), no 
inhibitor history, no other bleeding disorder
Part B: male, PUPs, no prior exposure to factor VIII concentrate or 
plasma (as of Amd 1)
[…]
Methodology
Part A (as of Amd 1):
The study consists of 6-months of treatment in PTPs with BAY 81-8973 for 
prophylaxis and treatment of breakthrough bleeding events to achieve at 
least 50 EDs. All subjects will be evaluated for inhibitor development and 
incremental recovery at Baseline, Months 1, 2, and 6.  Enrollment in the 
study will be staggered, with subjects age 6-12 years entering first, 
followed by subjects <6 years. (as of Amd 3)
Part B (as of Amd 1):
PUPs will be treated with BAY 81-8973 for all bleeding events and are 
required to start prophylaxis.  Treatment will continue until at least 50 
EDs.  Screening and baseline visits may be combined for this population.  
Subjects will be tested for inhibitors every 3-5 EDs up to ED 20 and again 
at ED 50.  Incremental recovery will be measured at Baseline, ED 20, 
and ED 50. 
Pharmacokinetics (PK) samples will be collected in a subset of subjects at 
pre-infusion and then 20-30 minutes, 4 hours (h), and 24 h post infusion.  
Participation in the PK portion of the study is voluntary and requires 
specific consent. (as of Amd 1)
In both Part A and Part B, all infusions and bleeding events will be 
documented in an electronic patient diary (EPD) throughout the study. 
(as of Amd 1)
Optional extension study (as of Amd 1):
Subjects in both Part A and B will be offered participation in an optional 
extension study to continue treatment with BAY 81-8973,  to accumulate 
at least 100 ED or until the time of market authorization.  During the 
extension study, visits to the treatment center will take place every 
6 months for inhibitor screening. (as of Amd 1)
The study is designed according the requirements defined in the European 
“Note for Guidance on the clinical investigation of recombinant FVIII and 
FIX products” CPMP/BPWG/1561/99.
[…]

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Number of subjects
Part A:
Total Number (N) = 50 PTPs)
age group 6-12 years:  N=25
age group <6 years:    N=25
Part B
N= at least 25, up to a maximum of approximately 50 PUPs (as of 
Amd 3)
age group <6 years
Total = at least 75, up to a maximum of approximately 100 (includes both 
Part A and B) (as of Amd 1, Amd 3)
[…]
New text:
[…]
Study objective(s)
Primary objective

To demonstrate the safety and efficacy of treatment with BAY 81-
8973 for prophylaxis and breakthrough bleeds in children with 
severe hemophilia A 
Secondary objectives

To assess the safety and efficacy (as of Amendment 1 [Amd 1])
of BAY 81-8973 during surgeries 

To assess incremental recovery of BAY 81-8973 (as of Amd 1)

To characterize pharmacokinetics in a subset of a minimum of 
6 previously treated patients (PTPs), previously untreated 
patients (PUPs), or Minimally Treated Patients (MTPs) (as of 
Amd 6) if parents’ consent (participation for pharmacokinetic 
(PK) sampling is optional). (as of Amd 3)
[…]
Dose(s)
Part A:
PTPs: 25 -50 International Units (IU)/kilogram (kg) (rounded to nearest 
size vial); prophylaxis with at least 2 infusions per week and treatment for 
breakthrough bleeds (as of Amd 1)
Part B: 
PUPs/MTPs 15-50 IU/kg; prophylaxis with at least 1 infusion per week 
and treatment for bleeds (as of Amds 1 and 6)
[…]
Diagnosis and main criteria for
inclusion
Severe hemophilia A (< 1% Factor VIII concentration [FVIII:C]), 
Part A: male, age 0-12 years, > 50 ED (as of Amd 1), no inhibitor history, 
no other bleeding disorder
Part B: male, PUPs, no prior exposure to factor VIII (FVIII) concentrate 
(as of Amds 1 and 6) or MTPs who have not previously received more 
than 3 injections with any FVIII concentrate and no current evidence of 
inhibitor antibody  (as of Amd 6)

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[…]
Methodology
Part A (as of Amd 1):
The study consists of 6-months of treatment in PTPs with BAY 81-8973 for 
prophylaxis and treatment of breakthrough bleeding events to achieve at 
least 50 ED. All subjects will be evaluated for inhibitor development and 
incremental recovery at Baseline, Months 1, 2, and 6.  Enrollment in the 
study will be staggered, with subjects age 6-12 years entering first, 
followed by subjects <6 years. (as of Amd 3)
Part B (as of Amds 1 and 6):
PUPs/MTPs will be treated with BAY 81-8973 for all bleeding events and 
are required to start prophylaxis.  Treatment will continue until at least 
50 ED.  Screening and baseline visits may be combined for PUPs.  
Subjects will be tested for inhibitors every 3-5 ED up to 20 ED and again 
at 50 ED.  Incremental recovery will be measured at Baseline, 20 ED, 
and 50 ED. 
Pharmacokinetics (PK) samples will be collected in a subset of subjects at 
pre-infusion and then 20-30 minutes, 4 hours (h), and 24 h post infusion.  
Participation in the PK portion of the study is voluntary and requires 
specific consent. (as of Amd 1)
In both Part A and Part B, all infusions and bleeding events will be 
documented in an electronic patient diary (EPD) throughout the study. 
(as of Amd 1)
Optional extension study (as of Amd 1):
Subjects in both Part A and B will be offered participation in an optional 
extension study to continue treatment with BAY 81-8973, to accumulate 
at least 100 ED or until the time of market authorization.  During the 
extension study, visits to the treatment center will take place every 
6 months. (as of Amds 1 and 6)
The study is designed according the requirements defined in the European 
“Note for Guidance on the clinical investigation of recombinant FVIII and 
FIX products” CPMP/BPWG/1561/99.
[…]
Number of subjects
Part A:
Total Number (N) = 50 PTPs
age group 6-12 years:  N=25
age group <6 years:    N=25
Part B
N= at least 25 PUPs, plus up to additional 25 PUPs/MTPs/ (as of Amds 3 
and 6)
age group <6 years
Total = at least 75, up to a maximum of approximately 100 (includes both 
Part A and B) (as of Amds 1 and 3)
[…]

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Section 1. Introduction
Additional text:
All subjects will receive a replacement therapy at the highest level of standard of care. For 
previously untreated patients (PUPs), and minimally treated patients (MTPs) (as of 
Amendment 6 [Amd 6]), there is a well-known risk for inhibitor development during the first 
20 exposure days (ED) with any FVIII product which decreases with increasing exposure.
Section 2. Study objectives
Additional text:

To assess pharmacokinetic parameters in a subset of children. (PTPs and PUPs/MTPs 
-participation in pharmacokinetic [PK] sampling is voluntary and requires consent). 
(as of Amds 1, 3 and 6)
Section 4. Study design
Old text:
The study is divided into two parts:   Part A will investigate a total of 50 PTPs up to 12 
years of age.  Part B will include at least 25, up to a maximum of approximately 50 PUPs.  
All subjects will receive prophylactic administration of BAY 81-8973…
[…]
New/ Additional text:
The study is divided into two parts:  Part A will investigate a total of 50 PTPs up to 12 years 
of age.  Part B will include at least 25 PUPs, plus up to additional 25 PUPs/MTPs (as of 
Amd 6). All subjects will receive prophylactic administration of BAY 81-8973.  Subjects in 
Part A will be treated with 25-50 IU/kg at least 2 times per week, or more frequently as 
needed for prophylaxis.  Treatment in Part B may begin with start of prophylaxis with 15-
50 IU/kg (minimum dose 250 IU) at least one day a week, or with the subject’s first 
bleeding event.  The study drug will be used both for treatment of bleeding events and 
prevention of bleeds and with surgical procedures. Individual subject dose decisions are at 
the discretion of the investigator. (as of Amds 1 and 3)
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in previous studies with 
BAY 81-8973.  PTPs age 6 to 12 years will begin enrollment first, followed by PTPs <6 years
(as of Amd 3).  Part B, for PUPs/MTPs (as of Amd 6) will begin enrollment after 20 children 
in Part A have had 50 ED. 

