A Phase 3, Single Group Treatment, Open-label, Study to Evaluate the Safety of BAY 94-9027 Infusions for Prophylaxis and Treatment of Bleeding in Previously Treated Children Aged 7 to <12 Years With Severe Hemophilia A
Phase: PHASE3
Conditions: Treatment of Bleeding, Prophylaxis of Bleeding, Hemophilia A, Children
Sponsor: Bayer

 
Document Type: Study protocol 
Official Title: 
A multi-center, pediatric phase III, non-controlled, open-label 
trial to evaluate the safety of BAY 94 9027 for prophylaxis and 
treatment of bleedings in previously Treated Patients aged 7-<12 
years with severe hemophilia A 
NCT Number: 
NCT05147662 
Document Date: 
06-Apr-2023 
 

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Title Page
Protocol Title: 
A Phase 3, single-group treatment, open-label, study to evaluate the safety of BAY 94-9027
infusions for prophylaxis and treatment of bleeding in previously treated children aged 7 to <12 
years with severe hemophilia A
Protocol Number:
21824
Protocol Version:
3.0
Amendment Number:
2
Amendment Scope:
Global
Compound Number:
Damoctocog alfa pegol (Jivi®), BAY 94-9027
Short Title:
A Phase 3 safety study of BAY 94-9027 in children 7 to <12 years 
of age with severe hemophilia A
Study Phase:
3
Acronym:
Alfa-PROTECT
Sponsor Name:
Bayer Consumer Care AG
Legal Registered Address: Bayer Consumer Care AG, Peter-Merian-Strasse 84, 4052 Basel, 
Switzerland
Regulatory Agency Identifier Number(s): EudraCT no.: 2021-004858-30
EU CT no.: 2023-504388-18-00
Protocol Date: 
06 APR 2023
Name:
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
Medical Monitor name and contact information will be provided separately.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of the 
clinical investigation.  Reproduction or disclosure of this document, whether in part or in full, to parties not
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD

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Document History Table 
DOCUMENT HISTORY 
Document 
Version  
Date 
Comments (if applicable) 
Amendment 2 (Global) 
3.0 
06 APR 2023 
 
Amendment 1 (Global) 
2.0 
25 MAY 2022 
 
Clinical Study Protocol 
1.0 
17 SEP 2020 
Version approved by Health 
Authorities 
 

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Protocol Amendment Summary of Changes Table 
Amendment 2 (06 APR 2023) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC and Article 2(2)(13) of the REGULATION (EU) No 536/2014 of the 
European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
Immunogenicity to the PEG moiety in Jivi is age related. Preliminary data from the initial 
patients dosed in this study indicate that when an immune response occurs, it is less severe in this 
age group than that typically observed in younger children 2-5 years of age. This reduced 
immune response has been characterized by low titers of anti-PEG antibodies (1:1 to 1:4) with 
mild to moderate reductions in FVIII recovery during EDs 2-4. Continued dosing with Jivi has 
demonstrated decreased levels of anti-PEG antibodies and improved FVIII recovery.  
The original protocol specifies that local FVIII recovery measurements are performed at the 
clinical site based on the investigator's discretion or when there is suspicion of reduced recovery. 
To better protect study participants against the potential for a bleed related to lower-than-
expected FVIII levels, this amendment recommends routine local FVIII recovery measurements 
be performed at the clinical site for the first 4 EDs. This more standardized approach will enable 
the treating clinician to adjust the dose and dosing interval for the subsequent EDs.  
Section #  
and Name 
Description of Change 
Brief Rationale 
Title Page 
GCL name change 
Updated to reflect current team 
responsibilities 
 
EU CT number added 
Added in compliance with EU CTR 
Document History Table 
Current amendment added 
 
Protocol Amendment 
Summary of Changes Table 
Updated to reflect changes 
implemented in current 
amendment 
 
1.3  Schedule of Activities 
(SoA) 
Laboratory chemistry added 
at Visit 2 
Correction for consistency between SoA 
and rest of protocol 
 
Guidance for FVIII recovery 
added to footnotes 
Age-appropriate frequency of FVIII 
recovery level assessment will reduce the 
potential for bleeds and improve clinician 
management of study drug. 
2.1  Study Rationale 
2.2  Background 
3  Objectives, Endpoints, and 
Estimands 
8.3.8  Adverse Events of 
Special Interest 
Age range for children in 
whom an immune response 
to anti-PEG antibodies in 
the first 4 EDs updated  
Change made for consistency throughout 
the protocol 
2.2  Background 
Description of 
immunogenicity to PEG and 
appropriate assessment of 
FVIII recovery levels in 
study participants added to 
section 
Age-appropriate frequency of FVIII 
recovery level assessment will reduce the 
potential for bleeds and improve clinician 
management of study drug. 
5.5  Criteria for Temporarily 
Delaying Study Intervention 
Condition added  
Delay due to logistical reasons allowed to 
avoid unnecessary rescreening 
procedures 
6.1  Study Intervention(s) 
Administered 
Guidance added regarding 
appropriate dose when 
post-infusion FVIII levels 
are lower than expected 
Reduce the potential for bleeds in 
participants with low titer anti-PEG 
antibodies. 
6.8  Concomitant Therapy 
Clarification added 
regarding emergency 
treatment at home during 
the first 2 weeks of study 
treatment 
Appropriate emergency treatment of 
bleeds that must be managed at home 
without medical supervision. 
8.2.3.1  Decreased Recovery 
Section added  
Specific treatment and laboratory 
evaluations added for participants with 
lower than expected recovery after the 
first exposures 
8.3.8  Adverse Events of 
Special Interest (AESI) 
Examples of Loss of 
Efficacy added 
Clarification added to ensure safe 
management of study participants 
 
FVIII level and FVIII 
inhibitor testing guidance 
Specific guidance only applies to study 
participants that have discontinued study 

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Section #  
and Name 
Description of Change 
Brief Rationale 
updated 
drug. 
10.2  Appendix 2: Clinical 
Laboratory Tests 
Local laboratory testing 
guidance updated 
Must be done as specified in the SoA, not 
just in cases where central laboratory 
results are not available. 
10.6  Appendix 6: Protocol 
Amendment History 
Section added 
Documentation of changes made in prior 
amendments 
 
Minor changes made throughout the document to correct typos, grammar, document headers, etc., 
are not individually summarized. 

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Table of Contents 
 
Title Page ................................................................................................................................... 1 
Document History Table .......................................................................................................... 2 
Protocol Amendment Summary of Changes Table ............................................................... 3 
Table of Contents ..................................................................................................................... 5 
Table of Tables ......................................................................................................................... 7 
1. 
Protocol Summary ............................................................................................................ 8 
1.1 
Synopsis ........................................................................................................................... 8 
1.2 
Schema ............................................................................................................................. 9 
1.3 
Schedule of Activities (SoA) ......................................................................................... 10 
2. 
Introduction ..................................................................................................................... 14 
2.1 
Study Rationale .............................................................................................................. 14 
2.2 
Background .................................................................................................................... 14 
2.3 
Benefit/Risk Assessment ............................................................................................... 15 
2.3.1 
Risk Assessment ......................................................................................................... 15 
2.3.2 
Benefit Assessment .................................................................................................... 17 
2.3.3 
Overall Benefit: Risk Conclusion ............................................................................... 18 
3. 
Objectives, Endpoints, and Estimands .......................................................................... 18 
4. 
Study Design .................................................................................................................... 21 
4.1 
Overall Design ............................................................................................................... 21 
4.2 
Scientific Rationale for Study Design ........................................................................... 21 
4.3 
Justification for Dose ..................................................................................................... 21 
4.4 
End of Study Definition ................................................................................................. 21 
5. 
Study Population ............................................................................................................. 22 
5.1 
Inclusion Criteria ........................................................................................................... 22 
5.2 
Exclusion Criteria .......................................................................................................... 22 
5.3 
Lifestyle Considerations ................................................................................................ 23 
5.4 
Screen Failures ............................................................................................................... 24 
5.5 
Criteria for Temporarily Delaying Study Intervention .................................................. 24 
6. 
Study Intervention(s) and Concomitant Therapy ........................................................ 24 
6.1 
Study Intervention(s) Administered ............................................................................... 24 
6.1.1 
Medical Devices ......................................................................................................... 26 
6.2 
Preparation, Handling, Storage, and Accountability ..................................................... 26 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................... 26 
6.4 
Study Intervention Compliance ..................................................................................... 27 
6.5 
Dose Modification ......................................................................................................... 27 
6.6 
Continued Access to Study Intervention After the End of the Study ............................ 27 
6.7 
Treatment of Overdose .................................................................................................. 27 
6.8 
Concomitant Therapy .................................................................................................... 27 
6.8.1 
Rescue Medicine......................................................................................................... 28 
7. 
Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal
 ........................................................................................................................................... 28 
7.1 
Discontinuation of Study Intervention ........................................................................... 28 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 29 
7.3 
Lost to Follow Up .......................................................................................................... 29 
8. 
Study Assessments and Procedures ............................................................................... 30 
8.1 
Efficacy Assessments .................................................................................................... 30 
8.1.1 
BAY 94-9027 consumption ........................................................................................ 31 
8.1.2 
Recording of Bleeding Episodes ................................................................................ 31 
8.1.3 
Clinical Outcome Assessments .................................................................................. 32 
8.1.3.1 
Hemophilia Specific Quality of Life (Haemo-QoL) Questionnaire ........................ 32 
8.1.3.2 
Patient/Caregiver Global Impression of Severity and Change ................................ 32 
8.2 
Safety Assessments ........................................................................................................ 32 
8.2.1 
Physical Examinations ................................................................................................ 33 
8.2.2 
Vital Signs .................................................................................................................. 33 

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8.2.3 
Clinical Safety Laboratory Tests ................................................................................ 33 
8.2.3.1 
Decreased recovery ................................................................................................. 34 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting .. 34 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information....................... 35 
8.3.2 
Method of Detecting AEs and SAEs .......................................................................... 35 
8.3.3 
Follow Up of AEs and SAEs ...................................................................................... 35 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................................... 36 
8.3.5 
Pregnancy ................................................................................................................... 36 
8.3.6 
Cardiovascular and Death Events ............................................................................... 36 
8.3.7 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs or 
SAEs ........................................................................................................................... 37 
8.3.8 
Adverse Events of Special Interest (AESI) ................................................................ 37 
8.3.8.1 
Clinical guidance for hypersensitivity reactions requiring treatment ..................... 37 
8.3.8.2 
Clinical guidance for loss of efficacy (LoE) ........................................................... 39 
8.3.8.3 
Assessment of Severity of AESI ............................................................................. 39 
8.3.9 
Other Important Events .............................................................................................. 40 
8.3.10 Medical Device Deficiencies ...................................................................................... 41 
8.4 
Pharmacokinetics ........................................................................................................... 41 
8.5 
Genetics ......................................................................................................................... 41 
8.6 
Biomarkers ..................................................................................................................... 41 
8.7 
Immunogenicity Assessments ........................................................................................ 42 
8.8 
Health Economics .......................................................................................................... 42 
9. 
Statistical Considerations ............................................................................................... 42 
9.1 
Statistical Hypotheses .................................................................................................... 42 
9.2 
Analysis Sets .................................................................................................................. 42 
9.3 
Statistical Analyses ........................................................................................................ 43 
9.3.1 
General Considerations............................................................................................... 43 
9.3.2 
Primary Endpoint(s)/Estimand(s) Analysis ................................................................ 43 
9.3.3 
Secondary Endpoint(s)/Estimand(s) Analysis ............................................................ 43 
9.3.3.1 
Analysis of Secondary Endpoints for the Primary Objective ................................. 43 
9.3.3.2 
Analysis of Secondary Endpoints for the Secondary Objective ............................. 44 
9.4 
Interim Analysis ............................................................................................................. 45 
9.5 
Sample Size Determination ........................................................................................... 45 
10. Supporting Documentation and Operational Considerations .................................... 47 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 47 
10.1.1 Regulatory and Ethical Considerations ...................................................................... 47 
10.1.2 Financial Disclosure ................................................................................................... 47 
10.1.3 Informed Consent and Assent Process ....................................................................... 48 
10.1.4 Data Protection ........................................................................................................... 49 
10.1.5 Dissemination of Clinical Study Data ........................................................................ 49 
10.1.6 Data Quality Assurance .............................................................................................. 49 
10.1.7 Source Documents ...................................................................................................... 50 
10.1.8 Study and Site Start and Closure ................................................................................ 50 
10.1.9 Publication Policy ....................................................................................................... 51 
10.2 Appendix 2: Clinical Laboratory Tests .......................................................................... 51 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow up, and Reporting .............................................................................................. 52 
10.3.1 Definition of AE ......................................................................................................... 52 
10.3.2 Definition of SAE ....................................................................................................... 54 
10.3.3 Recording and Follow Up of AE and/or SAE ............................................................ 55 
10.3.4 Reporting of SAEs ...................................................................................................... 56 
10.4 Appendix 4: AEs, SAEs, and Device Deficiencies: Definitions and Procedures for 
Recording, Evaluating, Follow up, and Reporting ........................................................ 57 
10.4.1 Definition of Medical Device AE ............................................................................... 57 
10.4.2 Definition of Medical Device SAE ............................................................................ 58 
10.4.3 Definition of Device Deficiency................................................................................. 59 
10.4.4 Recording and Follow Up of AE/SAE/Device Deficiencies ...................................... 59 
10.4.5 Reporting of AEs/SAEs Related to the Medical Devices........................................... 60 
10.5 Appendix 5: Abbreviations and Definitions .................................................................. 61 
10.5.1 Abbreviations ............................................................................................................. 61 

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10.5.2 Definitions .................................................................................................................. 63 
10.6 Appendix 6: Protocol Amendment History ................................................................... 63 
11. References ........................................................................................................................ 69 
 
Table of Tables 
Table 1–1: Schedule of Activities - main study (Part A) ......................................................... 10 
Table 1–2: Schedule of Activities – extension study (Part B) ................................................. 12 
Table 2–1: Summary of Risk Assessment................................................................................ 16 
Table 6–1: Study Intervention(s) Administered ....................................................................... 24 
Table 10–1: Protocol-required Safety Laboratory Tests .......................................................... 52 
 
 
 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
 
A Phase 3, single-group treatment, open-label, study to evaluate the safety of BAY 94-9027 
infusions for prophylaxis and treatment of bleeding in previously treated children aged 7 to <12 
years with severe hemophilia A. 
Short Title:  
A Phase 3 safety study of BAY 94-9027 in children 7 to <12 years of age with severe hemophilia 
A  
Rationale: 
 