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The total study duration (including screening period) per subject in Part A (as of Amd 1) will 
be approximately 6-8 months (as of Amd 1) during which the subjects will accumulate at least 
50 ED.  For Part B, subjects will continue in the study until achieving 50 ED.  
Consequently the duration will vary depending upon the frequency of prophylactic infusion 
and number of bleeding events.  All subjects in both Parts A and B (as of Amd 1) will be 
offered participation in an open-label extension study for an additional 6-12 months to allow 
observations for (as of Amd 1) at least 100 ED or until marketing authorization is obtained.  
Enrollment of PUPs/MTPs (as of Amd 6) in Part B and the extension study may continue 
after Part A and the extension study for PTPs have been completed. (as of Amd 1)
During the study, all subjects will receive treatment only with BAY 81-8973 for prophylaxis 
and treatment of bleeds.  In Part A, the (as of Amd 1) dosage range for prophylaxis 
treatment will be 25-50 IU/kg administered at least 2 times per week at the investigator’s 
discretion.  In Part B, PUPs/MTPs (as of Amd 6) may start at a lower dose at (as of Amd 1) 
once per week schedule at the investigator’s discretion. (as of Amd 1)
Section 5.1.1 Inclusion criteria
Old text:
[…]

Part B (PUPs) (Enrollment of PUPs may start after safety is evaluated in 20 children
in Part A with 50 ED) (as of Amd 1)
1.  Male, <6 years (as of Amd 3)
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or 
confirmed on (as of Amd 1, Amd 3) screening laboratory.
3.  No previous exposure to any FVIII product (as of Amd 1)
4. PUPs may be included if they will receive their first FVIII dose with BAY 81-8973 for 
treatment of first bleeds and agree to start prophylaxis as part of their care. (as of Amd 1)
[…]
New text:
[…]

Part B (PUPs/MTPs): Enrollment may start after safety is evaluated in 20 children in 
Part A with 50 ED (as of Amds 1 and 6).
1.  Male, <6 years (as of Amd 3)
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or 
confirmed on (as of Amd 1, Amd 3) screening laboratory.
3a.  PUPs: No previous exposure to any FVIII product (as of Amd 1)
3b. MTPs: Have previously received not more than 3 injections with any FVIII product and 
who have no current evidence of inhibitor antibody measured using the Nijmegen-modified 
Bethesda assay [<0.2 Bethesda units (BU)/mL]. MTPs may not receive FVIII within 48 h 
prior to the collection of samples for inhibitor testing at the Screening visit. (as of Amd 6)

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3c. MTPs: No history of FVIII inhibitor formation. (as of Amd 6)
4. PUPs may be included if they will receive their first FVIII dose with BAY 81-8973 for 
treatment of first bleeds and agree to start prophylaxis as part of their care. (as of Amd 1)
MTPs may be included if they agree to start prophylaxis as part of their care (as of Amd 6).
[…]
Section 5.1.2 Exclusion criteria
Additional text:
[…]
Part B only (PUPs/MTPs [as of Amd 6]):
[…]
Section 6.1.1 Regular prophylaxis
Additional text:
Test drug:
BAY 81-8973 
Dosage:
25-50 International Unit (IU)/kg; ≥ 2 times per week in PTPs, 
15-50 International Unit (IU)/kg; ≥ 1 time per week in 
PUPs/MTPs. (as of Amds 1 and 6)
(Smallest size vial is 250 IU, which may be used for initial treatment of PUPs/MTPs of any 
weight) (as of Amds 1 and 6)
Route of administration:
Manual intravenous (IV) infusion over 1 – 15 minutes (as of 
Amd 4) according to total volume (as of Amd 1)
Note: PTPs will continue their previous treatment up to 48 h before the first dose of 
BAY 81-8973 (as of Amd 3).
Duration:
Part A: 6 months and at least 50 ED 
Part B: 50 ED 
Extension study: at least 100 cumulative ED in subjects 
participating in the optional extension study or until market 
authorization (as of Amd 1)
(Enrollment of PUPs/MTPs may continue after PTPs have completed participation in 
Part A and the extension study) (as of Amds 1 and 6)
[…]
Taking into account these observations, the following is recommended for PUPs/MTPs
participating in Part B (as of Amds 1 and 6):
[…]

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Section 6.1.2 Breakthrough bleeds and surgeries
Additional text:
BAY 81-8973 will be used for the treatment of breakthrough bleeds. The dosage will be at the 
discretion of the investigator.  For PUPs/MTPs in Part B, see Section 6.1.1. (as of Amds 1 
and 6)
For any surgery that may occur during the course of the study, BAY 81-8973 should be used. 
During surgery (both major and minor) dosing with BAY 81-8973 will follow the same 
standard practice as followed for Kogenate® FS/Bayer (Appendix 14).  The guidelines are 
designed to maintain adequate hemostatic FVIII levels and provide varying instructions based 
upon the type of surgical procedure to be undertaken.  For PUPs /MTPs in Part B (as of 
Amds 1 and 6), surgery is not allowed as first treatment and should be avoided, when 
possible, during the first 20 ED. (as of Amd 1)
Section 7.1.1 Tabulated overview
Old text and new text in this section is detailed in the respective section in Change 1.
Section 7.1.2 Timing of assessments
Additional text:
The main study consists of a Screening period followed by at least 50 ED per subject.  The 
Screening and Baseline visits may be combined to one visit for PUPs.  There is no 
minimum interval between the Screening and Baseline visits for PUPs/MTPs (as of Amd 6)
or PTPs.  For PTPs, no longer than 8 weeks should pass between Screening and Baseline 
visits. (as of Amd 1)
Section 7.1.2.1 Visit 1 - Screening
Additional text:
[…]
In case of MTPs, the screening visit should only take place after a washout period of at 
least 48 h following any previous treatment with any FVIII replacement product (as of Amd 
6).
Section 7.1.2.2 Visit 2 - Baseline
Additional text:
[…]
For PUPs, the Baseline visit (as of Amds 1) may be combined with the Screening visit if all 
selection criteria can be confirmed based on medical records…

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[…]
Note:  For subjects in Part B (PUPs/MTPs), first exposure to study drug may be either for 
treatment of an uncomplicated bleed or for start of prophylaxis.  Inhibitor testing is 
mandatory every 3-5 ED until 20 ED are accumulated.  See discussion on treatment of 
PUPs/MTPs in Section 6.1.1. (as of Amds 1 and 6)
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation – requires signed informed 
consent.  This blood draw will be done once only, and can be performed at any visit 
except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition 
is suitable for an additional blood draw (as of Amds 4 and 6)
[…]
Section 7.1.2.3 Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B (as of Amd 1)
Additional text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)
Section 7.1.2.4 Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B (as of Amd 
1)
Additional text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)
Section 7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (as of Amd 1)
Additional text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)

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Section 7.1.2.6 Visit 6 – Part B only; ED 20 (20 ED +/- 1) (as of Amd 1)
Additional text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)

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Section 7.1.2.7 Interim visit – Only for Part B (30-40 ED) (as of Amd 1)
Additional text:
Visit only required for PUPs and MTPs who have less than 40 ED, 6 months after the 
Baseline visit.  The intent is to have at least one scheduled visit between completion of 
20 ED and the expected date of accumulating 50 ED.  The primary purpose of the visit is to 
assess the well being of the subject, ensure continued compliance with the treatment, and 
make any needed adjustments in dosage or infusion frequency based upon weight or 
bleeding events.
Section 7.1.2.8 Visit 8 – Final Visit (end of the main study and start of the optional 
extension study)
Additional text:
[…]
For PUPs and MTPs in Part B, this visit will take place after 50 ED with study medication
are accumulated, or in the case of early termination (as of Amd 6).  It is expected 50 ED 
will be achieved for most subjects between 6 and12 months after start of prophylactic 
treatment. (as of Amd 1)
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)
Section 7.1.2.9 Extension study visits – 6 months after completion of Part A or B; then 
every 6 months) (as of Amd 1)
Additional text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)

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Section 7.1.2.10 Extension final visit
Additional text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation, if not taken previously – requires 
signed informed consent.  This blood draw will be done once only, and can be 
performed at any visit except Screening (as of Amds 4 and 6)
Section 7.5.3.4 Inhibitor testing
Additional text:
Blood samples for FVIII inhibitor testing will be taken at Screening (PTPs and MTPs only), 
Baseline, at regularly scheduled intervals throughout the study, and at the (as of Amds 1 
and 6) final visit. The premise for inclusion of PTPs and MTPs in this study is the availability 
of a negative inhibitor result (as of Amds 1 and 6) as measured in the blood sample at 
Screening. A further sample will be taken at baseline before the first infusion (as of Amd 1). 
If the inhibitor testing result changes from negative at screening to positive at baseline, before 
the first infusion (as of Amd 1) of study medication, the subject must be withdrawn from the 
trial.
[…]
Section 7.6.2 Biomarker investigation (pharmacogenetics) (optional – consent required) 
(as of Amd 4)
Old text:
…This biomarker analysis is exploratory and will be analyzed for previously untreated 
patients (PUPs) only. (as of Amd 4)
New text:
…This biomarker analysis is exploratory and will be analyzed for PUPs and MTPs only. 
(as of Amds 4 and 6)
Section 8.6 Determination of sample size
Additional text:
[…]
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.  This study consists of two parts.  Part A (as of 
Amd 1) will include a total of 50 PTPs (as of Amd 1); 25 subjects age 6 – 12 years (as of 
Amd 3) and 25 subjects age <6 years. Part B will enroll at least 25, up to a maximum of 

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approximately 50 PUPs/MTPs age <6 years. (as of Amd 3) The total sample size will be at 
least 75, up to a maximum of approximately 100 subjects. (as of Amds 3 and 6)
13.4.2.8
Change 8
Section 7.1.1 Tabulated overview
Additional text in this section is detailed in the respective section in Change 1.
Section 7.1.2.1 Visit 1 – Screening
Old text:

FVIII:C level, inhibitor test (not required for PUPs) (as of Amd 1)
New text:

FVIII:C level for PUPs and MTPs, inhibitor testing (not required for PUPs but 
required for MTPs incl. a retention sample for ELISA) (as of Amds 1 and 6)
Section 7.1.2.2 Visit 2 – Baseline
Additional text:
[…]
This visit should start with the following assessments:
Confirmation of eligibility including check of laboratory test results.
Note: Eligible subjects (except PUPs) must be inhibitor negative at Baseline. MTPs 
must be inhibitor negative as evaluated at Screening Visit (as of Amd 6).
[…]
13.4.2.9
Change 9
Section 7.5.3.4 Inhibitor testing
Additional text:
[…]
Remaining rest of the plasma samples collected at specified study visits could be used for 
immunology or additional coagulation analysis, or for clarification of any clinical or 
laboratory adverse event and in no case for genetic analyses. (as of Amd 6)

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13.4.2.10 Change 10
Section 8.5 Planned interim analyses
Additional text:
The main study has a duration of 6 months. The 6-month data for PTPs (as of Amd 1) will be 
analyzed for regulatory purposes as an interim analysis. An interim analysis will be 
performed for 25 PUPs after they will have completed in Part B (as of Amd 6). If required 
for regulatory purposes, Part B data will be described in an interim analysis if at least 5 
PUPs have been recruited (as of Amd 3). The overall study will be closed after all subjects 
in Parts A and B (as of Amd 1) have completed the extension trial and an additional analysis 
will include all data from the main trial and the extension part.
13.4.2.11 Change 11
Section 6.1.1 Regular prophylaxis
Old text:

Prophylaxis should begin after a minimal number of on-demand FVIII 
exposures with BAY 81-8973 (no more than 2-3 bleeding events) or when the 
child is large enough to tolerate weekly infusion. (as of Amd 1)

Begin prophylaxis with a once-a-week schedule low dose of 250 IU (15-25 
IU/kg); the starting dose may be tailored to the patient’s weight or demonstrated 
bleeding tendency. (as of Amd 1)
New text:

Treatment can be initiated with an on-demand regimen. Prophylaxis should 
begin after a minimal number of on-demand FVIII exposures with 
BAY 81-8973 (no more than 2-3 bleeding events) or when the child is large 
enough to tolerate weekly infusion. (as of Amd 1 and 6)

Alternatively, prophylaxis can be started directly with a once-a-week schedule 
low dose of 250 IU (15-25 IU/kg); the starting dose may be tailored to the 
subject’s weight or demonstrated bleeding tendency. (as of Amd 1 and 6)
Section 7.1.2.2 Visit 2 – Baseline
Additional text:
[…]

Infusion of the first dose of study drug or dispensation of study drug for on-demand 
treatment in Part B (as of Amd 6).
[…]

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13.4.2.12 Change 12
Section 4. Study design
Old text:
[…]
In the event that any subject acquires an inhibitor to FVIII, Immune Tolerance Induction 
(ITI) will be offered. The subject may receive BAY 81 8973 up to 200 IU/kg daily for 18 
months.  Treatment will be at the discretion of the treating physician.  Data on treatment, 
FVIII measurements, and inhibitor levels will be collected. (as of Amd 1)
New text:
[…]
In the event that any subject acquires an inhibitor to FVIII, Immune Tolerance Induction 
(ITI) will be offered. The subject may receive BAY 81-8973 up to 200 IU/kg daily or 100 
IU/kg twice a day for 18 months.  Treatment will be at the discretion of the treating 
physician.  Subject commences on ITI therapy will be followed up within the extension 
study.  Data on treatment, FVIII measurements, and inhibitor levels will be collected. (as of 
Amds 1 and 6)
Section 6.1.5 Immune tolerance induction (ITI)
Old text:
If a subject develops an inhibitor, ITI should be considered. Clinically relevant inhibitor 
development is defined as the occurrence of at least 2 positive inhibitor titers combined with 
a decreased recovery (as of Amd 3).  All treatments, FVIII measurements, and inhibitor 
levels will be documented. (as of Amd 1)
New text:
If a subject develops an inhibitor, ITI should be considered. Clinically relevant inhibitor 
development is defined as the occurrence of at least 2 positive inhibitor titers combined with 
a decreased recovery (as of Amd 3).  Subject commences on ITI therapy will be followed up 
within the extension study.  All treatments, FVIII measurements, and inhibitor levels will 
be documented. (as of Amds 1 and 6)

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13.4.2.13 Change 13
Title page
Old text:
Sponsor’s medical expert:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Tel. 
(as of Amd 4)
New text:
Sponsor’s medical expert:
Bayer Healthcare, 67 Whippany Road, 
Whippany, NJ 07981, USA
Tel. 
(as of Amd 6)
Signature of the sponsor’s medically responsible person
Old text:
Name:
(as of Amd 4)
Role:  
Global Clinical Leader (GCL) 
/Medical Expert
New text:
Name:
(as of 
Amd 6)
Role:  
Global Clinical Leader (GCL) 
/Medical Expert
PPD
PPD
PPD
PPD
PPD
PPD

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Section 3 Investigators and other study participants
Old text:
Name: 
Title:    
Address:    Bayer HealthCare AG,
D-51368 Leverkusen, Germany
Tel.
(as of Amd 4)
New text:
Name: 
Title:    
Address:    Bayer Healthcare, 67 Whippany Road, 
Whippany, NJ 07981, USA
Tel. 
(as of Amd 6)
PPD
PPD
PPD
PPD
PPD
PPD

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13.5
Amendment 7
Description of Amendment
Amendment 7 involved the following changes:

Change of sponsorship information

Changes in the study administrative structure

Increase of the number of subjects that may be enrolled in Part B (PUPs/MTPs)

Addition of inhibitor evaluation at baseline using local laboratory testing in MTPs 
in Part B

Adoption of a staggered approach for subject enrollment

Minor editorial changes and corrections made to ensure clarity and consistency 
(not listed in detail).
13.5.1
Overview of changes
Change 1: Change of sponsorship information.
Rationale: The Sponsor was changed from Bayer Healthcare AG to Bayer AG for non-US 
territory and sponsor information for Bayer HealthCare Pharmaceuticals Inc. was added for 
US-territory. Bayer HealthCare AG merged with Bayer AG, an affiliated company within the 
Bayer Group, effective as of 1st July 2016. Thereby, Bayer HealthCare AG ceased to exist 
and Bayer AG became its legal successor and automatically took over all of the Bayer 
HealthCare AG’s rights, obligations and liabilities by law. As a result of the above mentioned 
merger, Bayer AG assumes the role of the sponsor.
Sections affected include:
Title page
Change 2: Changes in the study administrative structure.
Rationale: The Sponsor’s study medical expert has changed. Instead of 
, 
 
 has taken over this task.
Sections affected include:
Title page 

Signature of the sponsor’s medically responsible person
Section 3
Investigators and other study participants
Change 3: The option of recruiting more than 25 PUPs/MTPs in Part B has been included.
Rationale: The number of subjects that may be enrolled in Part B (PUPs/MTPs) has been 
increased, making the total sample size approximately 100, to allow more subjects to 
participate in the study. 
PPD
PPD

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Sections affected include:

Synopsis Number of subjects 
Section 8.6 Determination of sample size
Change 4: Addition of inhibitor evaluation at baseline using local laboratory testing in MTPs,
as part of inclusion criterion 3b in Part B.
Rationale: The inclusion criterion 3b for Part B has been amended to add further information 
on the inhibitor antibody testing for MTPs. A clause has been added introducing the 
evaluation of the absence of evidence (<0.6 Bethesda unit [BU/mL]) of inhibitor antibody for 
MTPs at baseline, using local laboratory testing. This further testing will confirm that patient 
has negative inhibitor titer before starting treatment. Also, a clause has been added to clarify 
that the administration of the study drug should start upon availability of results of local 
testing that confirm the inclusion criterion. The criterion for withdrawal from the study has 
also been adapted to better reflect the above change, and clarify the requirement of study 
participation.
Sections affected include:
Section 5.1.1
Inclusion criteria
Section 5.2.1
Withdrawal
Section 7.1.1
Tabulated overview

Section 7.1.2.2
Visit 2 – Baseline
Section 7.5.3.4
Inhibitor testing
Change 5: Adoption of a staggered approach for subject enrollment as inclusion criterion 7 in 
Part B (PUPs/MTPs):
Rationale: Additional safety measure to be implemented.
Sections affected include:

Section 4 Study design
Change 6: Minor editorial changes and corrections made to ensure clarity and consistency.
Rationale: Minor editorial clarifications and corrections have been included to add clarity,
consistency, and to reflect current practice.
Sections affected include:
Section 4
Study design
Section 6.1.1
Regular prophylaxis
Section 7.1.1
Tabulated overview

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Section 7.1.2.2
Visit 2 – Baseline

Section 7.1.2.3
Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B (as 
of Amd 1)

Section 7.1.2.4
Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B 
(as of Amd 1)

Section 7.1.2.5
Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (as of Amd 1)

Section 7.1.2.6
Visit 6 – Part B only; ED ~20 (20 ED +/- 1) (as of Amd 1)

Section 7.1.2.8
Final Visit (end of the main study and start of the optional 
extension study)

Section 7.1.2.9
Extension study visits – 6 months after completion of Part A or 
B; then every 6 months (as of Amd 1) 

Section 7.1.2.10
Extension final visit 
Section 7.3.2.1
Incremental recovery of Factor VII
Section 7.5.3.4
Inhibitor testing

Section 7.6.2
Biomarker investigation (pharmacogenetics) (optional – consent 
required) (as of Amd 4).
13.5.2
Changes to the protocol text:
In this section, all affected protocol sections are detailed; the sequence of the sections follows 
the structure of the original protocol. In the display of modifications, the “old text” refers to 
the protocol version preceding this amendment.  Deletions are crossed out in the “old text”. 
Additions are underlined in the “new text”.
13.5.2.1
Change 1
Title Page
Old text:
[…]
Clinical study phase:
III
Date:
19 FEB 2016
EudraCT no.:
2010-021781-29
Version no.:
5.0 
Study no.:
BAY 81-8973 / 13400   
Sponsor:
Bayer HealthCare AG,  D-51368 Leverkusen,  Germany
[…]

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New text:
[…]
Clinical study phase:
III
Date:
30 MAY 2017
EudraCT no.:
2010-021781-29
Version no.:
6.0 
Study no.:
BAY 81-8973 / 13400   
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915,
Whippany NJ 07981-0915, US (as of Amd 7)
[…]
13.5.2.2
Change 2
Title page
Old text:
Sponsor’s medical expert:
Bayer Healthcare, 67 Whippany Road, 
Whippany, NJ 07981, USA
Tel. 
(as of Amd 6)
New text:
Sponsor’s medical expert:
Bayer Healthcare, Rua Domingos Jorge, 1100, 
Predio 9301 2o andar, 
04779-900 São Paulo – SP Brasil
Tel. 
(as of Amd 7)
PPD
PPD
PPD
PPD

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Signature of the sponsor’s medically responsible person
Old text:
Name:
(as of Amd 6)
Role:  
Global Clinical Leader 
(GCL)/Medical Expert 
New text:
Name:
(as of Amd 6)
Role:  
Global Clinical Leader (GCL) 
(as of Amd 7)
Section 3 Investigators and other study participants
Old text:
Name: 
Title:    
Address:    Bayer Healthcare, 67 Whippany Road, 
Whippany, NJ 07981, USA
Tel. 
(as of Amd 6)
New text:
Name: 
Title:    
Address:    Bayer Healthcare, Rua Domingos Jorge, 1100, 
Predio 9301 2o andar, 
04779-900 São Paulo – SP Brasil
Tel. 
(as of Amd 7)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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13.5.2.3
Change 3
Synopis – Number of subjects
Old text:
[…]
Number of subjects
Part A:
Total Number (N) = 50 PTPs
age group 6-12 years:  N=25
age group <6 years:    N=25
Part B
N= at least 25 PUPs, plus up to additional 25 PUPs/MTPs (as of Amds 3, 
and 6)
age group <6 years
Total = at least 75, up to a maximum of approximately 100 (includes both 
Part A and B) (as of Amds 1 and 3)
[…]
New text:
[…]
Number of subjects
Part A:
Total Number (N) = 50 PTPs
age group 6-12 years:  N=25
age group <6 years:    N=25
Part B:
N= at least 25 PUPs, plus approximately an additional 25 PUPs/MTPs
(as of Amds 3, 6 and 7)
age group <6 years
Total =  approximately 100 (includes both Part A and B) (as of Amds 1, 3 
and 7)
[…]

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Section 8.6 Determination of sample size
Old text:
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.  This study consists of two parts.  Part A (as of 
Amd 1) will include a total of 50 PTPs (as of Amd 1); 25 subjects age 6 – 12 years (as of 
Amd 3) and 25 subjects age <6 years. Part B will enroll at least 25, up to a maximum of
approximately 50 PUPs/MTPs age <6 years. (as of Amd 3) The total sample size will be at 
least 75, up to a maximum of approximately 100 subjects. (as of Amds 3 and 6)
[…]
New text:
Adolescents and adults are included in 2 ongoing efficacy and safety studies of the clinical 
development program of BAY-81-8973.  This study consists of two parts.  Part A (as of 
Amd 1) will include a total of 50 PTPs (as of Amd 1); 25 subjects age 6 – 12 years (as of 
Amd 3) and 25 subjects age <6 years. Part B will enroll at least 25, plus approximately an 
additional 25 PUPs/MTPs age <6 years. (as of Amd 3 and Amd 7) The total sample size will 
be approximately 100 subjects. (as of Amds 3, 6 and 7) 
[…]
13.5.2.4
Change 4
Section 5 Inclusion criteria
Additional text:
[…]

Part B (PUPs/MTPs): Enrollment s may start after safety is evaluated in 20 children
in Part A with 50 ED (as of Amds 1 and 6).
1.  Male, <6 years (as of Amd 3)
2.  Severe hemophilia A defined as < 1% FVIII:C based on prior documented testing or 
confirmed on (as of Amd 1, Amd 3) screening laboratory.
3a.  PUPs: No previous exposure to any FVIII product (as of Amd 1)
3b. MTPs: Have previously received not more than 3 injections with any FVIII product and 
who have no current evidence of inhibitor antibody measured centrally using the 
Nijmegen-modified Bethesda assay [<0.2 Bethesda units (BU)/mL] at screening, with 
confirmation using local laboratory testing at baseline (<0.6 Bethesda unit [BU/mL]) (as of 
Amd 7). MTPs may not receive FVIII within 48 h prior to the collection of samples for 
inhibitor testing at the Screening and Baseline visits. (as of Amd 6 and Amd 7).
[…]

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Section 5.2.1 Withdrawal
Additional text:
[…]

A positive inhibitor result at Screening or Baseline visits (as of Amd 1). Evidence of 
inhibitor formation in MTPs prior to starting treatment with study drug ([defined as 
≥0.2 BU/mL by central laboratory testing at screening, and/or ≥0./6 BU/mL by local 
laboratory testing at baseline) (as of Amd 7)
[…]
Section 7.1.1 Tabulated overview

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[…]
Table 7-2b: Schedule of evaluations (Part B – PUPs/MTPs)
Visit 1 
Screening k
Visit 2
Baseline
Combine
d 
Screenin
g and 
Baseline
(PUPs 
only)
(as of 
Amd 6)
Visit 3 
ED ~5
(as of 
Amd 6
)
Visit 4
ED ~10
(as of 
Amd 6)
Visit 5 
ED ~15
(as of 
Amd 6)
Visit 6 
ED 
~20
(as of 
Amd 6)
Interim
Visit
30-40 
ED (as of 
Amd 1)
Final 
Visit or
50 ED f
Extension 
Visit
every 
6 months f
Extension
Final Visit f
Informed consent
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) (Amd 3)
X h (Amd 6)
X 
X
FVIII level before infusion and inhibitor c (Amd 1)
X
X
X
X
X
X j
X
Epitope mapping (inhibitor positive patients) (Amd 4)
   X e 
Recovery (20-30 min after infusion) (Amd 1)
X
X
X
X
X j
(Amd 6)
X
(Amd 6)
Pharmacokinetics (optional) (Amd 3)
    X d 
Biomarker investigation (optional) (Amd 4)
    X g 
Infusion of study drug (Amd 1)
   continuously in accordance with the prophylaxis regimen  
Electronic patient diary (EPD) documentation
            continuously             
Healthcare Resources Utilization Questionnaire(Amd 1)
X (Amd 1)
       monthly      

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Interaction between subject/parent and investigator
        weekly                       
  monthly  
Concomitant medication
X
          continuously        
For footnotes please see next page
a. CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
e
Epitope mapping to be performed in combination with confirmatory retest for inhibitory antibodies (as of Amd 4)
f
The Final Visit can be performed as soon as a minimum of 50 ED is achieved, but no later than 2 weeks after achieving 50 ED. For the regular Extension 
Visit (performed every 6 months), a window of ±2 weeks is allowed. The Extension Final Visit should take place no later than 2 weeks after 100 ED is 
achieved or until market authorization is obtained  (as of Amd 4)
g
The optional biomarker investigation (pharmacogenetics) requires a separate signed informed consent.  The single blood sample for this analysis can be 
taken at any visit except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional blood draw  (as of Amd 4)
h
Inhibitor to be evaluated at screening in MTPs only (ie, unnecessary to evaluate in PUPs) (as of Amd 6, include retention sample for inhibitor assessment 
by ELISA for MTPs). 
j
At the first extension visit 6 months after the start of the extension, and at any time in case of inhibitor development (as of Amd 6)
k
In case of MTPs, the screening visit should only take place after a washout period of at least 48 hours following any previous treatment with any FVIII 
replacement product (as of Amd 6).  