At the time of the initial biologic license application /marketing authorization application 
(BLA/MAA), the indication for BAY 94-9027 was restricted to previously treated hemophilia A 
patients 12 years and older, partly, because of the observation of an immune response to 
polyethylene glycol (PEG) in some children < 6 years, manifested as hypersensitivity and/or loss 
of efficacy (LoE). A significant decrease in the risk of an immune response to PEG was observed 
with an increase in age. Among the 25 previously treated patients, aged 7 to <12 years, in the 
pivotal study in pediatric patients <12 years of age with severe hemophilia A, no such cases were 
observed. However, due to the small sample size, as a safety margin, this age group (7 to <12 
years) was excluded in the initial MAA. This study will address the potential risk of 
hypersensitivity and lack of drug effect associated with anti-PEG antibodies during the first 4 
exposures to BAY 94-9027 in previously treated children 7 to <12 years of age with severe 
hemophilia A, and will provide supportive data for efficacy of prophylaxis treatment including 
long-term safety data.  
Objectives, Endpoints, and/or Estimands: 
Primary and secondary objectives and endpoints are described below. See Section 3 for the full 
list of objectives and endpoints. 
Objectives 
Endpoints 
Primary objective (main study) 
 
Safety 
 
To assess safety and tolerability of  
BAY 94-9027 replacement therapy in previously 
treated patients 7- <12 years of age with severe 
hemophilia A 
 
Primary endpoint  
x AESI (hypersensitivity and LoE*) associated with the 
first 4 EDs leading to discontinuation 
Secondary endpoints 
x Adverse drug reactions (ADRs) 
x Anti-drug antibody (ADA) development 
x Inhibitor development 
Secondary objective (main study and 
extension study) 
 
To describe clinical efficacy of BAY 94-9027 
Secondary endpoints 
x Annualized bleeding rate (ABR)  
x BAY 94-9027 consumption  
x Number of infusions/month and year (Annualized 
Infusion Rate) 
AESI = adverse events of special interest, ED = exposure day 
*  As defined in Section 8.3.8. 
Overall Design 
Short Summary: 
The purpose of this open-label, single-group, uncontrolled, prospective, multicenter study is to 
assess the safety of BAY 94-9027 in children aged 7 to <12 years with severe hemophilia A. 
Study details: 
x The treatment duration will be: 
o Main study (Part A): 6 months and ≥ 50 exposure days (EDs) 
o Extension study (Part B): 18 months  

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x The visit frequency will be twice a week for the first 4 EDs with study intervention, 
with visit frequency decreasing afterwards (see Section 1.3 SoA for details) 
Number of Participants: 
x At least 30 participants will be assigned to study intervention.  
x Additional participants may be enrolled in the event of treatment discontinuation during 
the first 4 EDs of Part A for reasons other than adverse events of special interest (AESI). 
Intervention Groups and Duration: 
x Part A: Each participant will receive BAY 94-9027 intravenously (IV) as prophylactic 
treatment 2x/week, with a dose of 40 IU/kg (up to 60 IU/kg – at the investigator’s 
discretion)  
x Part B: Each participant may continue on prophylaxis dose regimen as prescribed in part 
A (40 – 60 IU/kg, 2x per week) or the prophylaxis regimen may be adjusted to 60 IU/kg 
IV every 5 days at the investigator’s discretion 
Data Monitoring/Other Committee: 
No 
1.2 
Schema 
 
EDs = exposure days 
 

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1.3 
Schedule of Activities (SoA) 
Table 1–1: Schedule of Activities - main study (Part A) 
Period 
SCR 
Treatment 
Visit number 
Exposure day (ED) 
V1 
V2 
ED1 
V3 
ED2 
V4 
ED3 
V5 
ED4 
V6 
V7 
V8 
V9 
V10 
V11 
ED 50 /E.Disc. 
In person (IP) or phone call 
IP 
IP 
IP 
IP 
IP 
IP or a 
IP 
IP 
 
IP 
IP 
Relative time 
W = week, D=day 
Up to - 30 
Days 
D1 
(BSL) 
W1 
W2 
W2 
W4 
W8 
W12  
W16 
W20 
W26 
(Month 6) 
Allowed window 
 
±1 days for all visits from V2 to V5, inclusive  
±3 days for all visits from V6 to V11, inclusive 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination (height and weight) 
X 
 
 
 
 
 
 
X 
 
 
X 
Neurological assessment  
 
X b 
 
 
 
 
 
 
 
 
X 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
 
X c 
X c 
X c 
X c 
 
 
 
 
 
X 
Haemo-QoL questionnaire d 
 
X 
 
 
 
 
 
 
 
 
X 
Patient/Caregiver Global Impression of Severity 
 
X 
 
 
 
 
 
 
 
 
X 
Patient/Caregiver Global Impression of Change 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory assessments (chemistry and hematology) e 
X 
X f 
 
 
 
 
 
 
 
 
X 
PEG quantification 
 
X b 
 
 
 
 
 
 
 
 
X 
Urine / serum biomarkers for renal function  
 
X b 
 
 
 
 
 
 
 
 
X 
Immunogenicity (FVIII inhibitor, ADA) – pre-infusion g,h 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
FVIII levels g if no prior result available (Section 5.1) 
X 
 
 
 
 
 
 
 
 
 
 
Recovery (pre and 15-30 min post-infusion FVIII 
levels) g,h,i 
 
X 
X 
X 
X 
 
 
 
 
 
X 

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Table 1–1: Schedule of Activities - main study (Part A) 
Period 
SCR 
Treatment 
Visit number 
Exposure day (ED) 
V1 
V2 
ED1 
V3 
ED2 
V4 
ED3 
V5 
ED4 
V6 
V7 
V8 
V9 
V10 
V11 
ED 50 /E.Disc. 
In person (IP) or phone call 
IP 
IP 
IP 
IP 
IP 
IP or a 
IP 
IP 
 
IP 
IP 
Relative time 
W = week, D=day 
Up to - 30 
Days 
D1 
(BSL) 
W1 
W2 
W2 
W4 
W8 
W12  
W16 
W20 
W26 
(Month 6) 
Allowed window 
 
±1 days for all visits from V2 to V5, inclusive  
±3 days for all visits from V6 to V11, inclusive 
In-hospital infusion of BAY 94-9027 
 
X 
X 
X 
X 
 
 
 
 
 
X j 
AE review 
X k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study intervention l 
 
 
 
 
X 
 
X 
X 
X 
X 
(X) m 
Return used /unused study intervention 
 
 
 
 
 
 
X 
X 
 
X 
X 
Diary review n 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA = anti-drug antibodies (anti-PEG, anti-PEG IgM in all treated study participants; IgE only in study participants who experience a hypersensitivity reaction) ED = exposure 
days, BSL = baseline, E.Disc. = early discontinuation, FVIII = factor VIII, IP = in-person visit, QoL = Quality of Life, SCR = screening, V = visit,  
a: At the investigator’s discretion based on participant’s condition. 
b: May be performed at a visit other than baseline if the participant is already enrolled at the time Amendment 1 is implemented, PEG quantification and urine/serum 
biomarkers must be performed before infusion at the scheduled visit. 
c: Vital signs to be taken before and after infusion. 
d:  QoL questionnaire: Haemo-QoL Kids Short Form (8-16 years old version).  
e:  See Section 10.2 for details on laboratory parameters. 
f:  Only chemistry collected at Visit 2 
g: FVIII level and FVIII inhibitor tests must be done after a sufficient wash-out period depending on the participant’s previous FVIII product – at least 48 hours or 72 hours for 
standard half-life (SHL) and extended half-life (EHL) FVIII products respectively (screening and baseline visits). 
h:  FVIII inhibitor tests and pre-infusion FVIII levels for recovery must be done after a wash-out period of at least 72 hours after previous dose of study intervention (V3, V4, 
V5, V7, and V11/E.Disc.). If a 72-hour wash-out period is not possible (e.g. participant received previous infusion within 48 hours), no restriction is needed during the first 4 
EDs or at any visits for monitoring of ADA.  In this scenario, recovery should also be measured without wash-out.  
In case of early discontinuation, recovery is not required.  
i:  Local FVIII levels should be obtained to guide treatment for the next dose during the first 4 EDs.  
j: 
In-hospital infusion will not be performed at early discontinuation visits for adverse events of special interest (hypersensitivity or loss of efficacy) or other reasons. 
k:  Only study procedure related AEs. 
l:  Unscheduled visits are permitted at any time at the discretion of the investigator. In addition, participants may visit the study center for study intervention and supplies. 
m:  Drug dispensing for extension study (Part B). 
n:  Dispense diary at V2. 
 

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Table 1–2: Schedule of Activities – extension study (Part B) 
Extension visit number 
EV1–EV2 
EV3 
EV4–EV5 
EV6  
EV 7–EV 11 
EV 12 
EV 13–EV 17 
EV 18 / E. 
Disc. 
Follow-upa 
In person (IP) or phone call 
 
IP 
 
IP 
 
IP 
 
IP 
 
Month  
and allowed window 
Months 7-8b 
± 1week 
Month 9 
± 1week 
Months 10-11b 
± 1week 
Month 12 
± 1week  
Months 13-17b 
± 1week 
Month 18 
± 1week  
Months 19-23b 
± 1week 
Month 24 
± 1week  
7 to 14 days after 
EV18 / E. Disc. 
Physical examination (height and 
weight) 
 
X 
 
X 
 
X 
 
X 
 
Neurological assessment 
 
 
 
 
 
 
 
X 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
 
 
X 
 
X 
 
X 
 
Immunogenicity (FVIII inhibitor, ADA) c 
 
 
 
X 
 
X 
 
X 
 
Recovery (pre and 15-30 min post-
infusion FVIII levels) c 
 
 
 
X 
 
X 
 
X 
 
In-hospital infusion of BAY 94-9027 
 
 
 
X 
 
X 
 
X d 
 
AE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Return used/ unused study intervention 
 
X  
 
X 
 
X 
 
X 
 
Dispense study intervention e 
Intervention dispensed according to IxRS specification 
 
Diary review  
X 
X 
X 
X 
X 
X 
X 
X 
 
Haemo-QoL questionnaire f 
 
 
 
X 
 
X 
 
X 
 
Patient/Caregiver questionnaires g 
 
 
 
X 
 
X 
 
X 
 
Laboratory assessments (chemistry 
and hematology) h 
 
 
 
 
 
 
 
X 
 
PEG quantification 
 
 
 
 
 
 
 
X 
 
Urine/serum biomarkers for renal 
function  
 
 
 
 
 
 
 
X 
 
ADA = anti-drug antibodies (anti-PEG, anti-PEG IgM in all treated study participants; IgE only in study participants who experience a hypersensitivity reaction), ED = exposure 
days, E.Disc. = early discontinuation, EV = extension visit, FVIII = factor VIII, IP = in-person visit  
a: Follow-up call for early discontinuation in Part A and Part B. 
b: One phone call per month for all months included in this window of time. 
c: FVIII inhibitor tests and pre-infusion FVIII levels for recovery must be done after a wash-out period of at least 72 hours after previous dose of study intervention 
(EV6/E.Disc.). 

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Table 1–2: Schedule of Activities – extension study (Part B) 
Extension visit number 
EV1–EV2 
EV3 
EV4–EV5 
EV6  
EV 7–EV 11 
EV 12 
EV 13–EV 17 
EV 18 / E. 
Disc. 
Follow-upa 
In person (IP) or phone call 
 
IP 
 
IP 
 
IP 
 
IP 
 
Month  
and allowed window 
Months 7-8b 
± 1week 
Month 9 
± 1week 
Months 10-11b 
± 1week 
Month 12 
± 1week  
Months 13-17b 
± 1week 
Month 18 
± 1week  
Months 19-23b 
± 1week 
Month 24 
± 1week  
7 to 14 days after 
EV18 / E. Disc. 
d: In-hospital infusion not performed at early discontinuation visits for adverse events of special interest (hypersensitivity or loss of efficacy) or other reasons. 
e: Unscheduled visits are permitted at any time at the discretion of the investigator. In addition, participants may visit the study center for study intervention and supplies. 
f: QoL questionnaire-: Haemo-QoL Kids Short Form (8-16 years old version). 
g: Patient/Caregiver Global Impression of Severity and Patient/Caregiver Global Impression of Change. 
h: See Section 10.2 for details on laboratory parameters. 

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2. 
Introduction 
2.1 
Study Rationale 
At the time of the initial biologic license application /marketing authorization application 
(BLA/MAA), BAY 94-9027 has received marketing authorization for treatment and 
prophylaxis of bleeding in previously treated patients (PTPs) ≥ 12 years of age with 
hemophilia A.  
The indication for BAY 94-9027 (Jivi) was restricted to previously treated hemophilia A 
patients 12 years and older, partly because of the observation of an immune response to PEG 
in some children < 6 years, manifested as hypersensitivity and/or loss of efficacy (LoE) (JIVI 
SmPC 2018, JIVI® Prescribing information 2018). The immune response associated with 
anti-PEG IgM antibodies was observed within the first 4 EDs in some children 2-5 years of 
age leading to study discontinuation in all cases. Clinical symptoms were mild to moderate 
acute hypersensitivity and/or LoE. All patients could revert back to their previous factor VIII 
treatment. 
A significant decrease in the risk of an immune response to PEG was observed with an 
increase in age. Among the 25 PTPs, aged 7 to <12 years, in the pivotal study in pediatric 
patients < 12 years of age with severe hemophilia A, no such cases were observed. However, 
due to the small sample size, as a safety margin, this age group (7 to <12 years) was excluded 
in the initial BLA/MAA.  
This study addresses the uncertainty of the risk of potential hypersensitivity and lack of drug 
effects associated with anti-PEG antibodies during the first 4 exposures to BAY 94-9027 in 
previously treated children with severe hemophilia A, 7 to <12 years of age. In addition, will 
provide supportive data for efficacy of prophylaxis treatment and long-term safety data.  
2.2 
Background 
BAY 94-9027 is a recombinant FVIII (rFVIII) with extended half-life through reduced 
clearance from plasma by PEGylation while retaining the normal activity of the FVIII 
molecule. It has received marketing authorization for treatment and prophylaxis of bleeding 
(including perioperative management) in PTPs ≥ 12 years of age with hemophilia A 
(congenital FVIII deficiency) (JIVI SmPC 2018, JIVI® Prescribing information 2018). 
Pharmacokinetics, clinical efficacy and safety of BAY 94-9027 for treatment of bleeds and 
prophylaxis in hemophilia A have been assessed in one Phase 1 study and two Phase 3 studies 
including previously treated severe hemophilia A patients 2 to 65 years of age (Coyle et al. 
2014, Reding et al. 2017, Santagostino et al. 2020).  
Pharmacokinetics, safety, and efficacy of BAY 94-9027 in pediatric patients <12 years of age 
were assessed in the PROTECT Kids study (study 15912; NCT01775618), a Phase 3 
multicenter, open-label, noncontrolled study to assess BAY 94-9027 treatment for prophylaxis 
and treatment of bleeds in previously treated children (>50 ED) with severe hemophilia A. 
The study comprised a main study (in PTPs <12 years of age), Part 2 (in PTPs 2-5 years of 
age) and the extension study, and included a total of 73 patients, 44 in the age group < 6 years 
and 29 in the age group 6 to <12 years. The median total study duration was 5.4 years (N=73). 
Efficacy of prophylaxis treatment and treatment of bleeds was demonstrated for both age 
groups (Santagostino et al. 2020). The geometric mean terminal half-life (t½) for 