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[…]
Table 7-2b: Schedule of evaluations (Part B – PUPs/MTPs)
Visit 1 
Screening k
Visit 2
Baseline
Combine
d 
Screenin
g and 
Baseline
(PUPs 
only)
(as of 
Amd 6)
Visit 3 
ED ~5
(as of 
Amd 6
)
Visit 4
ED ~10
(as of 
Amd 6)
Visit 5 
ED ~15
(as of 
Amd 6)
Visit 6 
ED 
~20
(as of 
Amd 6)
Interim
Visit
30-40 
ED (as of 
Amd 1)
Final 
Visit or
50 ED f
Extension 
Visit
every 
6 months f
Extension
Final Visit f
Informed consent
X
X
X
Inclusion / exclusion criteria
X
X
X
Demographic data
X
X
Height, weight
X
X
X
X
X
X
X
X
X
X
X
Medical and surgical history
X
X
Previous medication (medication history)
X
X
Physical examination
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X (Amd 7) X (Amd 7)
Laboratory examination a
X
X
X
HSP-70 antibodies
X b
  X b
X b
FVIII baseline level and inhibitor (one stage) (Amd 3)
X h (Amd 6) Xh (Amd 7)
X
FVIII level before infusion and inhibitor c (Amd 1)
X
X
X
X
X
X j
X
Epitope mapping (inhibitor positive patients) (Amd 4)
   X e 
Recovery (20-30 min after infusion) (Amd 1)
X
X
X
X
X j
(Amd 6)
X
(Amd 6)
Pharmacokinetics (optional) (Amd 3)
    X d 
Biomarker investigation (recommended) (Amd 4 and 
Amd 7)
    X g 
Infusion of study drug (Amd 1)
   continuously in accordance with the prophylaxis regimen  
Electronic patient diary (EPD) documentation
            continuously             

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Healthcare Resources Utilization Questionnaire(Amd 1)
X (Amd 1)
       monthly      
Interaction between subject/parent and investigator
        weekly                       
  monthly  
Concomitant medication
X
          continuously        
For footnotes please see next page
a. CBC, chemistries; local labs as needed to reduce blood volume (Section 14.4)
b. 
In subjects > 7 kg at baseline visit.  See recommendations for blood draws in subjects <10 kg (Section 14.4)
c. 
Measured at least 48 h after last dose of FVIII
d
Blood samples at the following time points: before, 20-30 min, 4 h, and 24 h post-infusion following a washout of 48 h after last dose of FVIII. Exact times 
need to be entered into CRF
e
Epitope mapping to be performed in combination with confirmatory retest for inhibitory antibodies (as of Amd 4)
f
The Final Visit can be performed as soon as a minimum of 50 ED is achieved, but no later than 2 weeks after achieving 50 ED. For the regular Extension 
Visit (performed every 6 months), a window of ±2 weeks is allowed. The Extension Final Visit should take place no later than 2 weeks after 100 ED is 
achieved or until market authorization is obtained  (as of Amd 4)
g
The recommended biomarker investigation (pharmacogenetics) requires a separate signed informed consent (as of Amd 7).  The single blood sample for 
this analysis can be taken at any visit except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for an additional blood 
draw  (as of Amd 4)
h
Inhibitor to be evaluated at screening (central laboratory testing), and at t baseline (central and local laboratory testing), in MTPs only (ie, 
unnecessary to evaluate in PUPs) (as of Amd 6, include retention sample for inhibitor assessment by ELISA for MTPs). Study drug administration 
should start upon availability of result from local laboratory testing. (as of Amd 6 and Amd 7)
j
At the first extension visit 6 months after the start of the extension, and at any time in case of inhibitor development (as of Amd 6)
k
In case of MTPs, the screening visit should only take place after a washout period of at least 48 hours following any previous treatment with any FVIII 
replacement product (as of Amd 6).  

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Section 7.1.2.2 Visit 2 – Baseline
Additional text:
[…]
This visit should start with the following assessments:
Confirmation of eligibility including check of laboratory test results.
Note: Eligible subjects (except PUPs) must be inhibitor negative at Baseline. MTPs 
must be inhibitor negative as evaluated via central laboratory testing at Screening 
visit (as of Amd 6). A confirmatory inhibitor test must be taken at Baseline visit. 
Results from local laboratory testing must be negative (<0.6 BU/mL ) prior to 
administration of study drug. (as of Amd 7)
[…]
Section 7.5.3.4 Inhibitor testing
Old text:
[…]
In Part B, the requirement for a FVIII inhibitor testing before study entry (as of Amd 1) is 
not applicable for PUPs but is applicable for MTPs (as of Amd 6). The absence of inhibitors 
will be confirmed at the Baseline evaluation. After treatment is started (as of Amd 1),
PUPs/MTPs must be tested for inhibitor development every 3-5 ED until 20 ED are 
accumulated (as of Amd 6). Afterwards, blood samples for inhibitor testing and 
determination of FVIII:C trough level (>48 h after last FVIII treatment) are to be taken:
[…]
New text:
[…]
In Part B, the requirement for a FVIII inhibitor testing before study entry (as of Amd 1) is 
not applicable for PUPs but is applicable for MTPs (as of Amd 6). The absence of inhibitors 
will be assessed using central laboratory testing at Screening (<0.2 BU/mL), with 
confirmation using local laboratory testing at Baseline (<0.6 BU/mL) (as of Amd 7). After 
treatment is started (as of Amd 1), PUPs/MTPs must be tested for inhibitor development 
every 3-5 ED until 20 ED are accumulated (as of Amd 6). Afterwards, blood samples for 
inhibitor testing and determination of FVIII:C trough level (>48 h after last FVIII 
treatment) are to be taken:
[…]
13.5.2.5
Change 5
Section 4 Study design

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[…]
Enrollment will be staggered.  Part A will start after 20 adult/adolescent subjects have 
received 50 ED with BAY 81-8973 without safety concerns in previous studies with 
BAY 81-8973.  PTPs age 6 to 12 years will begin enrollment first, followed by PTPs <6 years
(as of Amd 3).  Part B, for PUPs/MTPs (as of Amd 6) will begin enrollment after 20 children 
in Part A have had 50 ED. As of Amd 7, enrollment will occur in staggered approach. 10 
patients will be enrolled, and will commence treatment for 20 ED. Enrollment of next 
sequence will start if no safety concerns are identified in the first group. Enrollment will be 
suspended if the inhibitor rate in the first cohort exceeds 50% following discussion with an 
independent Data Monitoring Committee (DMC). (as of Amd 7)
[…]
13.5.2.6
Change 6
Section 4 Study design
Additional text:
[…]
In the event that any subject acquires an inhibitor to FVIII, Immune Tolerance Induction 
(ITI) will be offered. The subject may receive BAY 81-8973 up to 200 IU/kg daily or 
100 IU/kg twice a day for 18 months.  Treatment will be at the discretion of the treating 
physician, although the detailed treatment plan should be agreed with the Coordinating 
Investigator (as of Amd 7).  Subject commences on ITI therapy will be followed up within 
the extension study.  Data on treatment, FVIII measurements, and inhibitor levels will be 
collected. (as of Amds 1 and 6).
Section 6.1.1 Regular prophylaxis
Old text:
[…]
Test drug:
BAY 81-8973 
Dosage:
25-50 International Unit (IU)/kg; ≥ 2 times per week in PTPs, 
15-50 International Unit (IU)/kg; ≥ 1 time per week in 
PUPs/MTPs. (as of Amds 1 and 6). 
[…]

Treatment can be initiated with an on-demand regimen. Prophylaxis should begin after 
a minimal number of on-demand FVIII exposures with BAY 81-8973 (no more than 2-
3 bleeding events) or when the child is large enough to tolerate weekly infusion. (as of 
Amd 1 and 6)

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
Alternatively, prophylaxis can be started directly with a once-a-week schedule low dose 
of 250 IU (15-25 IU/kg); the starting dose may be tailored to the subject’s weight or 
demonstrated bleeding tendency. (as of Amd 1 and 6)

Avoid starting prophylaxis during febrile illness or other identified inflammatory 
events. (as of Amd 1)

Increase frequency of infusion or dose as needed for breakthrough bleeding, increased 
physical activity, or weight gain. (as of Amd 1)