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BAY 94-9027 was 14.5 hours and 15.6 hours in patients aged <6 years ( n = 14 ) and 6 to <12 
years (n = 13), respectively (Shah et al. 2018).  
No subjects developed inhibitory antibodies to FVIII (≥0.6 BU/mL) during the study. A 
clinical immune response associated with anti-PEG IgM antibodies, manifested as symptoms 
of acute hypersensitivity and/or LoE (AESI) was observed within the first 4 EDs in young 
children 2-5 years of age leading to study discontinuation in all cases (Santagostino et al. 
2020). In cases of clinical immune response associated with anti-PEG IgM antibodies 
presenting with hypersensitivity reactions, these reactions were observed within 30 minutes of 
completion of study drug administration, and resolved within 30 minutes of occurrence 
without intervention. In all cases, clinical efficacy and recovery using the previous FVIII 
product was not impaired in the subjects affected. There was no immunoglobulin class switch 
to IgG, and the IgM titers disappeared over time suggesting no long-term memory response 
(Santagostino et al. 2020). No participant aged 7 to <12 years old (n = 25) experienced an 
AESI (hypersensitivity and/or LoE). A significant decrease in the risk of an immune response 
to PEG was observed with an increase in age. Thus, the clinical immune response associated 
with anti-PEG IgM antibodies, may be related to a developmental change in immunity, and 
although it is difficult to define a clear cut-off age for the change in risk, this phenomenon 
predominantly occurred in young children (2-5 years of age) with hemophilia A.  
Immunogenicity to the PEG moiety in Jivi appears to be age related, as it is suggested by 
preliminary data from the initial patients dosed in this study. More specifically, this early data 
suggests  that when an immune response occurs, it is less severe in this age group than that 
typically observed in younger children 2-5 years of age. This reduced immune response has 
been characterized by low titers of anti-PEG antibodies (1:1 to 1:4) with mild to moderate 
reductions in FVIII recovery during EDs 2-4. Continued dosing with Jivi has demonstrated 
decreased levels of anti-PEG antibodies and improved FVIII recovery. To better protect study 
participants against the potential for a bleed related to lower-than-expected FVIII levels, 
routine local FVIII recovery measurements should be performed at the clinical site for the 
first 4 EDs to evaluate the response to treatment in addition to performing FVIII recovery at 
the central lab. This standardized approach will enable the treating clinician to adjust the dose 
and dosing interval for the subsequent EDs.  
2.3 
Benefit/Risk Assessment 
Relevant emerging safety data, e.g., serious adverse events (SAEs), suspected unexpected 
serious adverse reactions (SUSARs), and serious safety-related protocol deviations, will be 
communicated as soon as possible between the sponsor, all study sites and investigators and 
trial participants/parents/caregivers.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of BAY 94-9027 may be found in the Investigator’s Brochure (IB). 
2.3.1 
Risk Assessment 
Due to the substantial experience with pegylated FVIII replacement products, the risks are 
well established. The most relevant treatment related complication for class of FVIII 
replacement products, is the development of FVIII inhibitors. For previously untreated 
patients (PUPs), the risk to develop inhibitors is considered very common (approximately 
30% to 50%) (Franchini et al. 2013, Peyvandi et al. 2016, Srivastava et al. 2020), whereas the 
risk for PTPs is considered uncommon (<1%). No confirmed case of inhibitor development 
was reported during the development program with BAY 94-9027 in PTPs.  

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Other known risks for class of FVIII replacement products are allergic type of 
hypersensitivity reactions which may progress to anaphylaxis including shock, cardiovascular 
events, and the possibility of catheter related complications. Data of more than 200 patients in 
the age range of 2 to 62 years demonstrated that these risks are not different for BAY 94-9027 
administered to PTPs. No case of anaphylaxis was reported, and no serious cardiovascular 
event was observed. 
A new risk identified during the development program for BAY 94-9027 is an immune 
response to PEG which resulted in LoE, observed as bruising or bleeding not responsive to 
treatment with BAY 94-9027 and very low recovery (sometimes undetectable) following 
infusion of BAY 94-9027 in the absence of FVIII inhibitors. LoE was accompanied by 
hypersensitivity reactions in some patients. This risk was most frequent in the age group less 
than 6 years and resulted in a premature termination of study treatment in approximately 23% 
(10/44) of cases in this age group. There were no cases of PEG immune response among the 
25 patients, aged 7 to <12 years, and only 1/134 patients ≥12 years had a PEG-related 
hypersensitivity reaction leading to study discontinuation. During post-marketing surveillance 
(PMS) with >1,000 new patients starts, the incidence of clinical events likely associated with 
antibodies to the PEG moiety has been consistent with that observed in the clinical trials for 
patients ≥12 years of age. All events have occurred on EDs 2-4.  
A potential class risk for pegylated FVIII replacement products is associated with PEG 
accumulation following long-term treatment. The dose of PEG contained with BAY 94-9027 
is low relative to other pegylated products (e.g., certolizumab pegol) resulting in a low total 
weekly and monthly PEG exposure below the level of concern in the pediatric population of 
0.4μmol-kg-month of PEG (EMA 2012). In distribution and excretion studies in rats, the 60 
kDa PEG moiety of Jivi® was shown to be eliminated from organs and tissues, and excreted 
in urine and feces (Baumann et al. 2019). 
In a long-term, 6-months chronic toxicity study in immunodeficient rats no indication of PEG 
accumulation or other effects related to administration of Jivi® were seen. ((JIVI SmPC 
2018), Section 5.3 ).  
In addition, no evidence for accumulation of PEG in plasma (median levels < 0.1 mg/L) nor 
in other organs such as kidneys, liver, and central nervous system was demonstrated for up to 
7 years of continuous treatment in the clinical extension studies of Jivi® in children and 
adults (PTPs 2 - 62 years of age) (Mancuso et al. , Reding et al. 2021).   
Blood samples will be collected at screening to confirm study eligibility, and during 
scheduled study visits as part of safety assessment for the study. The frequency of these 
assessments is likely more than is typical for standard of care. The study has kept the 
frequency of these assessments to the minimum required to reliably assess the safety of BAY 
94-9027 in study participants. For the majority of participants 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. Therefore, it is expected that the risk associated with blood draws is not 
more than would be expected with standard of care. 
Table 2–1: Summary of Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
 
Study Intervention  
Development of FVIII 
inhibitors  
 
The formation of neutralizing 
antibodies (inhibitors) to FVIII is a 
known and listed AE for FVIII 
Participants will be tested for FVIII 
inhibitors.  

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Table 2–1: Summary of Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
 
 
 
products. No confirmed case of 
FVIII inhibitor development was 
reported during the development 
program with BAY 94-9027 
x 
Inhibitor titer is assessed at 
scheduled study visits. 
x 
Planned time points for all safety 
assessments are provided in the 
SoA (Section 1.3). 
 
The informed consent will outline the 
important identified and potential risks. 
Anti-drug antibodies to 
PEG leading to 
hypersensitivity reaction 
and LoE  
Hypersensitivity and LoE have been 
reported in previous clinical studies 
with BAY 94-9027, mainly in 
children <6 years, during the first 4 
EDs. This was not observed in 
children in the age group 7-<12 
years.  
The first 4 doses of study intervention will 
be administered in the hospital under 
medical supervision, so that if a 
hypersensitivity reaction occurs, it can be 
adequately managed. 
  
Pre- and post-infusion FVIII levels will be 
measured intermittently as per SoA during 
the main study.  
 
Reporting these AEs as AESIs (Section 
8.2.3.1 and Section 8.3.8) 
 
Inclusion of stopping rule for study 
intervention administration in study protocol 
(Section 10.1.8) 
 
The informed consent will outline the 
important identified and potential risks. 
Hypersensitivity reaction 
in the absence of 
development of anti-PEG 
antibodies 
Hypersensitivity reaction to 
exogenously administered FVIII is a 
known and listed AE for FVIII 
products and have occurred with 
BAY 94-9027. In completed clinical 
studies with BAY 94-9027, one 6-
year-old patient developed 
hypersensitivity reaction in 
association with the first 
administration of BAY 94-9027 
The first 4 doses of study intervention will 
be administered in the hospital under 
medical supervision, so that if a 
hypersensitivity reaction occurs, it can be 
adequately managed. 
 
The informed consent will 
outline the important identified and potential 
risks. 
Study Procedures 
Pain and bleeding during 
blood draws 
Blood draws are standard 
procedures for assessment of 
safety  
Study procedures will be conducted at 
specialized hemophilia treatment centers 
by trained personnel. 
2.3.2 
Benefit Assessment 
Hemophilia A is an X-linked, congenital, potentially life-threatening disease that is caused by 
a deficiency of FVIII and results in impaired blood clotting. Patients with hemophilia A 
require infusions of replacement FVIII to prevent and treat spontaneous and trauma-related 
bleeding episodes.  
BAY 94-9027 is an extended half-life, recombinant FVIII (rFVIII) product approved for the 
prevention and treatment of bleeding episodes (including perioperative management) in PTPs 
≥12 years of age with hemophilia A. Efficacy of BAY 94-9027 for treatment of bleeds and 
prophylaxis in hemophilia A was demonstrated in two Phase 3 studies including previously 
treated severe hemophilia A patients 2 to 65 years of age (Reding et al. 2017, Santagostino et 
al. 2020). The potential benefits of the study intervention to participants are less frequent 
dosing and less reliance on central venous catheters, which may reduce physical and 

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emotional burden for the child and his family, leading to better adherence. This, in turn, may 
translate into improved FVIII activity coverage and good prophylactic protection from bleeds.  
2.3.3 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with BAY 94-9027 are justified by the anticipated 
benefits of prophylaxis treatment with BAY 94-9027 that may be afforded to study 
participants. 
3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary objective (main study) 
 
Safety 
 
To assess safety and tolerability of  
BAY 94-9027 replacement therapy in 
previously treated patients 7- <12 years of 
age with severe hemophilia A 
 
Primary endpoint  
x AESI (hypersensitivity and LoE*) associated with the first 
4 EDs leading to discontinuation 
 
Secondary endpoints 
x Adverse drug reactions (ADRs) 
x Anti-drug antibody (ADA) development 
x Inhibitor development 
Secondary objective (main study and 
extension study) 
 
To describe clinical efficacy of BAY 94-9027 
Secondary endpoints 
x Annualized bleeding rate (ABR)  
x BAY 94-9027 consumption  
x Number of infusions/month and year (Annualized Infusion 
Rate) 
Other 
 
To further investigate long-term safety 
x Quantitative PEG measurement  
x Renal safety-related urine and serum biomarkers 
x Liver enzymes  
x Neurological assessment 
To assess the impact of BAY 94-9027 in 
Health-related QoL   
Patient-reported outcomes (PROs) questionnaires 
To further investigate the study intervention 
and similar drugs (e.g., mode-of-action-
related effects, safety) and to further 
investigate pathomechanisms deemed 
relevant to hemophilia and associated 
health problems 
Various biomarkers (e.g., diagnostic, safety, 
pharmacodynamic, monitoring, or potentially predictive 
biomarkers) 
AESI = adverse events of special interest, ED = exposure day 
*  As defined in Section 8.3.8. 
 
Primary estimand 
The primary clinical question of interest for the primary objective is: 
What is the proportion of individuals with AESIs (hypersensitivity and LoE) associated with 
the first 4 EDs of BAY 94-9027 treatment and leading to discontinuation of BAY 94-9027 
treatment in previously treated males, 7 to <12 years of age with severe hemophilia A, and 

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without inhibitors to FVIII, who do not discontinue study for other reason than an AESI 
before the fourth ED with or without emergency use of other FVIII medication? 
The estimand is described by the following attributes: 
Population 
Previously treated (≥50 EDs) male individuals, 7 to <12 years of age, with 
severe hemophilia A (FVIII:C <1%) without inhibitors to FVIII (<0.6 BU/mL). 
Endpoint 
AESI (i.e., hypersensitivity or LoE, as defined in Section 8.3.8) associated with 
the first 4 EDs of BAY 94-9027 treatment leading to discontinuation. 
Treatment 
condition 
2x/week BAY 94-9027 prophylactic treatment at a dosage of 40 IU/kg, up to 60 
IU/kg, with or without emergency use of other FVIII products (treatment policy 
strategy*). 
Intercurrent 
events and 
strategies how 
to address 
them 
x 
Individuals with the intercurrent event ’treatment discontinuation for any 
reason other than AESI before the fourth ED’ will not be included in the 
assessment of the primary endpoint (principal stratum strategy*).  
x 
The intercurrent event ‘emergency use of other FVIII products’ is addressed 
by the treatment condition attribute following the treatment policy strategy* .  
Other relevant intercurrent events are not anticipated at this point in time. 
Population 
level summary 
Proportion of individuals who experience a primary endpoint AESI. 
*: Treatment policy strategy, and principal stratum strategy refer to the strategies for addressing intercurrent 
events as described in the ICH E9 (R1) guideline 
Rationale for estimand:  
In the pivotal Phase 3 studies PROTECT VIII and PROTECT Kids, an immune response 
associated with anti-PEG IgM antibodies was observed primarily in children 2-5 years of age. 
The immune response manifested as symptoms of hypersensitivity and/or LoE. All events 
occurred during the first 4 EDs of BAY 94-9027 and all led to study discontinuation. The 
primary estimand has been chosen to estimate the unknown risk of such events in previously 
treated children, 7 to <12 years of age, with severe hemophilia A. Since these events might 
occur up to the fourth ED, event-free children discontinuing before the fourth ED is reached 
do not provide sufficient information and will be excluded from the population of interest. 
Use of other FVIII products is not expected but might happen in emergency cases. Exposure 
to another FVIII medication is not considered an ED in terms of the primary endpoint. Four 
EDs with BAY 94-9027 are needed for the assessment. All AESIs associated with the first 4 
BAY 94-9027 treatments will be counted regardless of other FVIII exposure. 
Secondary estimand 
The key clinical question of interest for the secondary objective is: 
What is the ABR of previously treated males 7 to <12 years of age with severe hemophilia A 
without inhibitors to FVIII, or neutralizing ADA, who are on a continuous prophylaxis 
treatment with BAY 94-9027 for at least 3 months up to time when at least 50 EDs are 
reached (approximately 6 months) and for further 6 months by and across treatment regimens 
without major surgery and regardless of emergency use of other FVIII medication?  

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The estimand is described by the following attributes: 
Population 
Previously treated (≥50 EDs) male individuals, 7 to <12 years of age, with 
severe hemophilia A (FVIII:C <1%) without inhibitors to FVIII (<0.6 BU/mL). 
Endpoint 
Number of bleeds per individual observation period of continuous prophylactic 
treatment (overall and per treatment regimen) of at least 3 months up to time 
when at least 50 EDs are reached (approximately 6 months) and for further 18 
months of BAY 94-9027 treatment. [In this study, the 6- and 2- year periods are 
reflected by Part A and Part B of the study.] 
Treatment 
condition 
2x/week prophylactic treatment with BAY 94-9027 at a dosage of 40 IU/kg, up to 
60 IU/kg, with option to change to every 5 days prophylactic treatment with BAY 
94-9027 at a dosage of 60 IU/kg IV, after at least 50 EDs (with start of Part B) 
with or without emergency use of other FVIII medication (treatment policy 
strategy*). 
Intercurrent 
events and 
strategies how 
to address 
them 
x 
The intercurrent events ‘treatment discontinuation for any reason before 
Month 3’ and ‘development of an inhibitory antibody to FVIII or ADA that 
neutralizes activity sufficiently to interfere with effective treatment’ will be 
addressed by the endpoint attribute following the principal stratum strategy*.  
x 
The intercurrent events ‘treatment discontinuation for any reason after 
Month 3’ and ‘emergency use of other FVIII medication’ will be addressed 
by the treatment policy strategy*. 
x 
The intercurrent event ‘emergency major surgery’ is addressed by the 
endpoint attribute following the hypothetical strategy*. The time of the 
surgery will not be considered for the observation period and bleeds during 
the time of the surgery (i.e., bleeds related to the surgery procedure) will not 
be counted. An individual with this intercurrent event will be analyzed as if 
the surgery had not happened. 
Other relevant intercurrent events are not anticipated at this point in time. 
Population 
level summary 
Mean and 95% confidence interval for ABR estimated by a Negative Binomial 
regression. 
*: Treatment policy strategy, principal stratum strategy, and hypothetical strategy refer to the strategies for 
addressing intercurrent events as described in the ICH E9 (R1) guideline 
Rationale for estimand:  
Efficacy is assessed by the number of bleeds per year. The ABR during continuous 
prophylaxis treatment with BAY 94-9027 is of clinical interest in this study. An observation 
period shorter than 3 months does not constitute a stable prophylaxis treatment and does not 
allow a reliable evaluation of annualized bleeding rates. Individuals who develop a FVIII 
inhibitor or an ADA that neutralizes activity of BAY 94-9027 sufficiently to interfere with 
effective treatment require other treatment modalities and are therefore excluded from the 
population of interest. An emergency major surgery is a short-term event that requires specific 
treatment and leads to surgery-specific bleeding episodes. While the surgery period does not 
contribute to the ABR of prophylaxis treatment, the non-surgery related bleeds and treatment 
period can and will be evaluated. Bleeds treated with another FVIII product in an emergency 
case will be counted for the ABR as they occurred during prophylaxis treatment with 
BAY 94-9027. 

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4. 
Study Design 
4.1 
Overall Design 
This is an open-label, single-group, uncontrolled, prospective, multicenter study.  
It comprises of the main study (Part A) and the extension study (Part B).  
Part A will last for 6 months and at least 50 EDs. Extension study (Part B) will last 18 
months. 
For detailed visit schedule, refer to Section 1.3. Treatment administration is described in 
Section 6. 
4.2 
Scientific Rationale for Study Design 
The study design is similar to that of the previous study with the study intervention in 
pediatric patients (PROTECT Kids study) in order to allow for pooling of data. Although, the 
safety events under evaluation had only been observed in the young age group < 6 years in the 
previous study, this study will closely monitor safety during the first 4 ED by laboratory and 
clinical parameters in order to assess the occurrence of the AESI in the age group 7 to <12 
years. The additional 30 participants will provide a pooled sample size of 55 participants in 
the proposed age group. 
4.3 
Justification for Dose 
40 IU/kg IV was the mean prophylaxis dose and 60 IU/kg IV was the upper dose range during 
the PROTECT Kids study. During the extension study, participants may also be treated with 
60 IU/kg IV every 5 days which was also an effective dose used in the PROTECT Kids study.  
4.4 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. 
A participant is considered to have completed the study if he has completed all periods of the 
study including the last visit. 
Primary completion date is the date when the last participant completes Month 6 visit (or 
discontinues early). 

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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 7 to <12 years of age at the time of parent / legal guardian signing 
the informed consent  
Type of participant and disease characteristics 
2. Participants with known medical history of severe hemophilia A (participant’s own 
FVIII activity [FVIII:C] <1%. FVIII:C) based on reliable prior documentation in 
clinical records of the participants. If no reliable documentation is available, FVIII 
activity must be measured at the time of screening after a 48-72 hours wash-out period 
(depending on his previous product). 
Sex 
3. Male 
Treatment 
4. Participants must be previously treated with FVIII concentrate(s) (plasma derived or 
recombinant) for a minimum of 50 EDs at the time of signing the informed consent.  
Informed consent and Assent 
5. Participant has understood the study and if appropriate for his age, has signed an 
informed assent. The parent(s) or guardian(s) is capable of giving signed informed 
consent as described in Section 10.1.3 which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
6. Willingness and ability of participants and/or parents /caregivers to complete training 
in the use of the electronic patient diary (EPD) and to document infusions during the 
study.   
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. History of FVIII inhibitors. Inhibitor to FVIII is defined as a titer >0.6 BU/mL 
(Nijmegen-modified Bethesda assay) or clinical history suggestive of inhibitor 
requiring modification of treatment. Participants with a maximum historical titer of 
<1.0 BU/mL on no more than 1 occasion with the classical Bethesda assay but at least 
3 subsequent negative results [<0.6 BU/mL] are eligible.  
2. Current evidence of inhibitor to FVIII measured using the Nijmegen-modified 
Bethesda assay (>0.6 BU/mL) at the time of screening (central laboratory).  
Participants should not receive FVIII within at least 48 hours prior to the collection of 

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screening samples (See Section 1.3) and should have FVIII administered within the 
prior 2-3 weeks 
3. Any other inherited or acquired bleeding disorder in addition to hemophilia A 
(e.g., von Willebrand disease, hemophilia B)  
4. Platelet count <100,000 cells/μL 
5. Serum creatinine > 2x upper limit of normal 
6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5x upper limit 
of normal  
7. Known hypersensitivity or allergic reaction to drug substance, excipients or mouse or 
hamster protein 
8. Any other significant medical condition that the investigator feels would be a risk to 
the participant or would impede the study 
Prior/concomitant therapy 
9. Requires any pre-medication to tolerate FVIII treatment (e.g., antihistamines) 
10. Planned major surgery during the study  
11. Any individual who is currently receiving or received chemotherapy, immune 
modulatory drugs,  or has /had chronic use of oral or intravenous (IV) corticosteroids 
(> 14 days) within the last 3 months, other than anti-viral therapy 
12. Any individual who received commercially available subcutaneous factor substitution 
therapy (emicizumab) within the last 6 months  
Prior/concurrent clinical study experience 
13. The participant is currently participating in another investigational drug study or has 
participated in a clinical study involving an investigational drug within 30 days of 
study entry or previous participation in a clinical study with BAY 94-9027. 
Other exclusions 
14. Close affiliation with the investigational site; e.g., a close relative of the investigator, 
dependent person  
15. Otherwise vulnerable participants other than being a child 
16. The participant is identified by the investigator as being unable or unwilling to 
perform study procedures 
5.3 
Lifestyle Considerations 
Not applicable. 

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5.4
Screen Failures
A screen failure occurs when a participant or his legal guardian consents to participate in the 
clinical study but are not subsequently entered in the treatment phase of the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, and eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants should be assigned a new participant number.
5.5
Criteria for Temporarily Delaying Study Intervention
The following conditions may allow a participant to start the study intervention once the 
conditions have resolved and the participant is otherwise eligible:
x
Current febrile illness (temperature 38.0oC [100.4o F]) or other acute illness within 
48 hours before the first study intervention administration at baseline visit. If such 
an intercurrent acute event occurs, the screening period can be prolonged by 2 
weeks without a need to repeat the screening assessment.
x
Occurrence of a bleed within the required wash-out period for the baseline visit. If 
such an intercurrent acute event occurs, the screening period can be prolonged by 2 
weeks without a need to repeat the screening assessment. This is only allowed once. 
x
Participant is otherwise eligible and his condition is medically stable, but the 
baseline visit did not occur for logistical reasons (eg, study intervention not 
available at site). In this instance, the screening period may be prolonged by
additional 4 weeks without a need to repeat the screening assessment.  This is only 
allowed once.
6.
Study Intervention(s) and Concomitant Therapy
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
Table 6–1: Study Intervention(s) Administered
Intervention Name
Damoctocog alfa pegol
Dosage (For
Prophylaxis)
Main study (Part A): 40 IU/kg (up to 60 IU/kg at the investigator’s discretion), 2 times 
per week (2x/week) with the first 4 infusions under medical supervision. Thereafter, 
participants will continue their treatment as home treatment.
Dose may be increased up to 60 IU/kg (rounded up to full vials) if needed at any time 
during the study at the investigator’s discretion. Potential reasons for a higher dose 
are e.g., presence of target joints, known short half-life of previous FVIII, high physical 
activity level, individual need for high trough FVIII levels. 
Post-infusion FVIII levels may be lower than expected after the first exposures (e.g., 
recovery of <1.2 kg/dL) and may be related to low titer anti-PEG antibodies. 
 
CCI

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Table 6–1: Study Intervention(s) Administered  
Extension study (Part B):  Each participant may continue on prophylaxis dose 
regimen as prescribed in part A (40 – 60 IU/kg, 2x per week) or adjustments to 
prophylaxis dose / dose frequency can be made at the investigator’s discretion (based 
on the bleeding events and individual needs): 
- 
Dose may be increased to 60 IU/kg (rounded to full vials) 
- 
Dose frequency may be decreased to every 5 days (prophylaxis dose: 60 IU/kg 
rounded to full vials) 
Prescribed doses for prophylaxis infusions higher than approximately 60 IU/kg 
(including rounding to full vials) have not been studied and therefore are not 
recommended. Rounding to full vials could result in up to 75 IU/kg for some low body 
weights. This is acceptable in children. The dose/kg decreases with increase in 
weight. 
All treatment decisions for identifying the appropriate prophylactic treatment regimen 
should be guided by clinical judgment based on individual participant’s characteristics 
and treatment response.  
Bleeds will be treated with BAY 94-9027 as per the investigator’s instruction. The 
appropriate treatment of bleeding events is left to the discretion of the treating 
physician, local clinical practice, and may be extrapolated from published guidelines 
(e.g., World Federation of Hemophilia [WFH], International Society on Thrombosis 
and Haemostasis [ISTH], World Health Organization [WHO]). 
The dose for prophylaxis and bleeding will be rounded up to the available vial size. If 
rounding up is not acceptable, rounding down is possible according to investigator 
discretion.  
Type  
Biologic 
Route of 
Administration 
Intravenous (IV) infusion delivered over 1 to 15 minutes, according to total volume. It 
is recommended to use a peripheral venous access. If a participant has a central 
venous access device (CVAD), the use of this device is allowed, but a peripheral 
access should be evaluated and is preferred for the study intervention. 
Participants or caregivers should only self-infuse if they have been trained by the 
healthcare provider or hemophilia center. Participants may only self-infuse under 
supervision of their caregiver. 
Use 
Experimental 
Unit Dose Strength 
500 IU/vial, 1000 IU/vial 
Packaging and 
Labeling 
Packaging and Labeling:  
Study intervention will be provided as lyophilized powder in a glass vial. Each glass 
vial will be provided with a prefilled syringe of the appropriate amount of sterile ‘’water 
for injection’, European Pharmacopoeia and US Pharmacopeia, for reconstitution. 
Each glass vial will be labeled as required per country requirement.  
[Current/Former 
Name(s) or 
Alias(es)] 
Commercial name: Jivi® / BAY 94-9027 
For each of the prophylaxis regimens, participants should adhere as closely as possible to the 
assigned dosing frequency.  The day of treatment may vary within ±1 day to accommodate 
life events.  Occasional extra infusions prior to activities or events that would be expected to 
result in an increased risk of bleeding are permitted, but should not result in a change in the 
assigned dosing schedule. 
In case of severe, potentially life-threatening bleeding events, or the need for unplanned or 
emergency surgery, or if the investigational product cannot be obtained in a timely manner, 
the participant should be managed following local standard of care, using readily available 
factor products. 

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6.1.1 
Medical Devices 
The BAY 94-9027 vials will be supplied with the necessary medical devices to facilitate the 
preparation and infusion of the study intervention. The medical devices that are used in this 
study are the same as those marketed with Jivi, as well as Kovaltry, a rFVIII product 
manufactured by the Study Sponsor and is indicated for use in patients with congenital 
hemophilia A including patients in age group < 12 years of age. 
The medical devices provided by the sponsor for use in the study are: 
x Vial adapter 
x Prefilled syringe containing sterile Water for Injection  
x Administration set 
In case device deficiencies occur (including malfunction, use error and inadequate labeling) 
this shall be documented and reported by the investigator to the sponsor throughout the 
clinical investigation (see Section 8.3.10) and appropriately managed by the sponsor. 
6.2 
Preparation, Handling, Storage, and Accountability 
Instructions for the preparation of the study intervention according to the current approved 
Jivi® prescribing information will be provided to the participants. 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only eligible participants may receive study intervention and only authorized site staff 
may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff. 
3. The investigator or the head of the institution (where applicable) is responsible for 
study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
interventions are provided in a separate document.   
In accordance with the approved BAY 94-9027 labeling, BAY 94-9027 must be stored under 
refrigeration (+2°C to +8°C) at the site until dispensing.  Freezing must be avoided.   
At participants’ homes, BAY 94-9027 must be stored under refrigeration (+2°C to +8°C) or 
may be stored for a single period of up to 6 months at temperatures up to +25°C or 77°F.  
Freezing must be avoided.    
Reconstituted concentrate should be infused promptly (within 3 hours of reconstitution). 
Parents/caregivers will be provided with detailed instructions for proper storage of the study 
intervention at home. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 

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6.4 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and electronic case report 
forms (eCRFs). 
When participants are dosed at home, the information will be recorded in EPD 
(see Section 8.1).  Data on infusions for prophylaxis and treatment of bleeds will be collected. 
The parent/caregiver will interact with the investigator or delegate to verify and complete the 
EPD entries. 
Data on the EPD will be transmitted after each treatment or bleeding event is entered. The 
EPD data will be used to assess compliance with the prophylaxis treatment schedule and with 
the recording of all treatments and bleeding events, and to support the documentation of the 
study intervention inventory.  
Participation in the study may be terminated at the sponsor's discretion if a participant fails to 
comply with the above protocol requirements. 
All used and unused vials of study intervention must be returned to the study center at each 
study visit. At the end of the study, all used and unused study intervention vials will be 
counted by the sponsor’s representative for final drug accountability.  
6.5 
Dose Modification 
See Table 6–1 (Section 6.1) for potential dose modifications. 
6.6 
Continued Access to Study Intervention After the End of the Study 
After the end of the study, the participants will not have access to the study intervention. 
Subsequent treatment will be mutually agreed upon by the parents/caregivers and the 
investigator.  
6.7 
Treatment of Overdose 
No symptoms of overdose have been reported during the clinical development program for 
BAY 94-9027. If overdose occurs, contact the sponsor immediately. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the participant. The participant has to be 
closely monitored for any AE/SAE and laboratory abnormalities. 
6.8 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant received within 3 months of study enrollment, is receiving at the time of study 
enrollment or receives during the study must be recorded along with: 
x Reason for use 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency 