Avoid surgery or need for high dose intensive treatment lasting more than 4 days 
during the first 20 ED. (as of Amd 1)

Do not give FVIII as prophylaxis for vaccinations. (as of Amd 1)
[…]
New text:
[…]
Test drug:
BAY 81-8973 
Dosage:
25-50 International Unit (IU)/kg; ≥ 2 times per week in PTPs, 
15-50 International Unit (IU)/kg; ≥ 1 time per week in 
PUPs/MTPs. (as of Amds 1 and 6). Recommendations for 
starting prophylaxis in PUPs/MTPs are described below. (as of 
Amd 7)
[…]
Treatment recommendations (as of Amd 7)  

Treatment can be initiated with an on-demand regimen. Prophylaxis should begin after 
a minimal number of on-demand FVIII exposures with BAY 81-8973 (no more than 2-
3 bleeding events) or when the child is large enough to tolerate weekly infusion. (as of 
Amd 1 and 6)

Alternatively, prophylaxis can be started directly with a once-a-week schedule low dose 
of 250 IU (15-25 IU/kg); the starting dose may be tailored to the subject’s weight or 
demonstrated bleeding tendency. (as of Amd 1 and 6)

Increase frequency of infusion or dose as needed for breakthrough bleeding, increased 
physical activity, or weight gain. (as of Amd 1)

Avoid starting prophylaxis during febrile illness or other identified inflammatory 
events. (as of Amd 1)

Avoid surgery or need for high dose intensive treatment lasting more than 4 days 
during the first 20 ED. (as of Amd 1)

Do not give FVIII as prophylaxis for vaccinations. (as of Amd 1)
[…]

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Section 7.1.1 Tabulated overview
Additional text is shown in the tabulated overview together with Change 4 (see Section 
13.5.2.4).
Section 7.1.2.2 Visit 2 - Baseline
Old text:
[…]
For PUPs, the Baseline visit (as of Amd 1) may be combined with the Screening visit if all 
selection criteria can be confirmed based on medical records. The first dose of BAY 81-8973
may be for treatment of a bleed.  First treatment should not occur during high risk 
situations, surgery, or bleeds requiring prolonged or intensive treatment. (as of Amd 1)
[…]
Thereafter, the following activities will be performed:

Measurement of body height/length (as of Amd 1) and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before infusion.  (Blood pressure may be deferred if appropriate cuff 
size or equipment is not available). (as of Amd 1)

Update of concomitant medication and Healthcare Resources Utilization 
Questionnaire (as of Amd 1). (Appendix 14.3) 

HSP-70 antibodies (in children > 7kg) (as of Amd 1)

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment). (as of Amd 1)

Infusion of the first dose of study drug or dispensation of study drug for on-demand 
treatment in Part B (as of Amd 6).
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): 
collect blood sample for biomarker investigation – requires signed informed
consent.  This blood draw will be done once only, and can be performed at any visit 
except Screening, ideally at Visit 3 or whenever the subject’s body weight/condition 
is suitable for an additional blood draw (as of Amds 4 and 6)
[…]
New text:

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[…]
For PUPs, the Baseline visit (as of Amd 1) may be combined with the Screening visit if all 
selection criteria can be confirmed based on medical records. The first dose of BAY 81-8973
may be for treatment of a bleed.  First treatment should not occur during high risk 
situations, surgery, or bleeds requiring prolonged or intensive treatment (see Section 6.1.1). 
(as of Amd 1 and Amd 7)
[…]
The following activities will be performed (as of Amd 7):

Blood sample for inhibitor testing and determination of FVIII:C trough levels 
(≥ 48 h after last FVIII treatment). (as of Amd 1)

Measurement of body height/length (as of Amd 1) and weight

Measurement of vital signs: Systolic and diastolic blood pressure, heart rate, and body 
temperature before infusion.  (Blood pressure may be deferred if appropriate cuff 
size or equipment is not available). (as of Amd 1)

Update of concomitant medication and Healthcare Resources Utilization 
Questionnaire (as of Amd 1). (Appendix 14.3) 

HSP-70 antibodies (in children > 7kg) (as of Amd 1)

Infusion of the first dose of study drug or dispensation of study drug for on-demand 
treatment in Part B (as of Amd 6).
[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening, ideally at Visit 3 or whenever the subject’s body 
weight/condition is suitable for an additional blood draw (as of Amds 4 and 6). 
Additional informed consent is required (as of Amd 7).
[…]
Section 7.1.2.3 Visit 3 – Month 1 for Part A; ED ~5 (4 ED +/- 1) for Part B (as of Amd 1)
Old text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)

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[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
[…]
Section 7.1.2.4 Visit 4 – Month 2 for Part A; ED ~10 (9 ED +/- 1) for Part B (as of 
Amd 1)
Old text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)
New text:
[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
[…]
Section 7.1.2.5 Visit 5 – Part B only; ED ~15 (14 ED +/- 1) (as of Amd 1)
Old text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)
New text:
[…]

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
Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
[…]
Section 7.1.2.6 Visit 6 – Part B only; ED ~20 (20 ED +/- 1) (as of Amd 1)
Old text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)
New text:
[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
[…]
Section 7.1.2.8 Final Visit (end of the main study and start of the optional extension 
study)
Old text:
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)
New text:
[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)

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[…]
Section 7.1.2.9 Extension study visits – 6 months after completion of Part A or B; then 
every 6 months) (as of Amd 1) 
Old text:
[…]
The following procedures and assessments will be performed:

Measurement of body height/length (as of Amd 1) and weight
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 
informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)
[…]
New text:
[…]
The following procedures and assessments will be performed:

Measurement of body height/length, weight, and vital signs (as of Amd 1 and Amd 7)
[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
[…]
Section 7.1.2.10 Extension final visit
Old text:
[…]
The following procedures and assessments will be performed:

Measurement (as of Amd 1) of body height and weight
[…]

Optional pharmacogenetics in PUPs/MTPs (Part B and extension): collect blood 
sample for biomarker investigation, if not taken previously – requires signed 

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informed consent.  This blood draw will be done once only, and can be performed at 
any visit except Screening (as of Amds 4 and 6)
[…]
New text:
[…]
The following procedures and assessments will be performed:

Measurement (as of Amd 1) of body height, weight and vital signs (as of Amd 7)
[…]

Recommended (as of Amd 7) pharmacogenetics in PUPs/MTPs (Part B and 
extension): collect blood sample for biomarker investigation, if not taken previously 
– requires signed informed consent.  This blood draw will be done once only, and 
can be performed at any visit except Screening (as of Amds 4 and 6)
[…]
Section 7.3.2.1 Incremental recovery of Factor VIII (as of Amd 1)
Additional text:
[…]
Incremental recovery at 20-30 min after end of infusions (as of Amd 1) will be determined 
at Baseline, Month 1, 2, Month 6 (or final visit), 1st extension visit and final extension visit 
(as of Amd 6). Incremental recovery should only be measured when the subject is not actively 
bleeding. The exact sampling times before and after infusion (as of Amd 1) have to be 
documented in the CRF.
A determination of recovery should also be performed with the confirmatory inhibitor test. 
(as of Amd 7)
Section 7.5.3.4 Inhibitor testing
Additional text:
[…]
After treatment is started (as of Amd 1), PUPs/MTPs must be tested for inhibitor 
development every 3-5 ED until 20 ED are accumulated (as of Amd 6), and at the final visit 
(50 ED) (as of Amd 7). Afterwards, blood samples for inhibitor testing and determination of 
FVIII:C trough level (>48 h after last FVIII treatment) are to be taken:
[…].