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History of vaccinations received within 2 years of study enrollment (including vaccinations 
for COVID-19) should be collected for all participants. 
Prior use of pegylated medications (e.g., PEG- interferon, PEG-anti-tumor necrosis factor 
[TNF], PEG-vaccine) will be collected for all participants. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Bleeds which occur during the screening period through ED 4 will be treated with the 
participant’s own FVIII product. Thereafter, BAY 94-9027 will be used as the sole FVIII 
source for on-demand treatment of bleeds. In situations with a very low local recovery (see 
Section 8.2.3.1 for decreased recovery definition) after ED 1 through ED 4, study participants 
may administer their previous FVIII drug at home. 
Pre-medications to tolerate treatment with BAY 94-9027 are not allowed. The use of topical 
anesthetics prior to venipuncture is permitted.   
No other experimental drugs may be taken during the participation in this study.  
No immunosuppressive/immunomodulatory drugs may be taken during the study.  If such 
therapy is deemed necessary for the participant’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, 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, cyclooxygenase-2 (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 if 
specifically prescribed by a treating physician.  
6.8.1 
Rescue Medicine 
In the event of an AESI leading to discontinuation of study intervention, the participant will 
switch back to his previous FVIII medication. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not remain 
in the study. See the SoA (Section 1.3) for data to be collected at the time of discontinuation 
of study intervention and follow up and for any further evaluations that need to be completed. 
Additional participants may be enrolled in the event of treatment discontinuation during the 
first 4 EDs of Part A for reasons other than AESI. 
A participant will be withdrawn from the study and/or study intervention in the following 
cases: 
x A positive inhibitor result at Baseline visit (Visit 2) 
x At the request of the sponsor 

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x If, in the judgment of the investigator or the sponsor, the participant is not compliant 
with the protocol 
x Development of an inhibitory ADA that neutralizes BAY 94-9027 activity sufficiently 
to interfere with effective treatment or requires use of another FVIII product to treat 
bleeds 
x Development of an inhibitory antibody to FVIII that neutralizes activity sufficiently to 
interfere with effective treatment or requires use of a bypassing agent to treat bleeds 
x Lack of response to treatment (other than due to an inhibitor) 
x Anaphylaxis or severe hypersensitivity reaction (CTCAE version 5.0, Grade 3 or 
greater) associated with use of BAY 94-9027. See Section 10.1.8, study stopping 
rules, for more details  
x Failure to comply with scheduled appointments for study-related testing or with EPD 
data entry to an extent that compromises collection of critical data 
Use of another FVIII product for the treatment of bleeding (e.g., in an emergency) will not 
result in mandatory withdrawal of the participant. 
Prolonged periods >14 days or repeated breaks in the prophylaxis schedule should be avoided 
and could result in the study participant being removed from the study. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
The legal guardian and the pediatric participant have the right to withdraw permission 
(consent or assent, respectively) at any time during the study. If the study staff identify any 
reluctance in the legal guardian or pediatric participant (e.g., signs of verbal or physical 
dissent) about continued participation in the study, the pediatric participant’s continuation in 
the study should be reevaluated. The same principles that govern permission/assent/consent 
also govern its withdrawal.   
A participant will be withdrawn from the study for any of the following reasons: 
x Withdrawal of consent or assent if applicable (A pediatric participant’s dissent should 
be respected.) 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be collected at the time 
of study discontinuation and follow up and for any further evaluations that need to be 
completed. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
If the participant/parent/legal guardian withdraws consent for disclosure of future information, 
the sponsor may retain and continue to use any data collected before such a withdrawal of 
consent. 
7.3 
Lost to Follow Up 
A participant will be considered lost to follow up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 

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x The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or 
should continue in the study. 
x Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, by 
telephone calls, and if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. 
Study Assessments and Procedures 
x Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
x Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
x Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
x Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the timeframe defined in the SoA. 
8.1 
Efficacy Assessments  
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
Efficacy endpoints (bleeding episodes and BAY 94-9027 consumption) will be collected in 
the EPD. Parents/caregivers or participants, if intellectual status allows, will be provided with 
EPDs for the entire study and will be trained in the use of the device. Investigators or their 
delegate will interact with parents/caregivers or participants on a regularly scheduled basis to 
verify the data on the EPD for accuracy and completion.  Thus, the EPD will be considered 
the primary source for these data. 

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8.1.1 
BAY 94-9027 consumption 
Information on study intervention administration must be captured in either the eCRFs or in 
the EPDs, but not both. Information should not be duplicated. 
The following guidance should be used for clarification of whether the information should be 
recorded in the EPDs or in the eCRFs: 
x All use of study intervention outside the hospital/clinic should be recorded in the EPD.  
x Use of study intervention in the hospital/clinic as defined in the protocol (e.g., at 
protocol-defined visits for FVIII recovery) or during an emergency major surgery 
should be recorded in the eCRFs.  
- 
In the extremely unlikely event that an infusion at a protocol-defined visit is given 
for a bleed, the information should be recorded in the EPD rather than the eCRFs, 
since additional information needs to be collected for bleeding that is not collected 
in eCRFs.  
- 
Regular prophylaxis infusions that are not defined in the protocol as being 
administered in the hospital/clinic at a specific visit should be recorded in the EPD 
regardless of whether they are administered in the hospital/clinic (e.g., infusion 
information for a participant whose infusion would have been given at home but 
had to be given in the hospital because of venous access should be recorded in the 
EPD).  
Information recorded in the EPD will include: 
x Date and time 
x Vial numbers / number of vials and units administered 
x Reason for treatment  
- Prophylaxis 
- Spontaneous bleed first treatment 
- Trauma bleed first treatment 
- Minor surgery  
- Follow-up treatment 
- Unscheduled/preventative prophylaxis (for physical activities, suspected or 
non-evident bleeding following identified trauma) 
8.1.2 
Recording of Bleeding Episodes 
All bleeding episodes occurring after first dose of study intervention (regardless if treated or 
not, or treated at home or under medical supervision) as well as any potential treatment with 
other hemophilia drugs will be recorded in the EPD: 
x Date and time of onset 
x Type of bleeding (spontaneous, trauma, joint, muscle, skin/mucosal, internal, other) 
x Location 
x Intensity (mild, moderate, severe) 

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x Treated (yes/no): 
 If “yes”: Date and time 
 Product used: Study intervention / other drug 
 Doses 
If BAY 94-9027 is used for the treatment of a bleeding episode, the response to treatment 
(excellent, good, moderate, poor, or none).   
For guidance to the participants’ parents/caregivers, the following definitions for response to 
treatment are suggested.  Individual responses may vary:  
x Excellent: Abrupt pain relief and /or improvement in signs of bleeding with no 
additional infusion administered   
x Good:  Definite pain relief and/or improvement in signs of bleeding, but possibly 
requiring more than one infusion for complete resolution   
x Moderate:  Probable or slight improvement in signs of bleeding, with at least one 
additional infusion for complete resolution   
x Poor (or None):  No improvement or condition worsens.   
8.1.3 
Clinical Outcome Assessments 
8.1.3.1 
Hemophilia Specific Quality of Life (Haemo-QoL) Questionnaire 
In this study, the Haemo-QoL Short Form Questionnaire for children 8-16 years old will be 
used by all participants including participants who are 7- <8 years of age.  
The Haemo-QoL Short Form contains 35 questions covering 9 domains: Physical Health, 
View of Yourself, Family, Friends, Others, Sports, Dealing, and Treatment.  
The respondent burden for this questionnaire is approximately 15 minutes. The 
participant/parent/legal guardian will complete the questionnaire and the data will be entered 
in eCRF by the investigator or study site staff.  
8.1.3.2 
Patient/Caregiver Global Impression of Severity and Change 
These 4 instruments are made of one single-item measure. They will explore 
patient--perceived and caregiver-perceived overall severity and change in health status since 
the start of study intervention. These instruments will be used to anchor the scores of 
Haemo-QoL. The participant/parent/legal guardian will complete the questionnaire and the 
data will be entered in eCRF by the investigator or study site staff.  
The respondent burden for both questionnaires is approximately 2 minutes.  
8.2 
Safety Assessments  
The safety assessments for the study include: 
x 
(S)AEs, including AESI, AEs leading to discontinuation of study intervention (Section 
8.2.3.1 ) 
x 
FVIII inhibitor development using the Nijmegen-modified Bethesda assay. The first 
positive inhibitor test after a participant has started treatment with study drug will be 

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confirmed by testing a second (separately drawn) sample in a central laboratory. 
(Section 8.3.9) 
x 
Anti-drug antibodies 
x 
Physical examination findings, vital signs and laboratory values (Section 8.2.1 to 
8.2.3) 
x 
Evaluation of concomitant medication (Section 6.8) 
x 
Long-term safety assessments: 
o Quantitative PEG measurement 
o Liver enzymes  
o Urine and serum biomarkers  
o Neurological assessment.  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
Clinically significant abnormal findings will be reported as AEs in the eCRF 
8.2.1 
Physical Examinations 
A complete physical examination will include a review of body systems, and measurement of 
body height (cm), and weight (kg).   
Standard neurological assessment will be performed by the investigator (neurologist not 
required) at the timepoints indicated in the SoA (Section 1.3).  
8.2.2 
Vital Signs 
Measurement of vital signs will include: systolic and diastolic blood pressure, heart rate, and 
body temperature. Vital signs will be measured before and after administration of study 
intervention at time points indicated in the SoA (Section 1.3).   
8.2.3 
Clinical Safety Laboratory Tests 
x See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency.  
x The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
x Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant's condition. 
x All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 week after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or the Medical Monitor. 
x If clinically significant values do not return to normal/baseline within a 
period of time judged reasonable by the investigator, the etiology should be 
identified, and the sponsor notified. 
x All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA.  

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x If laboratory values from non-protocol-specified laboratory tests performed 
at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator 
(e.g., SAE or AE or dose modification), then the results must be recorded. 
8.2.3.1 
Decreased recovery 
In the event that recovery is lower than expected based on local FVIII post-infusion levels 
after the first infusions (e.g., recovery of <1.2 kg/dL):  
x Increase dose to 60 IU/kg, and/or  
x Additional prophylaxis infusion may be added  
x Assess response to treatment with local assessment of recoveries, post-infusion 
levels 
In patients with positive anti-PEG ADAs, obtain the following weekly until antibody 
titers are declining and FVIII recovery is stable.  
x  One each for both local and central lab:  
o Pre-infusion FVIII blood/plasma samples  
o FVIII blood/plasma samples 15-30 min post infusion for recovery 
x One for central lab: 
o Blood/plasma sample for anti-PEG IgM  
Once antibody titers are declining and FVIII recovery is stable, assess FVIII recovery 
and ADA monthly until ADAs disappear. 
For study participants that have discontinued study drug, FVIII inhibitor tests must be done 
after a sufficient wash-out period depending on the FVIII product the participant is receiving 
– at least 48 hours or 72 hours for SHL and EHL FVIII products respectively 
 
8.3 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting 
The definitions of adverse events (AEs) and SAEs can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legal guardian). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs including AEs that are serious, considered related to the study 
intervention or study procedures, or that caused the participant to discontinue the study 
intervention (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
 

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8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
(S)AEs (including AESI) will be collected from the start of study intervention until the last 
visit at the timepoints specified in the SoA (Section 1.3). (S)AEs which are related to 
protocol-required study procedures, e.g., (S)AE related to invasive study procedures will be 
recorded as (S)AEs from the signing of the ICF. 
Any medical occurrences/conditions that begin in the period between signing ICF and the 
start of study intervention, and which are not related to a protocol-required study procedure, 
will be recorded as medical history/current medical conditions, not as AEs. 
All SAEs and AESIs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours of learning of the event, as indicated 
in Section 10.3. The investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor.  
 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
Clinical Presentation of Adverse Events 
Study site staff should instruct the legal guardians and caregivers on how to report signs and 
symptoms (e.g., crying and pain) in the individual pediatric participant. They will be 
instructed to report both specific and non-specific symptoms (including vomiting, diarrhea, 
sleepiness, variation in the intensity, etc.). These non-specific symptoms may be the only 
manifestations of some adverse reactions observed in children. Care should be taken that the 
clinical presentation of adverse reactions is not misinterpreted as the manifestation of a pre-
existing or unrelated condition. 
Moreover, symptoms that are dependent on participant communication ability (e.g., nausea, 
pain, mood alterations) in younger or mentally disabled children could potentially be at risk 
for under- or mis-reporting. 
8.3.3 
Follow Up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AESI (as defined in Section 8.3.8), 
will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow up (as defined in Section 7.3). Further information on follow-up 
procedures is provided in Section 10.3.  

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8.3.4 
Regulatory Reporting Requirements for SAEs 
x Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met.  
x The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, institutional 
review boards (IRBs)/independent ethics committees (IECs), and investigators. 
x An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements. 
x For all studies except those using medical devices, investigator safety reports must 
be prepared for SUSARs according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs 
The following disease-related events (DREs) are common in patients with hemophilia A and 
can be serious/life-threatening: 
x Bleeding event 
Any bleeding event occurring during the study will not be documented as an AE, because this 
is captured in the assessment of efficacy. Because these events are typically associated with 
the disease under study, they will not be reported according to the standard process for 
expedited reporting of AEs. These events will be recorded in the EPD. 
NOTE: If the bleeding fulfills the criterion for an SAE (e.g., results in hospitalization), then 
the event should be recorded and reported as an SAE (Section 10.3.4). 
NOTE: If either of the following conditions applies, then the event must be recorded and 
reported as an SAE (instead of a DRE): 
x The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant  
OR 
x The investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.5 
Pregnancy 
Not applicable in this pediatric male participant population. 
8.3.6 
Cardiovascular and Death Events 
Death will be reported with the known cause of death as a SAE.  