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Section 7.6.2 Biomarker investigation (pharmacogenetics) (optional – consent required) 
(as of Amd 4)
Old text:
Section 7.6.2 Biomarker investigation (pharmacogenetics) (optional – consent required) 
(as of Amd 4)
The purpose of this genetic analysis is to identify markers for risk of inhibitor development 
in subjects treated with BAY 81-8973.  The markers to be analyzed are type of FVIII gene 
mutation if not available, single nucleotide polymorphisms (SNPs) in immunoregulators 
(eg, IL 10), HLA genotype, and FVIII polymorphisms. This biomarker analysis is 
exploratory and will be analyzed for PUPs and MTPs only. (as of Amds 4 and 6)
A separate informed consent for pharmacogenetic sampling is required and participation is 
optional.  (as of Amd 4)
If a subject elects to participate, a blood sample can be collected at any visit except 
Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for 
an additional blood draw.  Samples will be prepared and labeled according to laboratory 
specifications.  Details of the sample collection and shipment procedures will be provided in 
the Laboratory Manual. (as of Amd 4)
A subject does not need to agree to participate in the pharmacogenetic sub-study to be
enrolled in the main study. (as of Amd 4).
New text:
Section 7.6.2 Biomarker investigation (pharmacogenetics) (recommended – consent 
required) (as of Amd 4 and Amd 7)
The purpose of this genetic analysis is to identify markers for risk of inhibitor development 
in subjects treated with BAY 81-8973.  The markers to be analyzed are type of FVIII gene 
mutation if not available, single nucleotide polymorphisms (SNPs) in immunoregulators 
(eg, IL 10), HLA genotype, and FVIII polymorphisms. This biomarker analysis is 
exploratory and will be analyzed for PUPs and MTPs only. (as of Amds 4 and 6)
A separate informed consent for pharmacogenetic sampling is required and participation is 
recommended. (as of Amd 4 and Amd 7)
If a subject elects to participate, a blood sample can be collected at any visit except 
Screening, ideally at Visit 3 or whenever the subject’s body weight/condition is suitable for 
an additional blood draw.  Samples will be prepared and labeled according to laboratory 
specifications.  Details of the sample collection and shipment procedures will be provided in 
the Laboratory Manual. (as of Amd 4)
A subject does not need to agree to participate in the pharmacogenetic sub-study to be 
enrolled in the main study. (as of Amd 4). However, as this analysis provides important 
information about inhibitor development, participation is the sub study is recommended.
(as of Amd 7)

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13.6
Amendment 8
Amendment 8 is the sixth global amendment dated 01 FEB 2019, and is presented using a 
different approach from the previous amendments. The rationale for this amendment with an 
overview of the affected sections is provided in the “Protocol Amendment Summary of 
Changes Table” which can be found directly before the Table of contents in this document.
Changes in this document are made without annotations. A separate file with tracked changes 
against the last integrated protocol version is available upon request.

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14.
Appendices
14.1
Instruction for use of study medication
14.1.1
Presentation of vials with Bio-SET reconstitution cap

Study medication is intended for intravenous administration only and must be 
administered immediately after reconstitution. 
You must use aseptic conditions (meaning clean and germ free) during reconstitution 
and administration. Use only the medical devices (powder vial with Bio-Set device, 
pre-filled syringe containing solvent and venipuncture set) for reconstitution and 
administration that are provided with each package of study medication. 
Study medication must not be mixed with other infusion solutions. Follow the 
directions given by your doctor closely and use the instructions below as a guide:
1. Wash your hands thoroughly using soap and warm water. The solution must be prepared   
on a clean and dry surface.
2. Warm the unopened powder vial and the solvent syringe in your hands until they feel as 
warm as your hands. The material should not be warmer than body temperature (not 
exceed 37 °C). Wipe any observable moisture from the vial.
3. Remove the cap from the powder vial by gently moving it from side to side several times, 
whilst at the same time pulling upwards. Remove the stopper attached to the white cap 
from the syringe (A).
4. Gently screw the syringe on to the powder vial (B).
5. Place the vial on a rigid, non-slip surface and hold it firmly with one hand. Then, strongly 
press down the fingerplate near the syringe tip using your thumb and index finger (C) 
until the finger plate meets the top edge of the Bio-Set. 
This indicates that the system is activated (D).
6. Connect the plunger rod to the syringe by screwing it into the rubber stopper (E).

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7. Inject the solvent by slowly pushing the syringe’s plunger down (F).
8. Dissolve the powder by gently swirling the vial. Do not shake the vial! Ensure that the 
powder is completely dissolved before use. Do not use solutions that contain visible 
particles or that are cloudy (G).
9. Invert vial/syringe and transfer the solution into syringe by drawing the plunger out 
slowly and smoothly (H). Ensure that the entire contents of the vial are drawn into the 
syringe.
10. Apply a tourniquet. Determine the point of injection, clean the skin with an alcohol swab, 
and prepare site of injection antiseptically as advised by your doctor. Puncture the vein 
and secure the venipuncture set with a plaster.
11. Unscrew the syringe to disconnect the vial (I).
12. Attach the syringe to the venipuncture set by screwing it clockwise and ensure that no 
blood enters the syringe (J).
13. Remove tourniquet!
14. Inject the solution intravenously over several minutes, keeping an eye on the position of 
the needle. The speed of administration should be based on the subject’s comfort, but 
should not be faster than 2ml\min (maximum rate of infusion). (as of Amd 1)
15. If a further dose is required, remove the empty syringe by turning it anti-clockwise. 
Reconstitute the desired amount of product, repeating steps 2. – 9, using a new syringe 
and connect it to the venipuncture set.
16. If no further dose is required, remove the venipuncture set and syringe. Hold a swab 
firmly over the injection site on the outstretched arm for approx. 2 minutes. Finally, apply 
a small pressure dressing to the wound. 
NOTE: See accompanying instructions for Injection Set with Filter for injections after blood 
withdrawal.

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14.1.2
Presentation of vial and vial adapter (as of Amd 6)
Note: This section was introduced by amendment 6.
How to use BAY 81-818973

This medicine is intended for injection into a vein only and should be used within 
3 hours after reconstitution. 

Use only the items (vial adapter, pre-filled syringe containing solvent and 
venipuncture set) that are provided with each package of this medicine.  If these 
components cannot be used, please contact your doctor. If any component of the 
package is opened or damaged, do not use it.

You must filter the reconstituted product before administration to remove potential 
particulate matter in the solution. You are filtering by using the vial adapter.

This medicine must not be mixed with other infusion solutions. Follow the directions 
given by your doctor closely and use the detailed instructions for reconstitution and 
administration provided in the Annex of this leaflet below.

You will need alcohol swabs, gauze pads and plasters.
ANNEX: Detailed instructions for reconstitution and administration for presentation
with vial adapter:
1.
Wash your hands thoroughly using soap and warm water.
2.
Warm both an unopened vial and a syringe in your hands to a comfortable temperature 
(do not exceed 37°C).
3.
Remove the protective cap from the vial (A) and wipe the rubber 
stopper on the vial with an alcohol swab and allow it to air dry before 
use.  
4.
Place product vial on a firm, non-skid surface. Peel off the paper 
cover on the vial adapter plastic housing. Do not remove the adapter 
from the plastic housing. Holding the adapter housing, place over the 
product vial and firmly press down (B). The adapter will snap over the 
vial cap. Do not remove the adapter housing at this point.

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5.
Hold the pre-filled water for injections syringe upright, grasp the 
plunger rod as per the diagram and attach the rod by turning it firmly 
clockwise into the threaded stopper (C).
6.
Holding the syringe by the barrel, snap the syringe cap off the tip (D). 
Do not touch the syringe tip with your hand or any surface. Set the 
syringe aside for further use.
7.
Now remove and discard the adapter housing (E).
8.
Attach the pre-filled syringe to the threaded vial adapter by turning 
clockwise (F).
9.
Inject the diluent by slowly pushing down on the plunger rod (G).
10.
Swirl vial gently until all material is dissolved (H). Do not shake vial. 
Be sure that the powder is completely dissolved. Inspect visually for 
particulate matter and discoloration prior to administration. Do not use 
solutions containing visible particles or that are cloudy.
11.
Hold the vial on end above the vial adapter and syringe (I). Fill the 
syringe by drawing the plunger out slowly and smoothly. Ensure that 
the entire content of the vial is drawn into the syringe. Hold the syringe 
upright and push the plunger until no air is left in the syringe.
12.
Apply a tourniquet.
13.
Determine the point of injection and clean the skin with an alcohol swab.
14.
Puncture the vein and secure the venipuncture set with a plaster.

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15.
Holding the vial adapter in place, remove the syringe from the vial 
adapter (the latter should remain attached to the vial). Attach the 
syringe to the venipuncture set and ensure that no blood enters the 
syringe (J).
16.
Remove tourniquet.
17.
Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of the 
needle. The speed of administration should be based on your comfort, but should not be 
faster than 2 mL per minute.
18.
If a further dose needs to be administered, use a new syringe with product reconstituted 
as described above.
19.
If no further dose is required, remove the venipuncture set and syringe. Hold a pad 
firmly over the injection site on your outstretched arm for approximately 2 minutes. 
Finally, apply a small pressure dressing to the injection site and consider if a plaster is 
necessary.
14.2
Standard of Care
The dosage necessary to achieve hemostasis depends upon the type and severity of the 
bleeding episode, according to the following general guidelines: (Source: Package Insert 
Kogenate Bayer).  In this protocol, minor surgical procedures are defined as any surgical 
procedure (elective or emergent) that does not involve general anesthesia and/or respiratory 
assistance (eg, minor dental extractions, incision and drainage of abscess, or simple 
excisions). Major surgical procedures are defined as any surgical procedure (elective or 
emergent) that involves general anesthesia and/or respiratory assistance in which a major 
body cavity is penetrated and exposed, or a substantial impairment of physical or 
physiological functions is produced (eg, laparotomy, thoracotomy, craniotomy, fracture).
Degree of hemorrhage/ 
Type of surgical procedure
Factor VIII level 
required (%) (IU/dL)
Frequency of doses (hours)/ 
Duration of therapy (days) 
Hemorrhage
Early hemarthrosis, muscle bleed or 
oral bleed 
20 – 40
Repeat every 12 to 24 hours. At least 1 
day, until the bleeding episode as 
indicated by pain is resolved or healing is 
achieved.