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8.3.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
See Section 8.3.4 for DREs bleeding.   
8.3.8 
Adverse Events of Special Interest (AESI)  
The AESI in this study are: 
Hypersensitivity: defined as an immune reaction related to the administration of study 
intervention (BAY 94-9027). Hypersensitivity reactions may also occur in the absence 
of anti-PEG antibodies. It does not include hypersensitivity reactions which are not 
related to drug administration such as but not limited to rash related to contact 
dermatitis. 
The first 4 infusions of study intervention will be administered under medical 
supervision.  Participants will be monitored at the site for at least 60 minutes after 
infusion of study intervention. If allergic or anaphylactic reactions occur, the infusion 
will be stopped immediately and symptomatic treatment and therapy for 
hypersensitivity should be instituted, as appropriate.  Participants will be made aware 
that the potential occurrence of chest tightness, dizziness, mild hypotension, and 
nausea during or after the infusion can constitute an early warning for hypersensitivity 
and anaphylactic reactions. In such cases, the participant should immediately notify 
the investigator or the site staff of these symptoms.  
x LoE, associated with anti-PEG antibodies, has been observed primarily in previously 
treated hemophilia A patients 2-5 years of age within the 4 EDs to BAY 94-9027. LoE 
can present as bleeding, and must be confirmed by low recovery or post-infusion 
FVIII level, and a negative FVIII inhibitor test. When LoE is suspected, a sample for 
anti-PEG antibodies should be sent to the central lab.  
The following are considered LoE, even in the absence of a bleeding event: 
o Post-infusion FVIII that is not detectable or less than 15% with high titer (1:16 
or greater) PEG IgM antibodies 
o Recovery is insufficient due to anti-PEG IgM antibodies to maintain FVIII 
concentrations via modification of the dose and/or dosing interval to maintain 
adequate prophylaxis against bleeding  
A reduced recovery/post-infusion FVIII level is not considered LoE if adequate 
prophylaxis can be achieved with an increased dose and/or decreased interval 
(generally, recovery >0.5 kg/dL). 
The following information needs to be included on the eCRFs: time point of AESI in relation 
to administered study intervention, cumulative number of infusions of study intervention 
received as of time of adverse event, causal relation, duration, severity, symptoms, 
concomitant symptoms/disease, treatment, vaccination and time point, outcome, and history 
of previous allergic reactions.  
8.3.8.1 
Clinical guidance for hypersensitivity reactions requiring treatment 
A: In the event of a hypersensitivity reaction occurring at the study site, while study 
participant is under medical supervision, the following is to be done: 

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1. Prompt treatment of the hypersensitivity reaction as per local standard of 
care/guidelines 
2. Further observation for 1 hour after resolution of symptoms 
3. Obtain  
a. Two blood/plasma samples each for FVIII level, and FVIII inhibitor (1 for 
local lab and one for central lab. Note: sample for FVIII inhibitor can be 
omitted if already collected prior to infusion of study intervention as per SoA 
(Section 1.3 SoA)), AND 
b. One blood/plasma sample for anti -PEG, anti-PEG IgM and IgE (only for the 
central lab).   
4. Discontinue study intervention and resume prophylaxis treatment with prior FVIII 
product. 
5. Schedule a follow-up visit (early discontinuation visit) within 4 weeks after the event  
a. For assessment of general well- being of the study participant 
b. To perform assessments for early discontinuation of study participation as per 
SoA (Section 1.3 SoA) including evaluation of FVIII inhibitor and anti-PEG, 
anti-PEG IgM, IgE (only for the central lab) and excluding factor VIII 
recovery and in-hospital infusion of study intervention.   
B: If the event of a hypersensitivity reaction occurring while study participant is not under 
medical supervision at study site (e.g., at home), the following is to be done: 
1. Participants should seek prompt medical attention in case of occurrence of any 
symptom of hypersensitivity reactions and inform the investigator or site staff.   
If treatment of hypersensitivity reaction occurs at the study site, then follow the steps 
outlined in in “A” above. 
If treatment of hypersensitivity reaction occurs outside the study site, then follow the 
steps below: 
2. Discontinue study intervention and resume prophylaxis treatment with prior FVIII 
product  
3. Schedule a visit to the study site within 4 days of the reported event for  
a. Assessment of general well- being of the study participant 
b. AE review.  
At this visit obtain:  
c. Two blood/plasma samples each for FVIII level and FVIII inhibitor (1 
for local lab and one for central lab), AND 
d. One blood/plasma sample for anti-PEG, anti-PEG IgM and IgE (only for 
the central lab)  
4. Schedule a second follow-up visit (early discontinuation visit) approx. 4 weeks 
after the last visit (see step 3)  
a. For assessment of general well- being of the study participant, AND 

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b. Perform assessments for early discontinuation of study participation as 
per SoA (Section 1.3 SoA) including evaluation of FVIII inhibitor and 
anti-PEG, anti-PEG IgM, IgE (only for the central lab) and excluding 
factor VIII recovery and in-hospital infusion of study intervention.  
For study participants that have discontinued study drug, FVIII level and FVIII inhibitor tests 
must be done after a sufficient wash-out period depending on the FVIII product the 
participant is receiving – at least 48 hours or 72 hours for SHL and EHL FVIII products 
respectively. 
8.3.8.2 
Clinical guidance for loss of efficacy (LoE) 
LoE is defined in Section 8.3.8.  
In the event of reported LoE of the study intervention, the following is to be done: 
1. Schedule a visit within 4 days of the reported event  
2. Obtain  
a. Two pre-infusion blood/plasma samples each for FVIII level and FVIII 
inhibitor (1 for local lab and one for central lab), AND 
b. One blood/plasma sample for anti-PEG and anti-PEG IgM (for the central lab) 
3. Administer BAY 94-9027 (use current prophylaxis dose (IU/kg)) 
4. Obtain  
a. Two post-infusion blood/plasma samples (1 for local lab and one for central 
lab) for FVIII level (15-30 min post-infusion)  
5. Discontinue study intervention and resume prophylaxis treatment with prior FVIII 
product if LoE is confirmed by low post-infusion FVIII levels. Inform and discuss 
with sponsor. 
6. Schedule a second follow-up visit (early discontinuation visit) approx. 4 weeks after 
the last visit (see step 1) 
a. For assessment of general well- being of the study participant 
b. Perform assessments for early discontinuation of study participation as per 
SoA (Section 1.3 SoA) including evaluation of FVIII inhibitor and anti-PEG, 
anti-PEG IgM (only for the central lab) and excluding factor VIII recovery and 
in-hospital infusion of study intervention.  
 
8.3.8.3 
Assessment of Severity of AESI 
All AESIs will be graded for severity according to CTCAE version 5.0. If no exact matching 
code is available in CTCAE version 5.0, then use the following guide: 
Grade refers to the severity of the AESI. The CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this general guideline: 
x Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
x Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)* 

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x Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self care ADL** 
x Grade 4 Life-threatening consequences; urgent intervention indicated 
x Grade 5 Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self care ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Immune System Disorders 
CTCAE 
term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Allergic 
reaction 
Systemic 
intervention 
not 
indicated 
Oral 
intervention 
indicated 
Bronchospasm; 
hospitalization for clinical 
sequelae; intravenous 
intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
 Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
Navigational note: If related to infusion, use injury, poisoning and procedural complications: Infusion related 
reaction. Do not report both. 
Anaphylaxis 
- 
- 
Symptomatic bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it 
presents with breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness and may lead to 
death. 
Source: Common Terminology Criteria for Adverse Events (CTCAE), v 5.0, published November 27, 2017), US 
Department of Health and Human Services  
 
8.3.9 
Other Important Events  
Anti-drug antibody development 
All subjects will be tested for the development of anti-drug antibodies (anti- PEG and anti-
PEG IgM). Binding antibodies to PEG will be analyzed in an enzyme-linked immunoassay 
(ELISA). 
In participants who experience LoE, neutralization of activity of BAY 94-9027, observed as 
lower than expected FVIII recovery, a blood sample should be obtained to test for ADAs 
(Section 8.2.3.1).  
IgE will be analyzed in participants who experience hypersensitivity reactions due to 
development of ADA.   

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Development of FVIII inhibitor 
FVIII inhibitor testing will be done according to the Nijmegen-modified Bethesda assay. A 
positive inhibitor test is defined with a threshold of ≥ 0.6 BU/mL at the central laboratory. If 
an inhibitor to FVIII is detected after the participant has started treatment with study 
intervention, the investigator will be notified, and repeat testing within 2 weeks of notification 
should be obtained. The first positive measurement will be confirmed by a second different 
sample. After confirmation of the positive result, the inhibitor development will be reported as 
SAE.  
8.3.10 
Medical Device Deficiencies 
Medical devices approved for use with BAY 94-9027 are being provided for use in this study 
to facilitate the preparation and infusion of the study intervention. To fulfill regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during the 
study with such devices. 
The definition of a medical device deficiency can be found in Section 10.4.3. 
Device deficiencies only should be reported to the sponsor, by completing the product 
technical complaint (PTC) form and submitting the information via the ePTC form or by 
completing the PTC form and submission to the sponsor via ptc-imp@bayer.com.  
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes outlined 
in Section 10.4 of the protocol.  
8.4 
Pharmacokinetics 
Detailed PK analysis will not be performed, but FVIII recovery will be assessed frequently as 
per SoA (Section 1.3).  
8.5 
Genetics 
Genetics are not evaluated in this study. 
8.6 
Biomarkers 
Serum and urinary biomarkers will be measured for assessment of renal safety (Section 10.2). 
A limited amount of blood is collected; any remaining amount may be used for additional 
research on study intervention and/or disease understanding. Blood volume will not be 
increased for these research purposes. 
In addition, further investigations related to the mode of action or the safety of BAY 94-9027 
and similar drugs for the treatment of hemophilia may be performed. The same applies to 
further investigations deemed relevant to hematological diseases and associated health 
problems. Examples of these investigations include diagnostic, safety, pharmacodynamic, 
monitoring, or potentially predictive biomarkers. 
Results from any additional investigations may be reported separately.  

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8.7 
Immunogenicity Assessments 
See Section 8.3.8 and Section 8.3.9 . Immunogenicity will be assessed by measurement of 
FVIII inhibitors, anti-PEG and anti-PEG IgM antibodies.  
For participants who present a hypersensitivity reaction, IgE antibodies to BAY 94-9027 will 
be measured after the occurrence of the reaction. In case BAY 94-9027 reactive IgE 
antibodies were detected, specificity toward the FVIII or PEG moiety will be confirmed. 
8.8 
Health Economics 
Health economics parameters are not evaluated in this study. 
9. 
Statistical Considerations  
The statistical analysis plan will be finalized prior to first participant first visit and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. 
9.1 
Statistical Hypotheses 
Hypothesis testing is not planned for this study. Based on a Bayesian analysis for the primary 
endpoint, the posterior probability that the true incidence for an AESI is <5% will be 
estimated. 
9.2 
Analysis Sets 
Participant Analysis Set 
Description 
Safety analysis set 
(SAF Part A) 
A participant will be included in the SAF part A if he is enrolled into the part A of 
the study and has taken at least 1 dose of the study intervention. 
Modified Safety 
analysis set (mSAF 
Part A) 
A participant will be included in the mSAF part A if he is enrolled into the part A 
of the study and has taken up to 4 doses of the study intervention and does not 
discontinue study for other reason than an AESI before the fourth ED 
regardless of emergency use of other FVIII medication. 
Modified Intent-to-treat 
analysis set (mITT Part A) 
A participant will be included in the mITT part A if he is enrolled into the part A 
of the study, has taken at least 1 dose of the study intervention, and has 
subsequent data for infusions/bleeds documented in the EPD. 
Safety analysis set (SAF 
Part B) 
A participant will be included in the SAF part B if he is enrolled into the part B of 
the study and has taken at least 1 dose of the study intervention in Part B. 
Modified intent-to-treat 
analysis set (mITT Part B) 
A participant will be included in the mITT part B if he is enrolled into the part B 
of the study, has taken at least 1 dose of the study intervention in Part B, and 
has subsequent data for infusions/bleeds documented in the EPD 

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9.3 
Statistical Analyses 
9.3.1 
General Considerations 
Descriptive statistics will be used for all statistical analyses. The primary endpoint will be 
analyzed for part A. Secondary endpoints for the primary and secondary objectives will be 
analyzed for parts A, and B. More details will be provided in the statistical analysis plan. 
Assessment of safety will be performed based on the safety analysis set.  
Assessment of efficacy will be performed based on the modified ITT analysis set.  
9.3.2 
Primary Endpoint(s)/Estimand(s) Analysis 
See Section 3 for a description of the primary endpoint and estimand. 
The mSAF for part A analysis set will be used in this analysis, see Section 9.2. As described 
in Section 3, the primary estimand targets the stratum of participants who do not discontinue 
treatment with BAY 94-9027 for other reason than an AESI before the fourth ED regardless 
of emergency use of other FVIII medication.  
Due to the expected low incidence of AESIs (Santagostino et al. 2020), a Bayesian approach 
will be used for analysis of the primary endpoint.  
The 25 participants from age group 7 to <12 years of PROTECT KIDS study with 0 AESIs 
will be combined with the n participants and AESIs from this study for the analysis of the 
probability of an AESI (p), with a total observed sample size of 25 + n = N. The Bayesian 
model for the analysis is then specified as follows: 
 
ri ~ Bernoulli (p): 
occurrence of an AESI in participant i , i = 1,… , N; 
            p ~ Beta(1/4,1/4); 
prior for the probability of an AESI.G
The choice of the neutral prior Beta (1/4,1/4) is to avoid over influence of the prior and limit 
the degree of polarization of the prior toward 0 and 1. The posterior distribution based on the 
pooled data will then be Beta(x+1/4,N-x+1/4), where x is the number of participants in the 
pooled data who experience an AESI.  
To note, the above analysis by first pooling in the 25 participants from PROTECT KIDS prior 
to the Bayesian analysis is equivalent to treating the 25 participants with 0 AESIs as historical 
data and updating the initial prior Beta(1/4,1/4) to be Beta(0+1/4,25+1/4) as the updated prior 
for the analysis of participants from this study alone. 
The safety of BAY 94-9027 will be characterized by the resulting posterior distribution for 
the probability of AESI, including its mean, median, mode, and 90% two-sided credible 
intervals. The posterior probability that the incidence of AESI is <5% will be derived.  
9.3.3 
Secondary Endpoint(s)/Estimand(s) Analysis  
9.3.3.1 
Analysis of Secondary Endpoints for the Primary Objective 
To further address the primary objective, the following secondary endpoints will be analyzed: 
x Adverse drug reactions (ADRs) 
x Anti-drug antibody (ADA) development 
x Inhibitor development 

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The analyses for these 3 endpoints will be based on the SAF part A and SAF part B analysis 
sets, see Section 9.2 for details. 
Adverse drug reactions 
The number and proportion of participants with any ADRs will be presented.  
Anti-drug antibody response 
The number and proportion of participants with anti-drug antibodies will be presented along 
with by-participant listings for ADA responses. 
Inhibitor development 
The number and proportion of participants with confirmed FVIII inhibitors will be presented 
by titer (low titer: < 5 BU/mL, high titer: ≥ 5 BU/mL) along with by-participant listings for all 
measurements of FVIII inhibitors. Note that only inhibitors confirmed by a second positive 
measurement will be considered positive in the analysis, see Section 8.3.9. The listing will 
show all results. 
9.3.3.2 
Analysis of Secondary Endpoints for the Secondary Objective 
To address the secondary objective, the following secondary endpoints will be analyzed. 
x Number of bleeds per individual observation period of continuous prophylactic 
treatment to assess (annualized) bleeding rates  
x BAY 94-9027 consumption  
x Number of infusions/month and year (Annualized Infusion Rate) 
The analyses for these 3 endpoints will be based on the modified ITT analysis sets for Part A 
and Part B of the study, respectively, see Section 9.2 for details.  
Bleeding rates  
As described in Section 3, the estimand targets the stratum of participants who receive 
continuous prophylaxis treatment with BAY 94-9027 for at least 3 months without 
development of an inhibitory antibody to FVIII or ADA that neutralizes activity sufficiently 
to interfere with effective treatment. The subset of participants in the modified ITT analysis 
set fulfilling this condition will be used for estimation. 
For each participant, the number of bleeds will be related to the individual observation period 
to assess bleeding rates. Bleeding rates will be annualized at the individual participant level 
using the formula: 
ABR = (number of bleeds * 365.25)/(the available period in the study in days). 
Descriptive statistics (N, mean, median, standard deviation, range, Q1, and Q3) will be used 
to summarize the derived annualized bleeding rates on a group level.  
ABRs will be presented for the following types of bleedings: 
- 
Annualized total bleeding (sum of spontaneous bleeds and trauma bleeds) rate 
- 
Annualized spontaneous bleeding rate 
- 
Annualized trauma bleeding rate 
- 
Annualized joint bleeding rate 

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In addition, model-based estimates for the bleeding rates will be derived using a Negative 
Binomial model, where ݕ௜ denotes the number of bleeding episodes occurring during the time 
period ݐ௜ (possibly differing time periods of follow‐up) for participant ݅ǡ ݅ൌͳǡ ǥ ǡ ݊.  Assume 
that ܻ௜ follows a Negative Binomial distribution with mean ߤ௜ and a common dispersion 
parameter ߙ. Then ߤ௜ can be modeled as 
 ߤ௜ൌ ݐ௜൅ߚ଴ ǡ 
We thus have 
 ߤ௜ൌ ݐ௜൅ߚ଴ ֞
ఓ೔
௧೔ൌሺߚ଴ሻǤ  
With an estimate for the parameter ߚ଴ the mean rates of events per time unit can be estimated 
via ሺߚ଴ሻ. This estimate will be provided with its 95% confidence interval. 
Determination of Bleeding Count: 
Bleeds occurring on the same calendar day will be counted as one bleeding episode with 
aggregated bleeding sites. A spontaneous joint or spontaneous muscle bleed reported within 
72 hours after an identical bleed at the same site or infusion for such a bleed will not be 
counted as new bleed. Infusions for such bleeds will be considered to be follow-up infusions. 
(Srivastava et al. 2020)  
BAY 94-9027 consumption 
Summary statistics for BAY 94-9027 consumption will be provided for prophylaxis 
treatment, for treatment of bleeds, and overall. Consumption per year and per infusion will be 
presented based on total dose (IU) and dose per body weight (IU/kg).  
Number of infusions/month and year (Annualized Infusion Rate) 
Descriptive statistics (N, mean, median, standard deviation, range, Q1, and Q3) for the 
number of infusions, number of infusions per month, and annualized infusion rate will be 
presented. 
9.4 
Interim Analysis 
An interim analysis within a group sequential or adaptive design is not planned. Analysis of 
Part A will be conducted after the last participant completes Part A.  
A first analysis of Part B data will be conducted after all participants complete at least 6 
months of Part B. A final analysis will be done at the end of the study.  
9.5 
Sample Size Determination 
The selection of the sample size of 30 is based on the assumption that less than 5% of 
participant out of 30 will experience an AESI and that the data will be pooled with 25 
participants from the age group of 7 to <12 years of study 15912 (PROTECT KIDS; 
NCT01775618) for analysis of the incidence of AESIs. Additional participants may be 
enrolled in the event of treatment discontinuation during the first 4 EDs of Part A for reasons 
other than AESI. The study would strive for a balance between age group 7 to <9 years and 
9 to <12 years. 
A Bayesian Beta-binomial model with each participant having an AESI as a Bernoulli 
response and a neutral prior probability distribution Beta (1/4,1/4) is used. The choice of the 

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neutral prior Beta (1/4,1/4) is to avoid over influence of the prior and limit the degree of 
polarization of the prior toward 0 and 1.  
Under these assumptions, the posterior probability that the true incidence for an AESI is <5% 
will be > 90%.  
Details are described by the following scenarios:  
x If no participant out of 30 from the new study experience an AESI, then with the 
Bayesian analysis mentioned above, it is calculated that the median of the posterior 
distribution of the true incidence of AESI is <0.1% and there is >99% posterior 
probability that the true incidence of AESI is <5%. 
x If 1 participant out of 30 from the new study experience the AESI, it is calculated by a 
Bayesian Beta-binomial inference with a prior of Beta (1/4,1/4) for the pooled 55 
participants that the median of the posterior distribution of the true incidence of AESI 
is 1.7% and there is 91% posterior probability that the true incidence of AESI is <5%. 
x If 2 participants out of 30 from the new study experience the AESI, then the median of 
the posterior distribution of the true incidence of AESI is 3.5%, and there is 71% 
posterior probability that the true incidence of AESI is <5%. 
x If 3 participants out of 30 from the new study experience the AESI, then the median of 
the posterior distribution of the true incidence of AESI is 5.4%, and there is 46% 
posterior probability that the true incidence of AESI is <5%. 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
 
x This study will be conducted in accordance with the protocol and with the 
following: 
x Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) international ethical 
guidelines 
x Applicable ICH Good Clinical Practice (GCP) guidelines 
x Applicable laws and regulations 
x The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
x Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH GCP and national 
and international regulations. 
x Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
x The investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
x Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
x Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
The investigator will be responsible for reporting cases of suspected child abuse and/or 
neglect according to local regulations including local medical association (e.g., American 
Academy of Pediatrics, EU Academy of Pediatrics) or Health Department guidelines. 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 

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10.1.3 
Informed Consent and Assent Process 
x The investigator, or a person designated by the investigator, will provide the legal 
guardian (refer to Appendix 10.4 Abbreviations and Definitions) with the written 
ICF and the participant with the assent if applicable. They must be informed that 
participation is voluntary. The legal guardian will be required to sign written 
consent, and the participant if applicable will be required to sign written assent, 
that meets the requirements of 21 CFR 50, local regulations, International Council 
on Harmonisation (ICH) guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center after the nature of the study has been fully explained and before 
performance of any study-related activity. 
x Assent requirements for pediatric participants may vary across regions and 
countries; local regulations should be followed as appropriate.  Assent should be 
obtained from participants, depending on their age and intellectual status and 
according to local practice.  
x The medical record must include a statement that written informed consent from the 
legal guardian and assent from the pediatric participant (if deemed appropriate by 
local ethics review or local regulations) were obtained before the participant was 
enrolled in the study and the date the written consent and assent were obtained. 
The authorized person obtaining the informed consent must also sign the ICF and 
assent form attesting that the pediatric participant did not show signs of dissent 
particularly in those studies including toddlers and small children; it should be 
written in language appropriate to the child’s developmental and functional status. 
x Participants and their legal guardian must be re-consented and re-assented to the 
most current version of the ICF(s) during their participation in the study.  
x Minor participants who assent to a study and later withdraw that assent should not 
be maintained in the study against their will, even if their legal guardian still wants 
them to participate. 
x A copy of the informed consent and assent forms must be provided to the 
participant and the participant’s legal guardian. 
x As appropriate, participants may be given the opportunity to meet privately with a 
member of the site staff to ask confidential questions and to decline assent for 
confidential reasons, which, at their request, would not be shared with their legal 
guardian, unless required by local law. 
x There will be no attempt to recontact the participant at adulthood. However, the 
participant retains the right to withdraw assent/consent for storage of samples 
unless specified. 
x Stored samples will be coded throughout the sample storage and analysis process 
and will not be labeled with personal identifiers. Participants may withdraw their 
consent/assent for their samples to be stored for research. 
 

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10.1.4 
Data Protection 
x Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or biological samples that are transferred to the sponsor will 
contain the identifier only; participant names or any information which would make 
the participant identifiable will not be transferred. 
x The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
x The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5 
Dissemination of Clinical Study Data 
Result Summaries of Bayer's sponsored clinical trials in drug development Phases 2, 3 and 4 
and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded website ClinicalTrials.gov and EU Clinical 
Trials Register in line with the applicable regulations. 
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States (US) and European 
Union (EU) on or after January 01, 2014, as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative. 
 
10.1.6 
Data Quality Assurance 
x All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
x Guidance on completion of CRFs will be provided in the eCRF HelpText on the 
CRF and/or the eCRF Completion Instructions available online in the electronic 
data capture system. 
x The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
x Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance 

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issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the monitoring plan / contracts. 
x The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
x The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
x Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.  
 
10.1.7 
Source Documents 
x Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
x Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
x Definition of what constitutes source data and its origin can be found in the Source 
Data Location List (SDLL) or equivalent. 
x The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
x The sponsor will perform monitoring to confirm that data entered into the CRF by 
authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory 
requirements.  
10.1.8 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the first participant is recruited. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 

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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
x Discontinuation of further study intervention development 
For site termination: 
x Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
x Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
x Total number of participants included earlier than expected. 
Stopping rules 
In addition, the trial will be stopped if any of the following study intervention related events 
occurs: 
x One case of anaphylaxis (CTCAE version 5.0, Grade 3 or higher) or 
x One case of severe hypersensitivity/allergic reaction (CTCAE version 5.0, Grade 3 or 
higher)  
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate therapy and/or follow up. 
10.1.9 
Publication Policy 
x The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
x The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
x Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
Appendix 2: Clinical Laboratory Tests 
x The tests detailed in Table 10–1 will be performed by the central laboratory.  
x Local laboratory results are required as outlined in the SoA (Section 1.3) or in the 
event that the central laboratory results are not available in time for either study 
intervention administration and/or response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same 
time. See Section 8.3.8 for more details regarding local or central laboratory test in 

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the case of an AESI. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be 
recorded, and validated assays must be used. For determination of FVIII levels after 
infusion of BAY 94-9027, the use of a suitable and validated one-stage or 
chromogenic assay is crucial. 
x Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
x Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 10–1: Protocol-required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Hemoglobin 
Hematocrit 
Chemistry 
Serum: Creatinine, AST, ALT, Na, K, CO2, Cl, BUN, total bilirubin, renal serum 
biomarkers (will include e.g., cystatin C, Lipocalin-2) 
Urine 
Urinary biomarkers (will include e.g., total protein, albumin, βeta-2 
microglobulin, Kidney Injury Molecule-1 (KIM-1), Lipocalin-2) 
Immunogenicity 
x 
FVIII inhibitor (see Section 8.3.9) 
x 
Anti-drug antibodies (anti-PEG antibodies and anti-PEG IgM antibodies) 
x 
IgE antibodies in participants with a hypersensitivity reaction 
Other tests 
x 
FVIII levels (one-stage assay at Visit 1 or chromogenic assay thereafter) 
x 
Quantitative PEG measurement 
x 
vWF (only at Visit 2, pre-infusion) 
Investigators must document their review of each laboratory safety report. 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow up, and Reporting 
10.3.1 
Definition of AE 
 
AE Definition 
x An AE is any untoward medical occurrence in a clinical study participant, 
associated with the use of study intervention, whether or not considered related to 
the study intervention. 
x NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
 

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Events Meeting the AE Definition  
x Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
x Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected intervention-
intervention interaction. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study intervention or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
x The signs, symptoms, and/or clinical sequelae resulting from LoE will be 
reported as an AESI (either non-serious or serious, if they fulfill the definition 
of an AE or SAE). Lack of efficacy or failure of expected pharmacological 
action also constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition  
x Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition 
x The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition 
x Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen 
 

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10.3.2 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets the 
one or more of the criteria listed: 
a. 
Results in death 
b. 
Is life-threatening 
x The term life-threatening in the definition of serious refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to 
an event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
x In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
x Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
x The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
x This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
x Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
x Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 

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10.3.3 
Recording and Follow Up of AE and/or SAE 
AE and SAE Recording 
x When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
x The investigator will then record all relevant AE/SAE information. 
x It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the CRF/required form. 
x There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the 
medical records before submission to the Sponsor.  
x The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE.  
Assessment of Intensity 
x The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to one of the following categories:  
x Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
x Moderate: Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.   
x Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self care ADL. Self care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.   
 

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Assessment of Causality 
x The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. The investigator will use 
clinical judgment to determine the relationship. 
x A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out. 
x Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated. 
x The investigator will also consult the IB and/or product information, for 
marketed products, in his/her assessment. 
x For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
x There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it 
is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to 
the Sponsor. 
x The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
x The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.  
Follow up of AEs and SAEs 
x The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the Sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals.  
x New or updated information will be recorded in the originally submitted 
documents. 
x The investigator will submit any updated SAE data to the Sponsor within 24 
hours of receipt of the information. 
 
10.3.4 
Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
x The primary mechanism for reporting an SAE to the Sponsor will be the electronic 
data collection tool.  

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x If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 
x The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
x After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
x If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the sponsor’s Medical Monitor by telephone. 
x Contacts for SAE reporting can be found in investigator site file. 
 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
x Email transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the Sponsor. 
x In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
x Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
x Contacts for SAE reporting can be found in investigator site file. 
10.4 
Appendix 4: AEs, SAEs, and Device Deficiencies: Definitions and 
Procedures for Recording, Evaluating, Follow up, and Reporting  
x Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices. 
x The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list 
of sponsor medical devices. 
10.4.1 
Definition of Medical Device AE  
Medical Device AE  
x An AE is any untoward medical occurrence in a clinical study participant, users, or 
other persons, temporally associated with the use of study intervention, whether or 
not considered related to the medical device provided by the Study Sponsor. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of the medical device. This definition includes events 
related to the medical device and events related to the procedures involved. 

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10.4.2 
Definition of Medical Device SAE 
A Medical Device SAE is any SAE that: 
a. Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
x A life-threatening illness or injury. The term ‘life-threatening’ in the definition of 
serious' refers to an event in which the participant was at risk of death at the time 
of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
x A permanent impairment of a body structure or a body function. 
x Inpatient or prolonged hospitalization, planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration 
in health, is not considered an SAE. 
x Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
x Chronic disease (MDR 2017/745). 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect  

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10.4.3 
Definition of Device Deficiency 
Device Deficiency Definition 
x A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device 
deficiencies include malfunctions, use errors, and inadequacy of the 
information supplied by the manufacturer. 
10.4.4 
Recording and Follow Up of AE/SAE/Device Deficiencies 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE/SAE/device deficiency 
reported during the study and assign it to one of the following categories:  
x Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
x Moderate: Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
x Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self care ADL. Self care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.   
Assessment of Causality 
x The investigator will provide a preliminary assessment of the relationship 
between the event and the medical devices listed in Section 6.1.1. 
Follow-up of AE/SAE/device Deficiency 
x The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the Sponsor to elucidate the nature and/or causality of the 
AE/SAE/device deficiency as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
x If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide the Sponsor with a copy of any 
postmortem findings including histopathology.  
x New or updated information will be recorded in the originally completed form. 
x The investigator will submit any updated SAE data to the Sponsor within 24 
hours of receipt of the information. 
 