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Degree of hemorrhage/ 
Type of surgical procedure
Factor VIII level 
required (%) (IU/dL)
Frequency of doses (hours)/ 
Duration of therapy (days) 
More extensive hemarthrosis, 
muscle bleed or hematoma
30 – 60
Repeat infusion every 12 – 24 hours for 3 
– 4 days or more until pain and disability 
are resolved.
Life threatening bleeds such as 
intracranial bleed, throat bleed, 
severe abdominal bleed
60 – 100
Repeat infusion every 8 to 24 hours until 
threat is resolved
Surgery
Minor 
including tooth extraction
30 – 60
Every 24 hours, at least 1 day, until 
healing is achieved.
Major 
80 – 100
(pre- and postoperative)
a) By bolus injections
Repeat infusion every 8 – 24 hours until 
adequate wound healing occurs, then 
continue with therapy for at least another 
7 days to maintain a factor VIII activity 
of 30% to 60%
14.3
Healthcare Resources Utilization Questionnaire
The Healthcare Resources Utilization Questionnaire will be used to collect data on the 
subject.  This will include number of days lost from school, medical procedures or 
laboratory tests, complications, and hospitalizations due to hemophilia or other medical 
needs.  The questionnaire should be administered by the investigator or delegate monthly 
throughout the study period by interviewing a parent/caregiver. This can be performed 
either at scheduled study visits, or during regularly scheduled contact between the study site 
and the parent/caregiver. The answers will be entered on the paper questionnaire by the 
study site.  The completed questionnaire is a source document subject to review by the 
monitor.  
Healthcare Resources Utilization Questionnaire in LEO Kids (13400)
Instructions for the interviewer:

Only one parent or caregiver, the person with whom the child relates most closely, should answer the 
questions consistently 

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
Please record the answers in English.  

Please do not write any other information on the form.
Study Center: _________________ Subject number: __________   
Date of interview: ___________________ (MM/DD/YYYY) 
This form is being completed for the month of  _________________________ and year  __________.
For example:   Month of  June and year 2011  (answers include contacts from June 1 to June 30, 2011).
1. Did your son have any contact with health professionals this past month that were not required as part of 
the LEO Kids study? 
_____NO    ____YES
                        If yes, then complete:
Type of contact:  _______Office visit    ______ Phone call   (Check or enter how many if  
more than one.)
Reason for contact:  _________________________________________________________
Whom did your child see? Please check all that apply:
___Hematologist
___Family physician
___Pediatrician
___Nurse
___Pharmacist
___Other, specify:  ___________________________________________________    
2. Did your son have any procedures or tests performed in the past month that were not required as part of the 
LEO Kids study?
______NO   _____YES
If yes, please check all that apply: 
___ Blood test
  Number of times blood was drawn:  ______ (even if multiple tubes were 
collected)
                             ___ Urine test         Number of times specimen collected:  _______
___ Biopsy
  Number of times:  _________
___ X-ray
  Number of times:  _________   (can include multiple views)
___ MRI 
  Number of times:  _________
___ CT scan
  Number of times: _________
___ Joint surgery   Number of times: _________
3.  Did your son have any hospital visits in the past month? 
      ______NO   _____YES
            If yes, check the kind of visit:
            ___Hospital admission.  For how many nights? _____   (Include nights in ICU/PICU)
                          ___Emergency Department visit.  For how many nights? _____
                          ___Intensive Care Unit or Pediatric Intensive Care Unit (ICU or PICU).
                                  For how many nights? ___________
           Reason: ____________________________________________________
4.   Did your son miss any days of school due to hemophilia in the past month?

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       ______NO    _____YES   If yes, number of days missed? ________ (as of Amd 1)
14.4
Blood draws in subjects weighing less than 10 kg (as of Amd 1)
Every effort has been made to minimize the volumes of blood required for participation in 
the study.   For the majority of subjects in the study, the volumes drawn at any one visit are 
not expected to exceed more than 1 % of total blood volume, or 3% in any 1 month interval.  
However, in young infants, Part B of the study may require modification to allow 
participation by infants or small toddlers. (as of Amd 1)
Table 14.4a shows the estimated total blood volume for children 1-10 kg and the 
recommended amount of blood for study purposes.  These volumes (as of Amd 1) should be 
considered a guideline, and may be exceeded if determined to be safe by the investigator.  
Table 14.4a  Recommended Blood Draw Volumes (as of Amd 1)
Body Wt 
(Kg)
Body Wt 
(lbs)
Total blood 
volume (mL)
Allowable volume (mL) in 
one blood draw
( 1% of total blood volume)
Total volume (mL) 
drawn in a 30-day
period (3% of total 
blood volume)
1
2.2
100
1
3
2
4.4
200
2
6
3
6.3
240
2.4
7.2
4
8.8
320
3.2
9.6
5
11
400
4
12
6
13.2
480
4.8
14.4
7
15.4
560
5
16.8
8
17.6
640
6.4
19.2
9
19.8
720
7.2
21.6
10
22
800
8
24
Wt: Body weight/ Ernst, D. J. Applied Phlebotomy. Lippincott Williams & Wilkins. 2005
Table 14.4b shows the blood volumes needed for the tubes used for the central laboratory. 
(as of Amd 1)
Table 14.4b Volume of blood draws in Part B (as of Amd 1)
Visit 1 
Screening
Visit 2
Baseline
Visit 3 
~5 ED
Visit 4
~10 ED
Visit 5 
~15 ED
Visit 6 
20 ED
Interim 
visit
Final 
visit 
50 ED
Volume of 
blood (ml)
4.2
5.3
2.7
2.7
2.7
4.1
0
7.7
7.7
For infants at least 7 kg at study enrollment, the volumes listed for each individual visit 
should be well tolerated.  As the Screening and Baseline visits can be combined for PUPs, 
investigators need to be aware that the total volume required could exceed 1% of total blood 

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volume in children 9 kg or less.  The total volume at the combined Screening and Baseline 
visit may be reduced if the CBC and chemistries are processed through the local laboratory 
using minimal volumes and the results entered in the CRF.  The decision whether to use 
the local laboratory or to divide the blood sampling over more than one draw is at the 
investigator’s discretion, but the total amount of blood drawn should not exceed 3% of total 
blood volume over a 30 day interval. (as of Amd 1)
For infants who are 7 kg and smaller at study entry, the sampling schedule will be modified. 
The sample for collection of HSP-70 antibody (1.2 ml) will not be collected. (as of Amd 1)
FVIII trough level and inhibitor will be measured using a reduced volume (1.8 ml).  
Estimated blood volumes based upon these modifications are shown in table 14.4c. (as of 
Amd 1) 
Table 14.4c   Modified volume of blood in infants less than 7 kg (as of Amd 1)
Visit 1 
Screening
Visit 2
Baseline
Visit 3 
~5 ED
Visit 4
~10 ED
Visit 5 
~15 ED
Visit 6 
20 ED
Interim 
visit
Final 
visit 
50 
ED
Volume of 
blood (ml)
2.4 
4.1
2.7
2.7
2.7
4.1
0
6.5
6.5 (5.2)a
a. (…) Est volume if CBC and chemistries obtained with minimal volumes through local laboratory
For infants less than 7 kg, for whom the Screening and Baseline visits are combined, it is 
recommended that the screening CBC and chemistries be processed through the local 
laboratory using minimal volumes, and the results entered in the CRF.  Capillary samples 
may be used if care is used to minimize the risk of hemolysis.  It is assumed that the 
minimal volume needed for both CBC and chemistries is approximately 1.1 ml. (as of 
Amd 1)
Should an investigator wish to enroll a subject who weighs less than 5 kg, discussion with 
the sponsor is required. (as of Amd 1)
14.5
Laboratory evaluation for suspected inhibitor (as of Amd 1)
If an inhibitor is clinically suspected (a bleed that progresses or does not improve following 
appropriate therapy), the subject be managed according to local standard of care.  The 
investigator should immediately notify the sponsor and obtain the following information 
and blood tests:

time and dose of last infusion

infused product (if other than BAY 81-8973)

blood for central laboratory

pre and post FVIII level/ Activated Partial Thromboplastine Time 
(aPTT)

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
inhibitor to Factor VIII testing by the Nijmegen assay
If inhibitor is confirmed, the subject may receive immune tolerance therapy using BAY 81-
8973.  (See section 6.1.4)
If an inhibitor is detected as part of scheduled testing, the investigator will be notified.  A 
positive inhibitor test is defined with a threshold of ≥ 0.6 BU in the central laboratory. Any 
positive test must be confirmed by a second plasma sample.  Pre and post infusion samples 
will be required for confirmation. (as of Amd 1)