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10.4.5 
Reporting of AEs/SAEs Related to the Medical Devices 
x For any device related SAE:  the investigator should complete the Medical Device 
Incident form and electronically the complementary SAE page in RAVE. The 
Medical Device Incident form will be sent to the sponsor by email to 
PV.caseprocessing@bayer.com within 24 hours. 
x For any AE that was assessed as device related:  the investigator should complete 
the Medical Device Incident form and electronically the complementary AE page in 
RAVE. The Medical Device Incident form will be sent to the sponsor by email to 
PV.caseprocessing@bayer.com within 24 hours. 
If the device deficiencies could potentially lead to the death or serious deterioration 
of health (=serious injury) of the study participant or others, e.g., staff, complete the 
Medical Device Incident form only and send it to the sponsor by email to 
PV.caseprocessing@bayer.com. 
For any AE or SAE that occurred with the users or other person the investigator 
should complete the Medical Device Incident form only and send it to the sponsor 
via email to PV.caseprocessing@bayer.com within 24 hours. 
 

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10.5 
Appendix 5: Abbreviations and Definitions 
10.5.1 
Abbreviations 
 
ABR 
annualized bleeding rate 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
ADRs 
adverse drug reactions 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
anti-PEG 
anti-polyethylene glycol 
AST 
aspartate aminotransferase 
BLA 
biologic license application 
BSL 
baseline 
BU 
Bethesda Unit 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COX-2 
cyclooxygenase-2 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Event 
CVAD 
central venous access device 
DREs 
disease-related events 
ECG 
electrocardiogram 
eCRF 
electronic case report forms 
ED 
exposure day 
EHL 
extended half-life 
ELISA 
enzyme-linked immunoassay 
EPD 
electronic patient diary 
EV 
extension visit 
FVIII 
Factor VIII 
GCP 
Good Clinical Practice 
Haemo-QoL 
Haemo-QoL Kids Short Form (8-16 years old version) 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization 
IECs/IRB 
Independent Ethics Committee/ Institutional Review Board 
IgE 
immunoglobulin E 
IgM 
immunoglobulin M 
IP 
in-person visit 
ITT 
intent-to-treat 

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IU 
International Units 
IV 
intravenous 
IxRS 
interactive voice/web randomization system 
LoE 
loss of efficacy 
MAA 
marketing authorization application 
mITT 
modified intent-to-treat 
mSAF 
modified Safety analysis set 
PEG 
polyethylene glycol 
PK 
Pharmacokinetics 
PMS 
post-marketing surveillance 
PROs 
patient-reported outcomes 
PTC 
product technical complaint 
PTPs 
previously treated patients 
PUPs 
previously untreated patients 
QoL 
Quality of Life 
RBC 
red blood cell 
rFVIII 
recombinant FVIII 
SAE 
serious adverse event 
SAF 
safety analysis set 
SCR 
screening 
SDLL 
Source Data Location List 
SHL 
standard half-life 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SUSARs 
suspected unexpected serious adverse reactions 
USPI 
US prescribing information 
WBC 
white blood cell 
WFH 
World Federation of Hemophilia 
 

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10.5.2 
Definitions 
Term 
Definition 
Study intervention 
BAY 94-9027 
Legal guardian 
Parent(s) (preferably both if available or as per local requirements), legally 
appointed guardian(s), or legally acceptable representative(s), as defined by 
national and local laws and regulations, who consent(s) on behalf of the minor. 
For the purposes of this study, all references to informed consent and assent 
refer to the pediatric participant (child) and his or her legal guardian who have 
provided consent (and assent as applicable) according to the Informed 
Consent Process and Assent Form described in Section 10.1.3 Informed 
Consent and Assent Process 
Caregiver 
Delegated primary caregiver(s) who will be responsible for ensuring the study 
activities are conducted per protocol, e.g., accompany the participant to the 
study site on each assessment day according to the SoA; consistently and 
consecutively be available to provide information on the participant using the 
rating scales during the scheduled study visits; accurately and reliably 
dispense study intervention as directed; help the study site personnel ensure 
follow up. This person may be the legal guardian, or another appropriate 
person, delegated by the legal guardian 
Pediatric 
participant  
Persons with hemophilia A younger than 18 years of age participating in 
research study 
 
10.6 
Appendix 6: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents. 
Amendment 1: 25 MAY 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The amendment introduces an additional year of prophylactic treatment with Jivi® 
culminating in a total of 2 years treatment duration in children of 7-<12 years of age. This 
prolongation will allow for generation of long-term data planned to be pooled with long-term 
data from PROTECT KIDS (study 15912; NCT01775618) and support label extension in the 
pertaining age group.  
Furthermore, the treatment prolongation offers sustained study drug provision for 2 years and 
avoid unnecessary switches of responder patients to other approved FVIII products. 
Section #  
and Name 
Description of Change 
Brief Rationale 
Title Page 
Substance name added. 
Substance name and compound number 
used throughout the protocol. 
Acronym added. 
Current study acronym was not in use at 
the time of the original protocol. 
Registry ID removed. 
Text was erroneously included in the 
original protocol. 
Name of Global Clinical 
Leader changed. 
Changed to reflect current team 
responsibilities. 

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Document History Table 
New section created to 
summarize all 
amendments to the 
original protocol. 
Full document history listed including 
version numbers and dates for each 
protocol version added for clarity and 
completeness. 
Protocol Amendment 
Summary of Changes 
Table 
New section added. 
This section was added in this protocol 
amendment to explain the rationale of the 
amendment and summarize the changes 
made to the original protocol. 
1.1 Synopsis 
Rationale updated to 
include long-term safety. 
Extension of the study resulting in a total 
treatment duration of 2 years will 
generate long-term safety data  
Objectives and endpoints 
updated to include a 
cross-reference to 
Section 3. 
Added to clarify that only primary and 
secondary objectives and endpoints are 
described in the synopsis, but the full list 
of objectives and endpoints is available in 
Section 3. 
Duration of extension 
study (Part B) described 
in the short summary 
increased from 6 months 
to 18 months. 
Study prolongation will provide treatment 
to patients for 2 years and avoid 
unnecessary switches of responder 
patients to other approved FVIII products. 
Cross-reference in 
footnote to objectives 
and endpoints table 
corrected. 
Cross-reference in original protocol 
pointed to the wrong section. 
1.2 Schema 
Schema updated to 
reflect change in duration 
for the extension study 
(Part B) from 6 to 18 
months.  
Change reflects treatment prolongation.  
1.3 Schedule of Activities 
(SoA) 
Schedule of assessment 
for Part A (Table 1-1) 
revised to include PEG 
quantification, Urine / 
serum biomarkers for 
renal safety, and 
neurological assessment 
at Visit 2 and Visit 11. 
Footnote added for each 
of these assessments at 
Visit 2 added stating that 
the assessments can be 
performed at a visit other 
than baseline if the 
participant is enrolled 
before Amendment 1 is 
implemented. 
Added PEG-related safety assessments 
specifically associated with the long-term 
use of pegylated FVIII products.  
Footnote added to 
Schedule of assessment 
for Part A (Table 1-1) 
clarifying procedures for 
the early discontinuation 
visit for participants with 
adverse events of 
special interest (AESI).  
In-hospital infusion not performed at early 
discontinuation visits for adverse events 
of special interest (hypersensitivity or 
loss of efficacy). 
Return used /unused 
study intervention at Visit 
Visit 6 can be an in-person visit or a 

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6 removed from 
Schedule of assessment 
for Part A (Table 1-1). 
phone call, therefore  
participants were provided with a study 
intervention supply sufficient to last 
through Visit 7.  Participants who attend 
an in-person visit for Visit 6 should return 
study intervention at Visit 7. 
Footnote added to 
Schedule of assessment 
for Part A (Table 1-1) 
and Part B (Table 1-2) 
with a cross-reference to 
Section 10.2. 
Cross-reference added to direct to full 
details on clinical laboratory parameters. 
Schedule of assessment 
for Part B (Table 1-2) 
revised to reflect 
increase in duration from 
6 months to 18 months. 
Monthly visits for Months 
13 – 24 added.  
Change reflects increase in duration. 
Schedule of assessment 
for Part B (Table 1-2) 
revised to include PEG 
quantification, Urine / 
serum biomarkers for 
renal safety, and 
neurological assessment 
at Visit 18. 
Added PEG-related safety assessments 
specifically associated with the long-term 
use of pegylated FVIII products 
Footnotes in Schedule of 
assessment for Part A 
(Table 1-1) and Part B 
(Table 1-2) relabeled. 
Footnote labels revised to reflect 
additions and revisions to original 
schedules of assessments 
2.1 Study Rationale 
Text revised to reflect 
addition of long-term 
safety assessments. 
Study prolongation will allow generation 
of long-term safety data.  
2.3.1 Risk Assessment  
Text regarding potential 
class risk of pegylated 
FVIII replacement 
products and previous 
experience with Jivi® 
added. 
Potential class risk for pegylated FVIII 
replacement products following long-term 
treatment added as determined by EMA. 
From Jivi’s preclinical and long-term 
clinical program no PEG-related safety 
observations associated with long-term 
use of Jivi were reported.  
3 Objectives, Endpoints, 
and Estimands 
Other objectives revised 
to include investigation of 
long-term safety and 
associated endpoints.  
Revised to reflect prolongation of study 
duration and addition of long-term safety-
related measurements. 

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Other objectives revised 
to clarify that Patient-
Reported Outcomes 
questionnaires are used 
to assess health-related 
quality of life, not 
biomarkers. 
In the original protocol, patient-reported 
outcomes were incorrectly grouped as an 
endpoint for the biomarkers objective. 
Time period for endpoint 
of secondary estimand 
revised. 
Revised to reflect prolongation of study 
duration. 
4.1 Overall Design 
Duration of extension 
study (Part B) increased 
from 6 months to 18 
months. 
Study prolongation will provide treatment 
to patients for 2 years and avoid 
unnecessary switches of responder 
patients to other approved FVIII products. 
5.1 Inclusion Criteria 
Inclusion criterion 2 
reworded to clarify that 
FVIII activity does not 
need to be measured at 
the time of screening if 
the participant has 
reliable prior 
documentation in clinical 
records. 
Original text was not clear resulting in 
misunderstandings at study sites. 
6.2 Preparation, Handling, 
Storage, and 
Accountability 
Wording describing 
provision of instructions 
for use corrected. 
The original wording stating that 
participants would be provided with the 
Jivi® prescribing information was 
incorrect. Participants are provided with 
instructions for preparation of study 
intervention, which is based on the 
prescribing information. 
6.8 Concomitant Therapy 
Vaccination history 
revised from complete 
vaccination history to 
history of vaccinations 
received within 2 years 
of enrollment (including 
vaccination for COVID-
19). 
The history of vaccination has been 
shortened to the last 2 years in order to 
detect any hypersensitivity (HS) reactions 
that may have occurred close to the time 
of enrollment in the study. 
  
History of COVID-19 vaccination has 
been added as these vaccines contain 
PEG moieties which could have triggered 
HS reactions  
Prior use of pegylated 
medications added to the 
list of concomitant 
medication information 
collected. 
History of chronic use of pegylated 
products is needed in order to record 
other medications containing PEG 
moieties that might confound long-term 
PEG-related safety events   
8.2 Safety Assessments 
Anti-drug antibodies and 
long-term safety 
assessments added to 
the list of safety 
assessments performed 
for the study. 
Anti-drug antibodies added as they were 
originally missing   
 
Safety assessments added to assess the 
long-term use of pegylated FVIII 
products. 
 
Redundant mention of 
adverse events removed 
from the list of safety 
assessments performed 
for the study. 
Adverse events are already covered 
under the first bullet in the list of safety 
assessments. 
8.2.1 Physical 
Examination 
Neurological assessment 
added to the description 
Neurological assessment added as part 
of the PEG-related safety assessments 

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of physical examinations 
performed during the 
study. 
to investigate the potential long-term 
Jivi® safety. 
8.3.8 Adverse Events of 
Special Interest (AESI) 
Description of number of 
blood samples for AESIs 
corrected. 
One blood/plasma sample is sufficient to 
measure anti-PEG, anti-PEG IgM, and 
IgE. Original wording described collection 
of a distinct sample for measurement of 
IgE. 
 
Description for the 
follow-up (early 
discontinuation) visit for 
AESI events revised for 
clarity. Wording for 
assessments performed 
at this visit changed to 
emphasize measurement 
of FVIII inhibitor and anti-
PEG IgM at this visit and 
clarify that factor VIII 
recovery and in-hospital 
infusion of study 
intervention should not 
be performed for 
participants reported with 
AESIs. 
Language added to clarify that the follow-
up visit 4 weeks after the AESI is the 
early discontinuation visit for participants 
with AESIs. 
8.4 Pharmacokinetics 
Removed reference to 
Section 8.3.6. 
Reference was erroneously included in 
the original protocol. 
8.6 Biomarkers 
Reference to serum and 
urinary biomarkers in 
Section 10.2 added. 
Serum and urinary biomarkers added in 
this amendment as PEG-related safety 
assessments specifically associated with 
the long-term use of pegylated FVIII 
products. 
9.4 Interim Analysis 
Analysis plan for Part B 
revised to reflect 
increase in duration. 
Analysis of Part B to be 
conducted at Month 6 in 
addition to the analysis 
at the end of the study. 
Due to the increase in Part B duration 
from 6 months to 18 months, the plan to 
evaluate efficacy and safety of the 5-day 
regimen during the first 6 months of Part 
B has not been changed; therefore, the 
Month 6 analysis has been added in 
addition to the analysis at the end of the 
study. 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Serum chemistry 
parameters added. 
Added PEG-related safety assessments 
specifically associated with the long-term 
use of pegylated FVIII products 
Urinary parameters 
added. 
For other tests, 
quantitative PEG 
measurement and vWF 
added. Text describing 
measurement of FVIII 
revised to clarify that a 
one-stage assay is used 
only at Visit 1.  
10.4.5 Reporting of 
AEs/SAEs related to the 
Medical Devices 
Removed all instances of 
the word “manually” from 
instructions for 
completion of the 
Medical Device Incident 
form. 
Medical Device Incident form is 
completed electronically. Original 
language was causing 
misunderstandings at study sites. 

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11 References 
Two new references 
added. Outdated 
reference removed. 
References adapted based on edits 
made in Section 2.3.1 Risk Assessment. 
Throughout 
Minor editorial and 
document formatting 
revisions.  
Minor changes were made to correct 
typos, grammar, document headers, etc. 
have been made throughout the 
document. These minor changes are not 
individually summarized. 
 

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11. 
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